UNIVERSITY of CALIFORNIA, SAN DIEGO Human Platelet Metabolic

Home , DUTP diphosphatase, HAS2, Lysophospholipase, PDE1

UNIVERSITY OF CALIFORNIA, SAN DIEGO

Human Platelet Metabolic Network Reconstruction

A Thesis submitted in partial satisfaction of the requirements

for the degree Master of Science

Bioengineering

Sorena Rahmaniyan

Committee in charge:

Bernhard Ø. Palsson, Chair Marcos Intaglietta Geert W. Schmid-Schoenbein Neema Jamshidi

2011

Signature Page

The Thesis of Sorena Rahmaniyan is approved and it is acceptable in quality and form for publication on microfilm and electronically:

Chair

University of California, San Diego

2011

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DEDICATION

I would like to dedicate this work to my parents, Hadigheh and Ghodrat, for always believing in me and supporting me through ups and downs of my life.

I would also like to dedicate this work to all my friends and colleagues at the Baha’i Institute of Higher Education in Iran, who are discriminated and prevented from entering universities solely based on their believes.

TABLE OF CONTENTS Signature Page ...... iii Dedication...……………………………………………..…………….………………….iv Table of Contents ...... v List of Figures ...... vii List of Tables ...... viii Acknowledgements ...... ix Abstract ...... x 1. Introduction ...... 1 1.1 Platelet ...... 1 1.1.1 Platelet Biology: ...... 1 1.1.2 Platelet Physiology and Function: ...... 2 1.1.3 Platelet Biochemistry: ...... 3 1.1.4 Platelet Diseases: ...... 3 1.2 Systems Biology ...... 4 1.2.1 An Integrative Approach ...... 4 1.2.2 Metabolic network reconstruction ...... 5 2. Omics Data Mining ...... 7 2.1 Introduction ...... 7 2.2 Methods ...... 8 2.3 Results and Discussion ...... 9 3. Bibliomics and Manual Curation ...... 16 3.1 Introduction ...... 16 3.2 Core Reactions ...... 17 3.3 Manual Curation ...... 17 3.3.1 Specific Reactions ...... 17 3.3.2 Exchange Constraints ...... 18 3.3.3 Functionality of the Recon1 ...... 18 3.4 Results and Discussion ...... 19 4. Human Platelet Model ...... 28 4.1 Introduction ...... 28

4.2 Final Reconstruction ...... 28 4.3 Model content ...... 29 4.4 ModelFunctionality and Network Topology ...... 32 4.5 Simulations ...... 39 4.6 Conclusion ...... 42 Appendix…………………………………………………………………………………43 References ...... 87

LIST OF FIGURES Figure 1.1 TEM images of the human platelet showing some of the organelles in the cell. M: mitochondria, GL: glycogen, G: alpha granule, OCS: open canicular system, DB: dense body and MT: microtubules...... 2 Figure 2.progress of proteomic studies on platelet over the past ten years...... 12 Figure 3.translation of reported proteins from proteomics data into the reactions in recon1 was consistent across different studies...... 13 Figure 4. QC/QA of the proteomics data, by looking at the co-coverage of the proteomics datasets ...... 14 Figure 5.The pathway analysis based of the proteomics data, the top 30 pathways that have been reported in the proteomics studies, ranked based on the number of the studies they were reported on and the number of proteins reported for each pathway...... 15 Figure 6. The well established platelet reactions in bibliomics, categorized into subsystems ...... 26 Figure 7. the presence of the core reactions in bibliomics vs. proteomics ...... 27 Figure 8. the source distribution of the reactions in the model ...... 31 Figure 9. The ranking distribution of the platelet model’s reactions ...... 32 Figure 10.Network Connectivity, comparison of the connectivity of metabolites in the platelet model ( with connectivity of 10 and higher) with the same metabolite in the global model...... 33 Figure 11. the contribution of Eigen modes to the reconstruction of the stoichiometric matrix which follows the power low ...... 34 Figure 12. FVA analysis of the model for all the reactions ...... 35 Figure 13. comparison of the coset lengths with different cut off thresholds for correlation criteria...... 36 Figure 14. couple of the linear pathways picked up in the coset analysis of the model with correlation coefficient more than 0.95 ...... 37 Figure 15. Carbohydrate metabolism in platelet and its cosets ...... 38 Figure 16. Flux variability analysis of aspirin effect on platelet ...... 40 Figure 17.coset analysis of aspirin effect on platelet with a cut off value of 0.99 ...... 41 Figure 18.coset analysis of aspirin effect on platelet with a cut off value of 0.75 ...... 41

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LIST OF TABLES Table 1.The proteomics data structure...... 9 Table 2. The annotation of proteomics studies used for human platelet reconstruction ... 10 Table 3. The summary of the proteomics data ...... 12 Table 4. The core reactions (metabolic objectives) of human platelets, BCS: number of Biochemical Studies, NBCS: number of Non-Biochemical Studies, Prot: number of proteomics studies. The abundance of core reactions with no proteomics report is due to the platelet specific reactions with no GPR available for them, which lead to a miss connections of proteomics data and the reactions ...... 19 Table 5. list of the platelet specific reactions added to Roecon1 in SimPheny ...... 21 Table 6. list of the platelet specific Metabolites added to Roecon1 in SimPheny ...... 23 Table 7. The exchange constraints applied to the model and their categories ...... 25 Table 8. the content of human platelet model ...... 30 Table 9. the reaction confidence scores and their criteria ...... 31 Table 10. Network properties of the platelet metabolic network ...... 34 Table A1. the list of reactions and their properties in the model.…..……………………43 Table A2. the list of metabolites and their properties in the human platelet model……..67

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ACKNOWLEDGEMENTS

I would like to thank Dr. Bernhard Ø. Palsson, for giving me the opportunity of working under his supervision and learn from his ocean of knowledge.

I cannot be more grateful to Neema Jamshidi, who helped me and supported me all through the project even when there were only glimpses of hope left.

I also like to thank all my friends and colleagues in systems biology research group, specifically Aarash Bordbar for his none-stop cooperation, Kathy Andrews, Joshua Lerman, Harish Nagarajan, Jeff Orth and Nathan Lewis for all their supports.

ABSTRACT OF THE THESIS

Human Platelet Metabolic Network Reconstruction

Sorena Rahmaniyan

Master of Science in Bioengineering

University of California, San Diego, 2011

Professor Bernhard Ø. Palsson, Chair

In the past, metabolic network reconstruction has been used extensively for the analysis and discoveries in microorganisms such as E.Coli. furthermore, after the completion of human genome sequencing and building of the first human metabolic network reconstruction (Recon 1) in 2007, there has been a growing interest in reconstruction of tissue-specific metabolic networks based on the human metabolic network reconstruction. This work is an attempt to reconstruct human platelet’s metabolic network based on the Recon 1. The advancements in proteomics techniques have provided us with a wealth of high throughput dataset on human platelets. These datasets were carefully reviewed and annotated in order to obtain a solid and comprehensive

proteomic profile of human platelet. Then the metabolic functionality and capabilities of human platelet were identified in the literature. After applying some modifications and refinements to the Recon 1 to accommodate these metabolic capabilities, an algorithmic approach was used to tailor the platelet specific conditions to the Recon1. Once the in silico model of human platelet was created, its network properties and models functionalities were characterized using constraint based analysis such as flux balance analysis and flux variability analysis. The model’s solution space was further investigated using a sampling method and coset analysis. Finally the effect of aspirin on platelet was simulated and analyzed using the tools mentioned.

1. INTRODUCTION

1.1 Platelet

1.1.1 Platelet Biology:

Platelets are small enucleated blood cells that are 2-4 µm in diameter [1]. They have a very short life span of average 7-10 days[2,3],There are approximately 1011 platelets generated daily in our body and the normal average number of platelets in our blood is 150-400x109/L [4].Like the other blood cells, they are originated from hematopoietic stem cells in the bone marrow andthe final progenitors of platelets are megakaryocytes, giant multinucleated cells that will fragment into platelets [4,5] although the mechanism by which platelets are formed and released from Megakaryocytes is yet to be clarified[6,7]. The mechanism of the clearance of the platelets is not settled neither, some studies suggest the clearance of platelets byreticuloendothelial system[5], while others suggest clearance by liver through macrophages among many othersuggested pathways[8].

Although platelets do not have nucleus, but the presence of other organelles such as mitochondria, lysosomes in platelets are well established [9] There are also some organelles such as α-granules, dense tubular system and open canalicular system , that are unique to platelets[10]. Finally there are some studies indicating the presence of ribosomes and rough ER in the platelets. [11,12] Different electron microscopy techniques have been used for the study of platelet organelles and couple of these TEM images are presented below[13].

Figure 1.1 TEM images of the human platelet showing some of the organelles in the cell. M: mitochondria, GL: glycogen, G: alpha granule, OCS: open canicular system, DB: dense body and MT: microtubules. 1.1.2 Platelet Physiology and Function:

Circulation system is a closed system that requires certain volume of blood to be circulated, excess loss of blood can lead to serious damage to the body; hence hemostasis

, the process through which body stops bleeding, have a significant role in the body’s health. Platelets play a key role in the formation of blood clot and hemostasis [14]. The clot formation is a multi-step process,in which after a blood vessel is damaged, it first become constricted and then the platelets form a plug by sticking to each other and to the walls of the blood vessel and finally a network of fibrin and collagen is formed at the site of injury and the blood clot formation is complete. Not only platelets are the main components of the plug and coagulation, they also help the formation of blood clot and healing process through the release of different signaling metabolites and factors. They release factors such as adenosine di-phosphate (ADP), serotonin and thromboxane A2, all of which help the constriction of the blood vessel. Adenosine, thrombin, serotonin among many other agonists, can activate platelets, upon the activation, platelets become stickier and start sticking together and to the walls of the blood vessel. Also the activation of

3 platelets lead to a major shape change and internal changes in the cytoskeletal structure of the cell. These shape changes serves two purpose of releasing the granules contents and bringing the ends of the injury together. [5].

1.1.3 Platelet Biochemistry:

In order to carry on all these functionalities, platelets have specific demands and requirements. One of the main requirements for platelet’s activities such as shape change and respond to different activation pathways is the energy requirements. Platelets can utilize glucose, glycogen and fatty acids to produce energy. Some studies have looked at the maximum glycolysis rate in activated platelets and found it to be 13.5 times more than its equivalent in erythrocytes and muscle cells[15]. It should be able to pump ions in and out of the cell in order to keep its ion balances and many other housekeeping functionalities that demands a complete set of metabolic pathways and reactions. As such platelets have the main pathways of energy metabolism through breaking down glucose, glycogen and fatty acid oxidation [15]. It also has to metabolize nucleic acids such as adenosine and guanidine [15] and inositol phosphates as well as arachidonic acid in order to stay responsive to the signaling pathways [16, 17]. Finally it can carry out nitric acid synthesis which is an important vassal dilator [18,19].

1.1.4 Platelet Diseases:

There are several diseases associated with abnormal blood platelet count and platelet abnormal metabolism. Low platelet count will lead to different bleeding disorders

[20] and high platelet count will lead to myocardial infarction and thrombosis [21]. On the other hand, platelet metabolic dysfunction and abnormalities are also known to be

4 related to diseases such as myocardial infarction, uremia, migraine and etc. [22, 23,

24.]In addition of diseases that can be caused by platelets metabolic dysfunction, recently there has been a growing interest in using platelet’s metabolic changes as a biomarker for diagnosis off neurological disorders. Platelets have shown lots of metabolic similarities to neural metabolic activities, and have been studied as a model of monoamine oxidase activity in neurons [25]. Alzheimer, Parkinson, schizophrenia and depression are only some of the many disorders that have shown effects on platelet’s metabolic activities [26,

27, 28,29.]

1.2 Systems Biology

1.2.1 An Integrative Approach

Recent advancements in the area of ‘Omics’ technologies have provided us with a growing number of high throughput data on different organisms. These technologies look at all of the components of a biological system, as genomic technologies identify all the genes, proteomics, all the proteins and metabolomics, all the metabolites. But more than the data it is the analysis of the data that gives it, its value. Systems biology looks across the network of interactions between all the components of the biological entity. In systems biology, one integrates these datasets obtained for a specific organism or a cell type and creates a computational model that can be used for further discoveries and investigation of the organism. These computational models are known as ‘in silico’ models of the organism and a wide spectrum of analytical tools has been developed for the analysis of these models and to create simulation environments. Systems biology research group at University of California, San Diego, has developed one of these analytical environments, called COBRA toolbox (constraint based reconstruction and

5 analysis) which provides the researchers analytical tools such as flux balance analysis

(FBA) and flux variability analysis (FVA) [30].

1.2.2 Metabolic network reconstruction

A metabolic network reconstruction, is a knowledge based reconstruction that is manually curated and refined using the literature available on the organism, and can be used for variety of simulations through higher order of queries. The core of the metabolic network reconstruction is the stoichiometric matrix, a matrix that includes all the reactions and the metabolites of the organisms and the stoichiometric coefficients that connect them together. Different physiochemical constraints and principles can be applied to this network to find the meaningful, functional states of the system and its functional behavior. One of these principles is the conservation of mass in the form of mass action balances. It can be used to find the steady state fluxes of the reactions in the network and by further applying the thermodynamic constraints on these reactions, one can obtain the steady state solution space.

Upon the completion of the human genome annotation in 2004 [31] and only three years after that, the first human metabolic network reconstruction was created based in the build 35 of the genome[32].It contained 1865 genes and 2004 proteins that were found in human body, its stoichiometric matrix was 2766 x 3311. Since then, the model was used to create different tissue specific models and was applied for many discoveries, such as inter-cellular interaction of brain cells in the Alzheimer patients[35], or the infection of alveolar macrophages by M. Tuberculosis [33, 34]. One of the main applications of these genome-scale metabolic network reconstructions comes out of

6 putting it into a specific context, such as a specific tissue or cell type. Transcriptomics and proteomics techniques have enabled us to obtain such a specific dataset for different tissues and their different physiological states. There are two main approaches in building such a context specific reconstruction: first is the bottom-up approach, where, all the components and interactions in the network are collected from available context specific sources, and the other approach is top-down approach that uses a global available reconstruction and uses context specific data to specify the context specific model.

During the past years, there have been different algorithms developed for contextualizing these global reconstructions such as Shlomi and Becker’s method[36, 37]. In this study, the human reconstruction, Recon1, has been used as a scaffold and Becker’s GIMME method was applied to obtain human platelet specific model.

2. OMICS DATA MINING

2.1 Introduction

Platelets are enucleated and beside its mitochondrial DNA, it lacks the genetic materials, consequently there is no genomic data available on the platelet itself, and despite several studies that has been done on platelet’s transcriptomics and De Novo protein synthesis[38], the low abundant transcripts and the controversy of protein synthesis in platelet[39, 40], makes these omics datasets less reliable. On the other hand platelet is full of different proteins that provide a wealth of proteomic datasets on human platelets, and can be used for the reconstruction of platelet’s metabolic network.

Over the past decade, there has been a handful of proteomic studies on human platelets, some of these studies look at the whole cell proteomics[41] ,while the others have studied a sub-cellular fraction of platelet such as alpha-granule, membrane or cytosolic fraction [42]. Some of these studies are targeted at normal platelet vs. activated platelets[43] or in some cases diseased platelet[44]. Finally, some of these studies, not only have identifies the proteins in platelet, but also have measured the relative abundances of these proteins[45]. These datasets have reported the identified proteins in different formats and need to be translated and annotated into an unified format before integrating them. Some of the indexing that has been used in these studies includes the international protein index (IPI)[46] system and UniProt identifiers[47] or RefSeq identifiers[48].

2.2 Methods

In the course of human platelet reconstruction, over 50 proteomic studies have been reviewed and the relevance, reliability and availability of their datasets have been assessed. Out of these studies, thirty three have been chosen to be used for the metabolic network reconstruction of human platelets, the rest of the studies were excluded due to either lack of specificity to the human organism[49], or contamination with other blood cells such as leukocytes, or lack of availability of the dataset.The rest of these dataset has been carefully annotated as described below.

Once the list of the proteins identified in each study has been extracted from each study, these proteins were translated to their corresponding identifier in Uniprot. This translation was either through the Uniprot online mapping feature, or it was done using a database software package such as Microsoft Access.In order to map these proteomics data onto Recon1, the list of proteins were further mapped into the NCBI (national center for biotechnology information), Entrez gene ids and these Entrez ids were used to find the matching genes in the Recon1. At the end, to connect these genes to the reactions in

Recon1 that correspond to the original reported proteins the in silico model of human network was used. A SBML (systems biology markup language) version of human

Recon1 was extracted from BiGG (biochemical, genomic, genetic)database and imported into matlab, using the readCbModel method available in COBRA toolbox. Next the rxnGeneMat in the in silico model was used to extract the reactions corresponding to the gene list.

Once the proteins from all the proteomics studies have been mapped to their corresponding genes and reactions in Recon1, they were reconciled into a uniform data structure, containing the references to the studies that the protein has been reported on.

This structure was stored in both forms of an excel workbook as well as a matlab structure and is provided in the supplementary materials. The data structures used to store the proteomics data both in excel and matlab are presented in table 1.

Table 1.The proteomics data structure.

Data Excel Fields Matlab Vectors Author Studies studies Year Year total reported Proteins N/A Uniprot prots Entrez ID genes proteins Rxn ID rxns Refrences refs

2.3 Results and Discussion

Following table contains the annotation of the proteomic studies used in the reconstruction of human platelet metabolic network, the number of proteins corresponds to the total number of proteins that were successfully extracted and translated to Uniprot ids(Table 2.) The number of platelet proteins that were reported in the proteomic studies and the portion that were mapped to the entrez genes and number of Recon1 genes and reactions corresponding to these genes are also reported (Table3.)

Table 2. The annotation of proteomics studies used for human platelet reconstruction

mass Author year Analyzed sample protein separation Proteins spectrometry Platelets (cytosolic Marcus 2000 2-DE gel MALDI-TOF 23 fraction) O'Neil 2002 Platelets 2-DE gel Q-TOF 89 Platelets releasate McRedmont 2003 (Thrombin MudPIT MudPIT 66 stimulation) Gevaert 2003 Platelets LC: COFRADIC Q-TOF 160 Garcia 2004 Platelets 2-DE gel Q-TOF 257 Activated platelets Garcia 2004 by TRAP vs resting 2-DE gel Q-TOF 22 platelet Platelet releasate Platelet releasate Coppinger 2004 (thrombin MALDI-TOF 79 (thrombin stimulation) stimulation) Staes 2004 Platelets COFRADIC™ Q-TOF 23 Martens 2005 Platelets COFRADIC™ Q-TOF 565 Cytosolic and membrane protein Claeys 2005 2-DE Blue Native/SDS gel Q-TOF 48 fractions from platelets Membrane protein enrichment (sorbitol Moebius 2005 Platelet membrane gradient and Tritton X- Q-TOF 259 114 partition) then 16BAC/SDS-PAGE Platelets from Phosphorylated proteins healthy subjects Garcia 2007 immunoprecipitation Q-TOF 72 activated with CRP and SDS-PAGE vs not activated Platelet alpha Maynard 2007 SDS-PAGE LTQ-IT 150 granules Platelet dense MALDI-TOF/ Hernandez 2007 2-DE gel / LC 42 granules Ion-Trap 2-phase partitioning / Lewandrowski 2007 Platelet membrane Linear IT 79 ENSAS Membrane protein enrichment (affinity Senis 2007 Platelet membrane IT 88 chromatography)/Free Flow electrophoresis Peripheral Blood Haudek 2008 2-DE gel MALDI-TOF 389 Constituents Platelet releasate Piersma 2008 SDS-PAGE LTQ-FT ICR 866 (TRAP stimulation) Winkler 2008 Platelets 2-DE gel MALDI-TOF 14 Arias_Salgado 2008 Platelets 2-DE gel MALDI-TOF 7

Table 2. continued mass Author year Analyzed sample protein separation Proteins spectrometry Thon 2008 Platelets 2-DE gel / LC 2-DE gel / LC 327 Zahedi 2008 Platelets IMAC and SCX-LC Q-Trap or LTQ 272 2-phase partitioning / Lewandrowski 2009 Platelet membrane Linear IT 1268 ENSAS Platelets from healthy subjects Phosphorylated proteins Senis 2009 activated with immunoprecipitation Q-TOF 22 fibrinogen vs not and SDS-PAGE activated Platelets from healthy subjects Affinity purification liquid IEF / Tucker 2009 activated with (sulfo-NHSbiotin)/ liquid 75 SDS-PAGE fibrinogen vs not IEF / SDS-PAGE activated Activated platelets Nucleotide affinity Wong 2009 by TRAP vs resting chromatography / SDS- LTQ-IT 17 platelet PAGE IEF (Peptides and Rat vs Human Orbitrap/Q- Yu 2010 Proteins)/SDSPAGE/ 2D- 490 Platelets TOF LC Platelets from MALDITOF/TOF Pieroni 2010 healthy subjects vs 2-DE gel / nUPLC 159 / QTOF CF patients Platelets from 2-DE gel / Antibody Eidelman 2010 MALDI-TOF 165 males vs females microarray Platelets from non- ST segment acute coronary Fernandez 2010 2-DE gel MALDI-TOF 22 syndrome vs stable coronary artery disease patients Platelet alpha Maynard 2010 SDS-PAGE LTQ-IT 585 granules Platelet and SDS-PAGE/Membrane Qureshi 2010 Platelet plasma enrichment(membrane LTQ-IT 1682 membranes precipitation)/IMAC-LC Platelets from healthy subjects activated with MALDITOF/ Schulz 2010 anti-GPIV 2-DE gel 8 TOF monoclonal antibody vs. not activated

Table 3. The summary of the proteomics data

proteins (uniprot) genes (entrez ID) Metabolic Reactions Proteomics studies 3448 2999 --- In Recon1 941 460 1005

The number of proteins reported in each proteomic study was plotted against the year of the study(Figure2.) As mentioned before some of these proteomics studies were focused on a sub-proteome of platelets and consequently resulted in a low number of the proteins, whereas the other studies reported the whole platelet proteomics and resulted in larger dataset. To look at the progress of proteomics studies on platelet over the past decade a trendline between the largest datasets in each year were drawn and it shows an increasing growth of platelet proteomic studies.

Platelet Proteomics Progress

2000

1500

1000

500

0 numberofproteins found 1998 2000 2002 2004 2006 2008 2010 2012 year of the study

Figure 2.progress of proteomic studies on platelet over the past ten years. Although some of the studies found more than thousands of platelet proteins a big portion of these proteins did not mapped to the genes and reactions in Recon1. The following histograms shows the number of proteins reported in each study, the one to the

13 left represents all the proteins and the one to the right shows only the number of reported proteins that has been mapped to Recon1. For a better comparison of these two sets they have been plotted against each other and there is a linear correlation between these numbers with a r-square value of 0.97. The slope of the trendline is 0.16 that shows that almost homogenously across the studies, on average only %16 of the reported proteins

translated to a metabolic reaction in Recon1.

Proteins in proteomic datasets Proteins mapped to Recon1 10000 1000 1000 100 100 10 10

1 1

Yu Yu

Thon Thon

Schulz Schulz

Garcia Garcia

Tucker Tucker

Marcus Marcus

Haudek Haudek

Winkler Winkler

Martens Martens

Moebius Moebius

Maynard Maynard Maynard Maynard

Eidelman Eidelman

Coppinger Coppinger

McRedmont McRedmont

mappedProteins (Log )

Reported Proteins (Log Proteins(Log Reported)

Lewandrowski Lewandrowski Lewandrowski Lewandrowski Proteomics Studies Proteomics Studies

Mapping of the proteins to Recon1

300 y = 0.1659x - 2.9949 250 R² = 0.9651 200 150 100 50 0 0 200 400 600 800 1000 1200 1400 1600 1800 -50

Proteins associated with a reaction Reported Proteins

Figure 3.translation of reported proteins from proteomics data into the reactions in recon1 was consistent across different studies. For quality control and quality assurance of the proteomics data compiled on platelet, the coverage of each dataset is compared to other datasets. For smaller number

14 of studies up to 4-5, a van diagram would be best to look at the coverage of these datasets, but since the number of these studies exceeds thirty, another method has been utilized. For each protein the number of proteomic studies that has reported it was calculated and the proteins has been categorized based on the minimum number of the studies that reported the protein. The following histogram demonstrates the distribution of the proteins in each category. The higher categories contain most confident proteins based on the proteomic data.

Proteomics Coverage 300

250

200

150

proteins 100

0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 proteomic studies

Figure 4. QC/QA of the proteomics data, by looking at the co-coverage of the proteomics datasets Next the proteomics data were analyzed based on the existing pathways in

Recon1 to find the pathways with the most proteins reported for the human platelet. The histogram below, contains the 30 most presented pathways in human platelet, based on the proteomics data. The ranking of these pathways is based on the number of the proteomics studies that has reported a protein in the pathway, the total number of the proteins in the pathway that has been reported on the proteomics dataset is also included.

Pathways analysis of the Proteomics

Glycolysis/Gluconeogenesis Fructose and Mannose Metabolism Nucleotides Pyruvate Metabolism Glyoxylate and Dicarboxylate… Arginine and Proline Metabolism Glycerophospholipid Metabolism Miscellaneous Cysteine Metabolism Glutathione Metabolism Oxidative Phosphorylation N-Glycan Biosynthesis Tryptophan metabolism Citric Acid Cycle Valine, Leucine, and Isoleucine… Propanoate Metabolism Tyrosine metabolism Limonene and pinene degradation Transport, Extracellular Inositol Phosphate Metabolism beta-Alanine metabolism Fatty Acid Metabolism Transport, Lysosomal Lysine Metabolism Pentose Phosphate Pathway Transport, Mitochondrial Cholesterol Metabolism Eicosanoid Metabolism Starch and Sucrose Metabolism Aminosugar Metabolism 0 20 40 60 80

# of Studies # of proteins

Figure 5.The pathway analysis based of the proteomics data, the top 30 pathways that have been reported in the proteomics studies, ranked based on the number of the studies they were reported on and the number of proteins reported for each pathway.

3. BIBLIOMICS AND MANUAL CURATION

3.1 Introduction

The human metabolic network reconstruction, Recon1, contains all the reactions that are known to exist in human body. In order to be able to use this network for tissue specific discoveries and studies, this model needs to be refined to accommodate for the tissue-specific metabolic capabilities. Further refinement of the model and more specificity of the model will grant it a higher simulation power. For example, there are alternative of the same reaction that can happen in different tissues, using different cofactors or reactions based on the isoform of the protein, present in the tissue or the availability of the metabolites and cofactors for the reactions. This case and similar cases that adds specificity to the model needs to be counted for before based the reconstruction on Recon1 as a scaffold. This process of adding specificity to the Recon 1 and ensuring the capabilities of Recon1 in carrying platelet’s metabolic functionality is referred to as manual curation of the model . The data for this curation is mainly obtained from different literature sources such as tissue specific reference books or papers looking at a specific metabolism in the tissue. The collection of all these sources is termed Bibliomics referring to all the bibliography available on the tissue.

In the course of manual curation and bibliomic search, over 350 papers and 7 books on platelets were reviewed and annotated [50-202.] The annotation of these studies were mainly based on the information needed for the rest of manual curation process, such as: core reactions, exchange constrains and any metabolic connection between human platelet and human diseases.

3.2 Core Reactions

The first step in the bibliomics search, was to constitute a list of platelet metabolic functionalities and core reactions. Core reactions are the reactions that have been well studies and characterized in human platelets. Obtaining this list was an ongoing process all through the manual curation process. First a primary search was done to identify some of the main metabolic features of platelet metabolism and pathways. Then, literature was searched in more details for each of the potential reactions.In the cases that there was controversy in the literature on the existence of a reaction in the platelets, the more recent study with the stronger evidence (such as a direct biochemical assay.) was considered, but a note of other study and contradiction was made. Most of these studies used a direct biochemical assay in order to determine the activity of the reactions, while the others used some indirect biochemical assays or immunological assays.

3.3 Manual Curation

3.3.1 Specific Reactions

Each tissue has a set of specific metabolites and cofactors that are involved in different reactions. Some of these metabolites and reactions have already accounted for in the Recon1, while others neededto be added to the Recon1. List of these platelet specific metabolites and reactions were prepared and annotated according to the available databases on the metabolite’s properties such as charge, formulas and Inchi structure if available. Finally these metabolites and reactions were added to the Recon1 model,

Genomatica software package, Simpheny. First the reactions and metabolites were added

18 to the universal database of the Simpheny, and secondly, after creating the Recon1 model, in the Simpheny these reactions and metabolites were added to the model.

3.3.2 Exchange Constraints

The list of platelet uptake capabilities that were specifically mentioned in the literature was created as the bibliomics data was annotated. The literature was also searched for specific media conditions that were used for platelet ex-vivo studies. These conditions were further studied and analyzed to obtained an inclusive list of metabolites that can be taken up by human platelets. Finally availability of metabolites in human plasma were analyzed to obtain a list of metabolites available for uptake in the natural habitant of platelets. These uptake constraints were applied to the model in the simulation environment of the SimPheny. In order to apply these constraints, the lower boundary of the exchange reactions for the corresponding reactions were assigned to a negative value applying that the model can uptake these metabolites when needed. In the cases that these uptakes were active in human platelets and were part of the characteristics of human platelets, the upper bounds of the reaction was also set to a negative value to enforce the uptake of that specific metabolite all the time.

3.3.3 Functionality of the Recon1

Finally the model was put through a set of iterative modifications to ensure the activity of the platelet core reactions in Recon1. This involved loading the model in the simulation environment of the Simpheny and running the flux balance analysis to make sure each of the core reactions are able to carry out a flux at a steady state.Each case that the model failed to carry a flux through a core reaction was curated separately. But the

19 actions that were taken can be classified as: addition of a new platelet specific reaction, applying a new exchange constraint, applying a reversibility constraint or blocking a reaction that will lead to a loop, and addition of sink or demand reaction when necessary.

To find the right action needed to be taken for troubleshooting, the maps available for human Recon1 in the atlas environment of the SimPheny as well as further biblioic search were utilized. The corresponding map that contained the core reaction were loaded and the pathway connecting the core reaction was investigated for any broken connection or dead end metabolite, then further details on the suspected reactions or metabolites were obtained from literature.

3.4 Results and Discussion

The bibliomics data revealed 141core reactions (Table 4.) these reactions were annotated based on the studies that reported them and the methods that was used in the identification of the reaction, and their presence in the proteomics data. More than thirty of these objectives are specific to the platelet and has been added to the Recon1 (Table 5 and 6.)

Table 4. The core reactions (metabolic objectives) of human platelets, BCS: number of Biochemical Studies, NBCS: number of Non-Biochemical Studies, Prot: number of proteomics studies. The abundance of core reactions with no proteomics report is due to the platelet specific reactions with no GPR available for them, which lead to a miss connections of proteomics data and the reactions

Rxns BCS NBCS Prot. Rxns BCS NBCS Prot. Rxns BCS NBCS Prot. PEAMNO 0 3 4 CATp 1 1 12 PI4P5K_18_0_20_4 1 0 0 TYROXDAc 3 2 4 ICDHy 0 2 5 FAS180COA 1 2 6 TRYPTAOX 1 2 4 ABTArm 2 1 0 FACOAL160i 0 1 2 42A12BOOX 1 4 4 PGMT 1 1 6 C160CPT1 1 3 3 DOPASULT 0 4 4 ADNK1 1 1 0 G6PPer 0 1 0 4NPHSULT 0 4 4 ADNK1m 0 1 0 FA160ACPH 0 3 0 TYMSULT 0 1 4 ADA 3 1 0 FAOXC160 2 0 2

Table 4. continued Rxns BCS NBCS Prot. Rxns BCS NBCS Prot. Rxns BCS NBCS Prot. PGS_COX 1 0 0 GUACYC 1 6 2 DAGK_hs_18_0_20_4 0 0 0 PGS_PO 0 0 0 TMDPP 0 1 6 AGPAT1_18_0_20_4 0 2 0 ALOX12 1 3 8 HXPRT 4 0 4 CDS_18_0_20_4 1 0 0 HPETOX 1 2 0 PUNP5 1 0 9 PLA2_2_18_0_20_4 5 0 0 LTC4Sr 0 0 2 NTD11 1 0 0 CEPTC_18_0_20_4 2 0 0 GGT6 2 0 0 AMPDA 2 0 2 PSSA2_hs_18_0_20_4 1 0 0 GGT5r 2 0 0 PRPPS 1 0 1 LPS2_hs_18_0_20_4 1 0 0 GLPASE1 1 2 8 ADSS 1 0 1 LPS3_hs_20_4 1 0 0 GLGNS1 1 1 1 ADSL1 2 0 0 GLYK 1 0 1 TXASr 2 0 4 ADAe 0 1 0 5HOXINDACTOX 1 0 2 TXBS 2 0 0 FBP 1 0 0 34DHPLACOX 1 0 0

BDHm 1 0 0 GLNS 1 1 1 5HOXINOXDA 1 0 4 HS1ly 3 0 0 H2CO3D 2 0 9 C160CPT2 1 3 0 GAPD 1 3 17 SPODM 5 0 6 C160CRNt 1 3 0 PDHm 0 6 3 SPODMm 5 0 7 GPAM_hs_18_0 0 0 0 GLYOX 0 2 1 HCO3_CLt 1 0 3 CEPTC_16_0_18_0 2 0 0 LGTHL 0 2 4 HOXG 1 1 1 PLA2_2_16_0_18_0 5 0 0 DPGM 0 2 5 BILIRED 0 1 3 LPS2_hs_16_0_18_1 1 0 0 PYK 3 4 19 GUAPRT 2 0 4 LPS3_hs_18_1 1 0 0 PGK 0 3 11 NNDPR 0 1 0 LPASE_18_0 0 0 0 CYOR- TPI 1 2 5 u10m 2 1 4 LPS2_hs_16_0_18_0 1 0 0

GTHO 2 6 3 ADEt 1 2 0 LPS3_hs_18_0 1 0 0

PGM 1 1 5 ADNt 2 0 1 HCO3_NAt 1 0 0 ENO 1 3 12 PDE1 0 2 2 AKGDm 1 0 4 HEX1 1 6 6 PDE4 0 2 3 G6PDH2r 1 1 8 PGI 2 2 8 NDPK1 0 2 7 NRPPHRSULT 0 4 0 PFK 2 3 8 NDPK2 0 2 7 XAOx 1 0 0 FBA 2 2 15 NDPK3 0 2 7 AGPAT1_16_0_18_0 0 2 0 LDH_L 1 6 10 NDPK4 0 2 7 AGPAT1_16_0_18_1 0 2 0 GND 2 1 5 NDPK9 0 2 7 PPAP_16_0_18_0 1 1 0

G3PD1 1 1 0 TKT1 0 1 3 PPAP_16_0_18_1 1 1 0

CYOOm2 3 7 4 TKT2 0 1 3 GPAM_hs_16_0 0 0 0

SUCD1m 2 5 1 ASPTA 0 1 1 PIPLC_18_0_20_4 4 1 0

CSm 3 3 5 MDHm 2 0 6 PI4PLC_18_0_20_4 4 1 0 ATPS4m 1 1 8 PFK26 1 0 0 PI45PLC_18_0_20_4 4 1 0 GLUDxm 0 7 4 GTHP 1 4 10 PIK4_18_0_20_4 1 0 0 NADH2- GLUt6 1 1 1 u10m 2 5 2 GLUNm 1 2 0

Table 4. continued

Rxns BCS NBCS Prot. Rxns BCS NBCS Prot. Rxns BCS NBCS Prot. NOS1 1 5 1 ADPT 4 1 6 PSSA1_hs_18_0_20_4 1 0 0 NOS2 1 5 1 ADK1 3 5 9 CEPTE_18_0_20_4 1 0 0 NaKt 3 1 2 ADNCYC 1 0 3 CDIPTr_18_0_20_4 1 0 0

Most of the platelet specific reactions and metabolites belongs to glycerophospholipd metabolism, and the rest refer to arachidonic acid metabolism. This is due to the different fatty acid composition of the phospholipids in each tissue.

Table 5. list of the platelet specific reactions added to Roecon1 in SimPheny

Abbreviation Equation Subsystem alpa_hs_16_0 + stcoa -->coa + Triacylglycerol Synthesis,pl AGPAT1_16_0_18_0 pa_hs_16_0_18_0 alpa_hs_16_0 + odecoa -- Triacylglycerol Synthesis,pl AGPAT1_16_0_18_1 >coa + pa_hs_16_0_18_1 alpa_hs_18_0 + arachdcoa -- GlycerophospholipidMetabolism,pl AGPAT1_18_0_20_4 >coa + pa_hs_18_0_20_4 cdpdag_hs_18_0_20_4 + Glycerophospholipid Metabolism, inost<==>cmp + h + pl CDIPTr_18_0_20_4 pail_hs_18_0_20_4 ctp + h + pa_hs_18_0_20_4 --> Glycerophospholipid Metabolism, CDS_18_0_20_4 cdpdag_hs_18_0_20_4 + ppi pl cdpchol + dag_hs_16_0_18_0 Glycerophospholipid Metabolism, -->cmp + h + pl CEPTC_16_0_18_0 pchol_hs_16_0_18_0 cdpchol + dag_hs_16_0_18_1 Glycerophospholipid Metabolism, -->cmp + h + pl CEPTC_16_0_18_1 pchol_hs_16_0_18_1 cdpchol + dag_hs_18_0_20_4 Glycerophospholipid Metabolism, -->cmp + h + pl CEPTC_18_0_20_4 pchol_hs_18_0_20_4 cdpea + dag_hs_18_0_20_4 -- Glycerophospholipid Metabolism, CEPTE_18_0_20_4 >cmp + h + pe_hs_18_0_20_4 pl atp + dag_hs_18_0_20_4 Glycerophospholipid Metabolism, <==>adp + h + pl DAGK_hs_18_0_20_4 pa_hs_18_0_20_4 glyc3p + pmtcoa --> Triacylglycerol Synthesis,pl GPAM_hs_16_0 alpa_hs_16_0 + coa glyc3p + stcoa --> Triacylglycerol Synthesis,pl GPAM_hs_18_0 alpa_hs_18_0 + coa h2o + lpchol_hs_16_0 --> GlycerophospholipidMetabolism,pl LPASE_16_0 g3pc + h + hdca

Table 5. continued

Abbreviation Equation Subsystem h2o + lpchol_hs_18_0 --> g3pc + h LPASE_18_0 + ocdca GlycerophospholipidMetabolism,pl dag_hs_16_0_18_0 + h2o --> h + LPS2_hs_16_0_18_0 hdca + mag_hs_18_0 Triacylglycerol Synthesis,pl dag_hs_16_0_18_1 + h2o --> h + LPS2_hs_16_0_18_1 hdca + mag_hs_18_1 Triacylglycerol Synthesis,pl dag_hs_18_0_20_4 + h2o --> h + LPS2_hs_18_0_20_4 mag_hs_20_4 + ocdca Triacylglycerol Synthesis,pl h2o + mag_hs_18_0 -->glyc + h + LPS3_hs_18_0 ocdca Triacylglycerol Synthesis,pl h2o + mag_hs_18_1 -->glyc + h + LPS3_hs_18_1 ocdcea Triacylglycerol Synthesis,pl h2o + mag_hs_20_4 -->arachd + LPS3_hs_20_4 glyc + h Triacylglycerol Synthesis,pl h2o + pchol_hs_18_0_20_4 -- PCHOLP_18_0_20_4 >chol + h + pa_hs_18_0_20_4 GlycerophospholipidMetabolism,pl h2o + pail45p_hs_18_0_20_4 --> PI45PLC_18_0_20_4 dag_hs_18_0_20_4 + h + mi145p Inositol Phosphate Metabolism,pl atp + pail4p_hs_18_0_20_4 -->adp PI4P5K_18_0_20_4 + h + pail45p_hs_18_0_20_4 GlycerophospholipidMetabolism,pl h2o + pail4p_hs_18_0_20_4 --> PI4PLC_18_0_20_4 dag_hs_18_0_20_4 + h + mi14p Inositol Phosphate Metabolism,pl atp + pail_hs_18_0_20_4 -->adp + PIK4_18_0_20_4 h + pail4p_hs_18_0_20_4 GlycerophospholipidMetabolism,pl h2o + pail_hs_18_0_20_4 --> PIPLC_18_0_20_4 dag_hs_18_0_20_4 + h + mi1p-D Inositol Phosphate Metabolism,pl h2o + pchol_hs_16_0_18_0 --> h PLA2_2_16_0_18_0 + lpchol_hs_16_0 + ocdca GlycerophospholipidMetabolism,pl h2o + pchol_hs_16_0_18_1 --> h PLA2_2_16_0_18_1 + lpchol_hs_16_0 + ocdcea GlycerophospholipidMetabolism,pl h2o + pchol_hs_18_0_20_4 -- PLA2_2_18_0_20_4 >arachd + h + lpchol_hs_18_0 GlycerophospholipidMetabolism,pl h2o + pa_hs_16_0_18_0 --> PPAP_16_0_18_0 dag_hs_16_0_18_0 + pi Triacylglycerol Synthesis,pl h2o + pa_hs_16_0_18_1 --> PPAP_16_0_18_1 dag_hs_16_0_18_1 + pi Triacylglycerol Synthesis,pl pchol_hs_18_0_20_4 + ser-L PSSA1_hs_18_0_20_4 <==>chol + ps_hs_18_0_20_4 GlycerophospholipidMetabolism,pl pe_hs_18_0_20_4 + ser-L PSSA2_hs_18_0_20_4 <==>etha + ps_hs_18_0_20_4 GlycerophospholipidMetabolism,pl sink_ps_hs_18_0_20_4 ps_hs_18_0_20_4 <==> GlycerophospholipidMetabolism,pl

Table 5. continued

Abbreviation Equation Subsystem PGS_COX arachd + h + (2) o2 --> prostgg2 AA Metabolism nadph + prostgg2 --> h2o + nadp + PGS_PO prostgh2 AA Metabolism 12HPET + (2) gthrd<==> 12harachd + HPETOX gthox + h2o AA Metabolism TXBS h + h2o + txa2 --> txb2 AA Metabolism sink_12harachd(c) 12harachd <==> AA Metabolism sink_5moxact(c) 5moxact <==> Tryptophan Metabolism sink_homoval(c) homoval<==> Tyrosine Metabolism sink_idour(ly) idour<==> chondroitin Sulfate Degradation sink_ind3ac(c) ind3ac <==> Tryptophan Metabolism sink_txb(c) txb2 <==> AA Metabolism sink_ACP ACP <==> Fatty Acid Metabolism sink_palmACP palmACP<==> Fatty Acid Metabolism

Table 6. list of the platelet specific Metabolites added to Roecon1 in SimPheny

abbreviation OfficialName formula charge alpa_hs_16_0 lysophosphatidic acid (homo sapiens, C16 C19H37O7P -2 alpa_hs_18_0 lysophosphatidic acid (homo sapiens, C18:0) C21H41O7P -2 cdpdag_hs_18_0_20_4 diacylglycerol (homo sapiens, C18:0, C20:4) C50H83N3O15P2 -2 dag_hs_16_0_18_0 diacylglycerol (homo sapiens, C16:0, C18:0) C37H72O5 0 dag_hs_16_0_18_1 diacylglycerol (homo sapiens, C16:0, C18:1) C37H70O5 0 dag_hs_18_0_20_4 diacylglycerol (homo sapiens, C18:0, C20:4) C41H72O5 0 lysophosphatidylcholine (homo sapiens, 0 lpchol_hs_16_0 C16:0) C24H50NO7P lysophosphatidylcholine (homo sapiens, 0 lpchol_hs_18_0 C18:0) C26H54NO7P mag_hs_18_0 monoacylglycerol 2 (homo sapiens C18:0) C21H42O4 0 mag_hs_18_1 monoacylglycerol 2(homo sapiens C18:1) C21H40O4 0 mag_hs_20_4 monoglycerol 2 (homo sapiens C20:4) C23H38O4 0 pa_hs_16_0_18_0 phosphatidic acid (homo sapiens, C16 C37H71O8P -2 pa_hs_16_0_18_1 phosphatidic acid (homo sapiens, C16 C37H69O8P -2 phosphatidic acid (homo sapiens, C18:0, -2 pa_hs_18_0_20_4 C20:4) C41H71O8P phosphatidylinositol 4,5-bisphosphate (homo -5 pail45p_hs_18_0_20_4 sapiens, C18:0, C20:4) C47H80O19P3 1-Phosphatidyl-1D-myo-inositol 4-phosphate -3 pail4p_hs_18_0_20_4 (homo sapiens, C18:0, C20:4) C47H81O16P2 phosphatidylinositol (homo sapiens, C18:0, -1 pail_hs_18_0_20_4 C20:4) C47H82O13P

Table 6. continued

abbreviation OfficialName formula charge phosphatidylcholine (homo sapiens, C16:0, 0 pchol_hs_16_0_18_0 C18:0) C42H84NO8P phosphatidylcholine (homo sapiens, C16:0, 0 pchol_hs_16_0_18_1 C18:1) C42H82NO8P phosphatidylcholine (homo sapiens, C18:0, 0 pchol_hs_18_0_20_4 C20:4) C46H84NO8P phosphatidylethanolamine (homo sapiens, 0 pe_hs_18_0_20_4 C18:0, C20:4) C43H78NO8P phosphatidylserine (homo sapiens, C18:0, -1 ps_hs_18_0_20_4 C20:4) C44H77NO10P prostgg2 prostaglandin G2 C20H32O6 0 txb2 Thromboxane B2 C20H34O6 0

The exchange constraints that has been applied to the Recon1 model can be categorized into four categories.First is the exchange of general metabolites such as O2,

CO2, h and h2o, next category is the metabolites that has been specifically pointed out in the literature to be taken up by the platelets, then another category is the amino acids found abundantly in the human’s plasma and can be uptaken by human platelets, finally they were some metabolites that have to be uptaken by platelet in order that platelet model can carries on its functionalities, these metabolites and the exchange reactions assigned for them, in addition to the information about the category they fall in has been listed in the table below.

Table 7. The exchange constraints applied to the model and their categories

Exchange Rxn Metabolite category Exchange Rxn Metabolite category EX_co2(e) co2 1 EX_nrpphr(e)_r nrpphr 2 EX_o2(e)_r o2 1 EX_trypta(e)_r trypta 2 EX_h(e) h 1 EX_tym(e)_r tym 2 EX_h2o(e) h2o 1 EX_arachd(e) arachd 2 EX_pi(e) pi 1 EX_glyc(e) glyc 2 EX_so4(e) so4 1 EX_leuktrA4(e) leuktrA4 2 EX_srtn(e)_r srtn 2 EX_met-L(e)_r met-L 3 EX_4nph(e)_r 4nph 2 EX_orn(e)_r orn 3 EX_ade(e)_r ade 2 EX_phe-L(e)_r phe-L 3 EX_adn(e)_r adn 2 EX_trp-L(e)_r trp-L 3 EX_arg-L(e)_r arg-L 2 EX_ala-L(e) ala-L 3 EX_dopa(e)_r dopa 2 EX_asn-L(e) asn-L 3 EX_gal(e)_r gal 2 EX_gly(e) gly 3 EX_glc(e)_r glc-D 2 EX_cspg_d(e)_r cspg_d 4 EX_glu-L(e)_r glu-L 2 EX_hspg(e)_r hspg 4 EX_bhb(e) bhb 4

The core reactions were ranked based on the number of bibliomic sources referring to them and the 26 highest ranked reactions were chosen for pathway analysis of the bibliomic-derived data (Figure 6.) Between these highest rank pathways, one can recognizes energy metabolism pathways such as glycolysis, TCA cycle and oxidative phosphorylation, as well as some signaling related pathways, such as nucleotides and inositol phosphate pathways. Also notable is the nitric oxide synthesis that plays an important role in signaling and cause vasodilation, and monoamine oxidase activity that is well known in different neurons.

Top Core Reactions

CYOOm2 Oxid. Phos. NADH2-u10m

GTHO Met. Glut. GLUDxm ADK1

tides GUACYC Nucleo PYK HEX1 LDH_L

Glycolysis PDHm PFK SUCD1m

TCA CSm

NOS1

Pro Met

Arg/ NOS2 t.

H. GTHP

GT Me

PLA2_2_18_0_20_4 GPL. Met. PLA2_2_16_0_18_0 PIPLC_18_0_20_4 PI4PLC_18_0_20_4

I.P. Met. PI45PLC_18_0_20_4

TYROXDAc Tyr. Met. 42A12BOOX

. ADPT

Sal

v.P ath

SPODM Det. ROS. SPODMm

0 2 4 6 8 10 12 14

Biochemical studies non-Biochemical studies

Figure 6. The well established platelet reactions in bibliomics, categorized into subsystems To compare the data obtained from proteomics and the bibliomics data, the reaction-mapped proteomics data was used. The number of bibiomic studies for each reaction is plotted against the number of proteomic studies supporting that. Different pathways were looked at, in the search of any cluster forming, but most of the pathways

27 are scattered across the proteomics and bibliomics studies. Some, like tyrosine metabolism are more studied in literature than using proteomics approach, and some pathways like nucleotides are the reverse.

Figure 7. the presence of the core reactions in bibliomics vs. proteomics

4. HUMAN PLATELET MODEL

4.1 Introduction

Constraint Based Reconstruction Analysis (CoBRA) has been used in systems biology extensively over the past decade and due to its highly use, systems biology

Research group (SBRG) at UCSD has developed a matlab based toolbox to serve this purpose. Once a metabolic network has reconstructed through a method similar to what has been done here, it can be loaded into the COBRA environment, to be further analyzed. COBRA toolbox provide the researchers with variety of analytical tools, including Flux Balance analysis (FBA), Flux Variability Analysis (FVA), sampling[51] and etc. In addition to these analytical tools, it creates an environment for different in silico experiments and simulations such as gene knock out and drug effects. Recently a tool has been added to this toolbox that utilizes different algorithms such as GIMME

(gene inactivity moderated by metabolism and expression) by Becker[35] and Shlomi’s algorithm [37] to create tissue specific models based on the organism’s model.

4.2 Final Reconstruction

Once the Recon1 model has been refined to accommodate the functionalities of human platelets, it is ready to be used as the scaffold for the reconstruction. This platelet specific reconstruction was created using the GIMME algorithm[36], as mentioned in the introduction chapter, this algorithms utilized the expression profile of the tissue and the functionality objectives of the tissue to find the minimal subset of the global metabolic network, which best correspond to the tissue. GIMMEp is a modified version of GIMME that accounts for proteomics data rather than a expression profile. It requires three inputs:

29 the global model, the expression structure and the set of core reactions. All these inputs have been collected and prepared as described in the previous sections, only few modifications remained to be made on the proteomics data, so that it can meet the requirements of the GIMMEp method. An expression structure contains two vector, first vector is the list of the genes that has been reported on an expression profile experiment and the second is the present/ absent vector in a binary form. Such structure was built in matlab based on the Recon1 genes and the proteomics data collected. Also the global model has been extracted from the SimPheny simulation environment and imported in the matlab COBRA environment. Then the corresponding GPR data has been added to the model based on Recon1 GPR data. Finally a list of core reactions has been made in matlab and then GIMMEp was ran using these three structures. The result of GIMMEp was a different list of reactions (including expressed, unknown and orphan reactions) and the tissue specific model. Then the content of the model has been further tested and verified as explained below.

4.3 Model content

A COBRA model contains variety of information, including different properties of the components of the model and the networks that connect these components together. The main components of the model are the metabolites, the reaction and the genes. The stoichiometric matrix (S) connects the metabolites and the reactions of the model and a reaction-gene matrix (rxnGeneMat) connects the reactions and genes of the model. Further information about metabolites such as their full name, formula and charge are also available in the form of vectors, furthermore the subsystems of each

30 reaction has been stored in a form of a vector. The platelet model contains almost a third of the Recon1 reactions and a fourth of its metabolites (Table 8.)

Table 8. the content of human platelet model Platelet model Recon1 genes 867 1905 Reactions: 924 3862 Intra-cellular 557 2412 Transport 271 1030 Exchange 96 420 Metabolites: 714 2815 Extracellular 116 420 Cytosol 386 1026 Mitochondria 99 393 Lysosomal 52 217 Peroxisome 35 143 Gaps: Sinks 9 12 Demands 8 27

The reactions in the model has been tracked down to the sources they come from and the following figure shows the distribution of the reaction pool by the source that has led to their addition to the model. Slightly more than half of these reactions were added to the model based on the metabolic capabilities of the model and applying the mass action balances.

Bibliomics Proteomics

58 83 277

Metabolic capabilities 506

Figure 8. the source distribution of the reactions in the model

Furthermore a confidence score has been assigned to each of the reactions in the model based on their support from proteomics or bibliomics data . Following table explains the criteria used for ranking these reactions (Table 9.) In the current setting the number of studies reporting a protein is the only determinant of the proteomics confidence, though in a future effort, one can consider the number of peptides found in each study for the protein as well for the indication of a better support of the presence of the protein in the platelet.

Table 9. the reaction confidence scores and their criteria

Confidence Score Criteria for Assigning the Confidence Score 1 Associated protein found in both bibliomics and proteomics 3 Associated protein found only in the bibliomics 2 Associated protein found in more than 4 proteomic studies 1 Associated protein found in less than 5 proteomic studies 0 Reaction added algorithmically

Reactions Confidence Scores

12% 4 24% 3 2 55% 1 6% 43% 0 (exchange) 6% 0 (internal) 9%

Figure 9. The ranking distribution of the platelet model’s reactions

4.4 Model Functionality and Network Topology

Human platelets metabolic network, consists of a 714x924 stoichiometric matrix, the rank of which is 658, a fairly large matrix. Further analysis has been done in exploring the network topology and the model functionality. First the connectivity and participation of the compounds in the model were calculated. Thiswas done by forming the binary equivalent of the stoichiometric matrix and multiplying it by its own transpose matrix. When multiplied from left it will result in compound adjacency and when multiplied from right it will result in the reaction adjacency matrix. The diagonal elements of these matrices correspond to the connectivity and participations of the metabolites and the reactions in the network. The connectivity of a metabolite represents its appearance and influence on the network. Here the connectivity of the most connected metabolites in human platelet has been compared to its corresponding connectivity in

Recon1.

Network Connectivity

250

200

ADP 150

CoA 100 ATP

50 Glutamine, serine

0 connectivityof metabolites the in global model 0 10 20 30 40 50 60 70 80 90 connectivity of metabolites in the platelet model

Figure 10.Network Connectivity, comparison of the connectivity of metabolites in the platelet model ( with connectivity of 10 and higher) with the same metabolite in the global model.

The metabolites below the line are the ones that proved more significant in the platelet model and the ones on the top of the line less connected, compared to the human network of Recon1. Glutamine , alanine, serine and other amino acids along ADP belong to the first category and ATP and CoA belong to the second.

Next the rank of S matrix was calculated and the matrix was decomposed using the singular value decomposing (SVD) method. This revealed sets of orthonormal bases for the four fundamental sub-spaces of the stoichiometric matrix: the null space, left null space, row space and the column space. The null space of the platelet reconstruction is of a size of 266 and the left null space has a dimension of 56. The obtained eigen modes from singular value decomposition of the stoichiometric matrix, are the weights for the

34 reconstruction of this matrix mode by mode. It is well known that the cumulative contribution of these modes will be in an exponential manner, this fact has been confirmed in Figure 11.

Table 10. Network properties of the platelet metabolic network

Network properties Property’s value Stoichiometric Matrix 714 x 924 Rank 658 Null space 266 Left null space 56 Row space 658 Column space 658

Eigen modes' contributions

1.2 y = 0.048x0.4761 1 R² = 0.9977 0.8 0.6 0.4 0.2

contributiontothe reconstruction

23 45 67 89

529 639 111 133 155 177 199 221 243 265 287 309 331 353 375 397 419 441 463 485 507 551 573 595 617 eigen mode

Figure 11. the contribution of Eigen modes to the reconstruction of the stoichiometric matrix which follows the power low

The assessment of the activity of reactions in the network has been done by flux variability Analysis (Figure 12.) It represents the distribution of allowable fluxes for each reaction in the network at steady state. Some of the fluxes span all the possible flux

35 values and are not restricted by the network,while others are constraint through their connections in the network and the applied mass action balances.

Figure 12. FVA analysis of the model for all the reactions

Furthermore a sampling of the solution space was obtain, using the gpSampler method in cobra toolbox. This method samples the solution space randomly and uniformly. The sampling result was used to define the cosets in the model. The cosets are sets of reactions that correlate with each other in the solution space. These cosets have been calculated with different cut off values for the correlation coefficient, and they have been plotted based on their length (number of reactions in the coset) for the cosets of 5 and higher length. The hard cosets are the sets of reactions that are correlated with a correlation coefficient of 1.One of these hard cosets with the highest length (coset 31) was chosen to be mapped and it turned out to correspond to the linear pathway of heparan

36 sulfate degradation. The linearity of the pathway explains the high correlation of these reactions, as one changes the rest have to change in order to keep the conservation of mass (Figure 14). Another interesting point is the merging of cosets 1 and 19 at a cut off value of 0.85, the same observation can be made for cosets 5 and 40. After mapping the merged coset of 1 and 19, it turns out to be another linear path which corresponds to the classical pathways of tryptophan metabolism and NAD metabolism (Figure 14.)

Figure 13. comparison of the coset lengths with different cut off thresholds for correlation criteria.

Figure 14. couple of the linear pathways picked up in the coset analysis of the model with correlation coefficient more than 0.95

Finally, parts of carbohydrate metabolism, including glycolysis, TCA cycle and pentose phosphate pathway, has been mapped out and the cosets with cut off vaue of 0.65 were in the pathway were identified (Figure 15.) The pentose phosphate pathway fits into two major cosets, one of which includes three reactions of salvage pathway. As far as glycolysis pathway and TCA cycle there is one major coset containing parts of each pathway. Notably the pyruvate does not get transported to the mitochondria directly, instead it uses alternate paths such as lactate or phenoleno pyruvate to continue the metabolism inside mitochondria.

G6PDH2r, GND, PGL, RPE, TKT1, TKT2, TALA

PPM, PRPPS,

GUAPRT, NTD9, PUNP3

PYK, LDH_Lm,

L_LACtcm, PCm, PEPCKm, MDH CITtbm, ASOTAm

Figure 15. Carbohydrate metabolism in platelet and its cosets

4.5 Simulations

The final goal of a metabolic network reconstruction is to analyze the functional states of the model and the phonotypical behavior of the organism. For this purpose the model is used to simulate the organism or cell type behavior under certain conditions.

Here, the platelet model was used to simulate the platelet’s behavior and metabolic changes under the effect of aspirin. Aspirin is a well-known anti-platelet drug and the mechanism of its effect is well recognized that it blocks the cyclooxygenase activity. This condition was simulated by blocking the flux through the corresponding reactions to cyclooxygenase and the behavior of the model was studied using FVA and sampling methods.

The FVA analysis of the aspirin affected platelet and its comparison with the normal platelet model, revealed two sets of reactions that were affected. The first set were completely blocked, since they were directly involved with the arachidionic acid metabolism pathway and the second set were affected by only %10 and they all belonged to the glucuronate inter-conversion pathway.

Figure 16. Flux variability analysis of aspirin effect on platelet

The sampling and coset analysis of the aspirin effect on platelet at 0.99 cut off only shows the disappearance of two of the cosets, cosets 49 and 93 (Figure 17.) On the other hand when the models are compared at a cut off value of 0.75 there are more significant changes observed. Specifically there is a significant increase in the size of cosets 1, 19 and 31 (Figure 18.) Further investigation revealed that these cosets mostly correspond to lysosomal pathways such as heparan sulfate degradation and chondroitin sulfate. A pathway analysis can be used for the further analysis of potential connections between these lysosomal pathways and the cyclooxygenase pathway.

Figure 17.coset analysis of aspirin effect on platelet with a cut off value of 0.99

Figure 18.coset analysis of aspirin effect on platelet with a cut off value of 0.75

4.6 Conclusion The metabolic network reconstruction of human platelet was created, on a knowledge-based. Using the available proteomics data on human platelets and the human network, recon1 as a scaffold the platelet specific model was algorithmically constructed after numerous iterations of manual curation. The platelet metabolic network contains

714 metabolites and 924 reactions that are based on 141 metabolic capabilities (core reaction) derived by bibliomics data and 546 proteins mapped on Recon1 from proteomics data.

The model contains the major carbohydrate metabolisms, such as glycolysis, TCA cycle, pentose phosphate pathway and fatty acid oxidation as well as many phospholipid metabolism pathways such as inositol phosphate metabolism and phospholipase A2 ans

C. Finally the model accounts for arachidonic acid metabolisms such as lipooxygenase and cyclooxygenase pathways.

The platelet metabolic reconstruction was used to simulate the effects of aspirin on the human platelet metabolism. The flux variability analysis and sampling analysis of the aspirin affected platelet indicated the incapability of platelets to produce thromboxane

A2, under the effect of aspirin. On the other hand there were some minor alterations in the glucuronate metabolism flux spans and some changes in the coset lengths corresponding to heparan sulfate degradation and chondroitin sulfate degradation. There is variety of other simulations that this model can be used for, such as dosage dependent effect of aspirin, platelet metabolic activity in different diseases and the effect of different drug on such altered metabolism.

APPENDIX Table A1. the list of reactions and their properties in the model. lower upper Abbreviation Name subSystem bound bound DM_Ser-Gly/Ala-X- DM_Ser-Gly/Ala-X-Gly(ly) Exchange 0.00 11.97 Gly(ly) DM_atp(c) atp demand Exchange 0.00 627.59

DM_datp(m) dATP demand Exchange 0.00 60.90

DM_kdn(c) DM_kdn(c) Exchange 0.00 68.57

DM_sprm(c) DM_sprm(c) Exchange 0.00 32.88

EX_1mncam(e) 1-Methylnicotinamide exchange Exchange 0.00 10.00

EX_2hb(e) 2-Hydroxybutyrate exchange Exchange 0.00 10.00

EX_2mcit(e) 2-Methylcitrate exchange Exchange 0.00 10.00

EX_34dhoxpeg(e) 3,4-Dihydroxyphenylethyleneglycol exchange Exchange 0.00 24.00

EX_4abut(e) 4-Aminobutanoate exchange Exchange 0.00 214.21

EX_4hphac(e) 4-Hydroxyphenylacetate exchange Exchange 0.00 22.00

EX_4nph(e)_r 4-Nitrophenol exchange Exchange 0.00 100.00

EX_4nphsf(e) 4-Nitrophenyl sulfate exchange Exchange 0.00 100.00

EX_abt(e) L-Arabinitol exchange Exchange 0.00 82.06

EX_ac(e) Acetate exchange Exchange 0.00 297.18

EX_acac(e) Acetoacetate exchange Exchange 0.00 191.58

EX_ade(e)_r Adenine exchange Exchange 0.10 2.00

EX_adn(e)_r Adenosine exchange Exchange 0.10 2.00

EX_adrn(e) adrenic acid exchange Exchange 0.00 99.90

EX_akg(e) 2-Oxoglutarate exchange Exchange 0.00 130.60

EX_ala-D(e) D-Alanine exchange Exchange 0.00 468.56

EX_ala-L(e) L-Alanine exchange Exchange -100.00 368.56

EX_arachd(e) nC20:4 exchange Exchange -100.00 301.09

EX_arg-L(e)_r L-Arginine exchange Exchange 0.10 2.00

EX_asn-L(e) L-Asparagine exchange Exchange -10.00 192.34 (R)-3-Hydroxybutanoate transport via H+ Exchange EX_bhb(e) -10.00 217.58 symport EX_bilirub(e) Bilirubin exchange Exchange 0.00 18.16

EX_camp(e) cAMP exchange Exchange 0.00 54.19

EX_cgly(e) Cys-Gly exchange Exchange 0.00 10.00

EX_co(e) Carbon monoxide exchange Exchange 0.00 18.16

EX_co2(e) CO2 exchange Exchange -100.00 598.72 chondroitin sulfate D (GlcNAc6S-GlcA2S) Exchange EX_cspg_d(e)_r 0.00 5.00 proteoglycan exchange EX_cys-L(e) L-Cysteine exchange Exchange 0.00 10.00

EX_cytd(e) Cytidine exchange Exchange 0.00 72.99

EX_dad-2(e) Deoxyadenosine exchange Exchange 0.00 68.90

EX_dcyt(e) Deoxycytidine exchange Exchange 0.00 80.92

EX_dopa(e)_r Dopamine exchange Exchange 0.10 2.00

Table A1. continued lower upper Abbreviation Name subSystem bound bound EX_dopasf(e) Dopamine 3-O-sulfate exchange Exchange 0.00 22.00

EX_drib(e) Deoxyribose exchange Exchange 0.00 103.27

EX_duri(e) Deoxyuridine exchange Exchange 0.00 74.94

EX_fru(e) D-Fructose exchange Exchange 0.00 88.98

EX_gal(e)_r D-Galactose exchange Exchange 0.10 2.00

EX_glc(e)_r D-Glucose exchange Exchange 0.10 2.00

EX_gln-L(e) L-Glutamine exchange Exchange 0.00 228.98

EX_glu-L(e)_r L-Glutamate exchange Exchange 0.10 2.00

EX_gluala(e) 5-L-Glutamyl-L-alanine exchange Exchange 0.00 171.94

EX_gly(e) Glycine exchange Exchange -100.00 176.84

EX_glyc(e) Glycerol exchange Exchange -10.00 160.40

EX_glyc-S(e) (S)-Glycerate exchange Exchange 0.00 151.44

EX_h(e) H+ exchange Exchange -248.99 1359.35

EX_h2o(e) H2O exchange Exchange -100.00 336.11

EX_h2o2(e) Hydrogen peroxide exchange Exchange 0.00 149.90

EX_ha(e) hyaluronan exchange Exchange 0.00 25.14

EX_ha_pre1(e) hyaluronan biosynthesis, precursor 1 exchange Exchange 0.00 50.29

EX_hco3(e) Bicarbonate exchange Exchange 0.00 349.46

EX_hdca(e) Hexadecanoate (n-C16:0) exchange Exchange 0.00 436.11

EX_hspg(e)_r heparan sulfate proteoglycan exchange Exchange 0.00 7.86

EX_hxan(e) Hypoxanthine exchange Exchange 0.00 89.69

EX_ins(e) Inosine exchange Exchange 0.00 68.04

EX_lac-D(e) D-lactate exchange Exchange 0.00 326.53

EX_lac-L(e) L-Lactate exchange Exchange 0.00 326.53

EX_leuktrA4(e) Leukotriene A4 exchange Exchange -10.00 99.90

EX_leuktrB4(e) Leukotriene B4 exchange Exchange 0.00 109.90

EX_leuktrD4(e) Leukotriene D4 exchange Exchange 0.00 10.00

EX_leuktrE4(e) leukotriene E4 exchange Exchange 0.00 10.00

EX_leuktrF4(e) leukotriene F4 exchange Exchange 0.00 10.00

EX_meoh(e) methanol exchange Exchange 0.00 66.33

EX_mercplaccys(e) 3-mercaptolactate-cysteine disulfide exchange Exchange 0.00 5.00

EX_met-L(e)_r L-Methionine exchange Exchange 0.00 10.00

EX_mthgxl(e) Methylglyoxal exchange Exchange 0.00 289.03

EX_nh4(e) Ammonia exchange Exchange 0.00 380.45

EX_no(e) Nitric oxide exchange Exchange 0.00 49.95

EX_nrpphr(e)_r Norepinephrine exchange Exchange 0.10 2.00

EX_nrpphrsf(e) Sulfate derivative of norepinephrine exchange Exchange 0.00 24.00

EX_o2(e)_r O2 exchange Exchange 0.10 100.00

EX_o2s(e) Superoxide anion exchange Exchange 0.00 99.90

EX_ocdca(e) octadecanoate (n-C18:0) exchange Exchange 0.00 301.09

Table A1. continued. lower upper Abbreviation Name subSystem bound bound EX_orn(e)_r Ornithine exchange Exchange 0.00 10.00

EX_phe-L(e)_r L-Phenylalanine exchange Exchange 0.00 10.00

EX_pheacgln(e) alpha-N-Phenylacetyl-L-glutamine exchange Exchange 0.00 10.00

EX_pi(e) Phosphate exchange Exchange -10.00 275.84

EX_pro-L(e) L-Proline exchange Exchange 0.00 457.24

EX_prostgd2(e) Prostaglandin D2 exchange Exchange 0.00 49.95

EX_pyr(e) Pyruvate exchange Exchange 0.00 325.30

EX_ser-L(e) L-Serine exchange Exchange 0.00 299.52

EX_so4(e) Sulfate exchange Exchange -100.00 108.55

EX_srtn(e)_r Serotonin exchange Exchange 0.10 2.00

EX_succ(e) Succinate exchange Exchange 0.00 349.82

EX_thym(e) Thymine exchange Exchange 0.00 110.16

EX_tmndnc(e) timnodonic acid exchange Exchange 0.00 39.96

EX_trp-L(e)_r L-Tryptophan exchange Exchange 0.00 10.00

EX_trypta(e)_r Tryptamine exchange Exchange 0.10 2.00

EX_txa2(e) Thromboxane A2 exchange Exchange 0.00 49.95

EX_tym(e)_r Tyramine exchange Exchange 0.10 2.00

EX_tymsf(e) Tyramine O-sulfate exchange Exchange 0.00 22.00

EX_urate(e) Urate exchange Exchange 0.00 61.44

EX_urea(e) Urea exchange Exchange 0.00 153.05

EX_uri(e) Uridine exchange Exchange 0.00 76.29

EX_xyl-D(e) D-Xylose exchange Exchange 0.00 11.97

EX_xylt(e) Xylitol exchange Exchange 0.00 82.06

sink_12harachd(c) sink_12harachd(c) Sink 0.00 195.29

sink_5moxact(c) sink_5moxact(c) Sink 0.10 12.00

sink_homoval(c) sink_homoval(c) Sink 0.00 22.00

sink_idour(ly) sink_idour(ly) Sink 0.00 23.58

sink_ind3ac(c) sink_ind3ac(c) Sink 0.10 12.00

sink_txb(c) sink_txb(c) Sink 0.00 49.95

1MNCAMti N1-Methylnicotinamide transport Transport, Extracellular 0.00 10.00

25HVITD2t 25-hydroxyvitamin D2 transport from cytoplasm Transport, Extracellular 0.00 100000.00

25HVITD2tin 25-hydroxyvitamin D2 transport in cytoplasm Transport, Extracellular 0.00 100000.00

25HVITD2tin-m 25-hydroxyvitamin D2 transport in mitochondria Transport, Mitochondrial 0.00 100000.00 25-hydroxyvitamin D2 transport from 25HVITD2tm Transport, Mitochondrial 0.00 100000.00 mitochondria 25HVITD3t 25-hydroxyvitamin D3 transport from cytoplasm Transport, Extracellular 0.00 100000.00

25HVITD3tin 25-hydroxyvitamin D3 transport in cytoplasm Transport, Extracellular 0.00 100000.00

25HVITD3tin-m 25-hydroxyvitamin D3 transport in mitochondria Transport, Mitochondrial 0.00 100000.00 25-hydroxyvitamin D3 transport from 25HVITD3tm Transport, Mitochondrial 0.00 100000.00 mitochondria

Table A1. continued lower upper Abbreviation Name subSystem bound bound Glycine, Serine, and 2AMACHYD 2-Aminoacrylate hydrolysis 0.00 404.98 Threonine Metabolism 2DR1PP 2-deoxy-D-ribose 1-phosphate phosphorylase Pyrimidine Catabolism 0.00 182.51

2HBO_r 2-Hydroxybutyrate:NAD+ oxidoreductase Propanoate Metabolism 0.00 10.00

2HBt2_r 2-hydroxybutyrate cotransport with proton Transport, Extracellular 0.00 10.00

2MCITt 2-methylcitrate transport via diffusion Transport, Extracellular 0.00 10.00 3,4-Dihydroxyphenylethyleneglycol:NAD+ 34DHOXPEGOX Tyrosine metabolism 0.00 24.00 oxidoreductase 3,4-Dihydroxyphenylethyleneglycol transport 34DHOXPEGt Transport, Extracellular 0.00 24.00 (diffusion) 3,4-Dihydroxyphenylacetate:amet O- 34DHPHAMT Tyrosine metabolism 0.00 22.00 methyltransferase 3,4-Dihydroxyphenylacetaldehyde:NAD+ 34DHPLACOX Tyrosine metabolism 0.00 22.00 oxidoreductase 3,4-Dihydroxyphenylacetaldehyde:NADP+ 34DHPLACOX(NADP) Tyrosine metabolism 0.00 22.00 oxidoreductase 3HAO 3-hydroxyanthranilate 3,4-dioxygenase Tryptophan metabolism 0.00 10.00 bicarbonate transport (Na/HCO3 1:3 3HCO3_NAt Transport, Extracellular -100000.00 100000.00 cotransport) 3-Methoxy-4-hydroxyphenylacetaldehyde:NAD+ 3M4HDXPAC Tyrosine metabolism 0.00 22.00 oxidoreductase 3-Methyl-2-oxopentanoate mitochondrial 3MOPt2im Transport, Mitochondrial 0.00 100000.00 transport via proton symport 3-Methoxytyramine:oxygen oxidoreductase 3MOXTYROX Tyrosine metabolism 0.00 22.00 (deaminating) 4-[(1R)-2-Amino-1-hydroxyethyl]-1,2- 41R2A1H12BOOX benzenediol:oxygen Tyrosine metabolism 0.00 24.00 oxidoreductase(deaminating)(flavin-containing) 4-(2-Aminoethyl)-1,2-benzenediol:oxygen 42A12BOOX Tyrosine metabolism 0.00 22.00 oxidoreductase(deaminating)(flavin-containing) 4-aminobutanoate mitochondrial transport via 4ABUTtm Transport, Mitochondrial 0.00 100.78 diffusion L-4-hydroxyglutamate semialdehyde Arginine and Proline 4HGLSDm_r 0.00 100000.00 dehydrogenase, mitochondrial Metabolism 4-Hydroxyphenylacetaldehyde:NADP+ 4HOXPACDOX(NADP) Tyrosine metabolism 0.00 22.00 oxidoreductase 4-methyl-2-oxopentanoate mitochondrial 4MOPt2im Transport, Mitochondrial 0.00 100000.00 transport via proton symport 4NPHSFte_r xenobiotic transport Transport, Extracellular 0.00 100.00

4NPHSULT 4-Nitrophenol Sulfotransferase CYP Metabolism 0.00 100.00

4NPHte xenobiotic transport Transport, Extracellular 0.00 100.00

5AOPtm_r 5-Aminolevulinate mitochondrial transport Heme Biosynthesis 0.00 145.31 5-Hydroxyindoleacetaldehyde:NAD+ 5HOXINDACTOX Tryptophan metabolism 0.00 12.00 oxidoreductase 5-Hydroxytryptamine:oxygen 5HOXINOXDA Tryptophan metabolism 0.10 12.00 oxidoreductase(deaminating)(flavin-containing) AACOAT Acetoacetyl-CoA:acetate CoA-transferase Propanoate Metabolism -349.50 522.83 4-aminobutyrate transaminase, reversible ABTArm Glutamate metabolism 0.00 100.78 (mitochondrial) Pentose and Glucuronate ABTD_r L-arabinitol 4-dehydrogenase 0.00 82.06 Interconversions ABTti L-arabinitol transport via passive diffusion Transport, Extracellular 0.00 82.06

ABUTD Aminobutyraldehyde dehydrogenase beta-Alanine metabolism 0.00 130.69 4-aminobutyrate reversible transport in via ABUTt4(2)r Transport, Extracellular -214.21 1882.78 sodium symport (1:2) ACACT1 acetyl-CoA C-acetyltransferase Cholesterol Metabolism 0.00 100000.00

ACACT1r acetyl-CoA C-acetyltransferase Tryptophan metabolism -100000.00 349.50

ACACT1rm acetyl-CoA C-acetyltransferase, mitochondrial Tryptophan metabolism -317.04 588.55

Table A1. continued lower upper Abbreviation Name subSystem bound bound ACACt2_r acetoacetate transport via proton symport Transport, Extracellular 0.00 191.58 Acetoacetate mitochondrial transport via H+ ACACt2m Transport, Mitochondrial -588.73 746.99 symport acetoacetate intracellular transport unknown ACACtx_r Transport, Peroxisomal 0.00 672.67 mechanism ACCOAC acetyl-CoA carboxylase Fatty Acid Metabolism 0.00 657.83

ACGALK N-acetylgalactosamine kinase Aminosugar Metabolism 0.00 10.00

ACGALK2 N-acetylgalactosamine kinase (ITP) Aminosugar Metabolism 0.00 10.00

ACGALtly N-acetyl-galactosamine lysosomal efflux Transport, Lysosomal 0.00 10.00

ACGAMK N-acetylglucosamine kinase Aminosugar Metabolism 0.00 313.95

ACGAMPM phosphoacetylglucosamine mutase Aminosugar Metabolism 0.00 313.95

ACGAMtly N-acetyl-glucosamine lysosomal efflux Transport, Lysosomal 0.00 149.40

ACITL ATP-Citrate lyase Citric Acid Cycle 0.00 629.19 N-Acetylneuraminate 9-phosphate pyruvate- ACNAM9PL2 Aminosugar Metabolism 0.00 68.57 lyase (pyruvate-phosphorylating) ACONT aconitase Citric Acid Cycle 0.00 1391.39

ACONTm Aconitate hydratase Citric Acid Cycle -1385.93 443.30

ACS acetyl-CoA synthetase Glycolysis/Gluconeogenesis 0.00 449.07 S-Adenosyl-L-methionine:N-acetylserotonin O- ACSOMT Tryptophan metabolism 0.10 12.00 methyltransferase ACt2r acetate reversible transport via proton symport Transport, Extracellular -297.18 235.46

ADA Adenosine deaminase Purine Catabolism 0.00 188.94

ADAe Adenosine deaminase, extracellular Nucleotides 0.00 189.15

ADEt adenine reversible transport, cytosol Transport, Extracellular 0.10 2.00

ADK1 adenylate kinase Nucleotides -100000.00 100000.00

ADK1m adenylate kinase, mitochondrial Nucleotides -100000.00 100000.00

ADK3 adentylate kinase (GTP) Nucleotides -100000.00 100000.00

ADK3m adentylate kinase (GTP) Nucleotides -100000.00 100000.00 Arginine and Proline ADMDC adenosylmethionine decarboxylase 0.00 65.76 Metabolism ADNCYC adenylate cyclase Nucleotides 0.00 313.95

ADNK1 adenosine kinase Nucleotides 0.00 627.71

ADNK1m adenosine kinase, mitochondrial Nucleotides 0.00 71.79

ADNt adenosine facilated transport in cytosol Transport, Extracellular -187.15 2.00

ADNtm adenosine facilated transport in mitochondria Transport, Mitochondrial 0.00 71.79

ADPRDP ADPribose diphosphatase Nucleotides 0.00 209.30

ADPT adenine phosphoribosyltransferase Salvage Pathway 0.00 314.01

ADRNCOAtx fatty acid intracellular transport Transport, Peroxisomal 0.00 57.09

ADRNt fatty acid transport via diffusion Transport, Extracellular -100000.00 100000.00

ADSK adenylyl-sulfate kinase Nucleotides 0.00 627.89

ADSL1 adenylosuccinate lyase Nucleotides 0.00 353.32

ADSS adenylosuccinate synthase Nucleotides 0.00 353.32

AGDC N-acetylglucosamine-6-phosphate deacetylase Aminosugar Metabolism 0.00 355.11 1-acylglycerol-3-phosphate O-acyltransferase 1 AGPAT1_16_0_18_0 0.00 125.58 (C16:0, C18:0)

Table A1. continued lower upper Abbreviation Name subSystem bound bound 1-acylglycerol-3-phosphate O-acyltransferase 1 AGPAT1_16_0_18_1 0.00 125.58 (C16:0, C18:1) 1-acylglycerol-3-phosphate O-acyltransferase 1 AGPAT1_18_0_20_4 0.00 156.97 (C18:0, C20:4) alanine-glyoxylate transaminase (irreversible), Alanine and Aspartate AGTix 0.00 199.80 (peroxisomal) Metabolism AHC adenosylhomocysteinase Methionine Metabolism 0.10 196.13

AKGDm 2-oxoglutarate dehydrogenase Citric Acid Cycle 0.00 107.25

AKGMALtm alpha-ketoglutarate/malate transporter Transport, Mitochondrial -1702.58 100000.00

AKGt4_3_r AKG transport via sodium symport Transport, Extracellular 0.00 130.60 L-alanine/L-asparagine Na-dependent exchange ALAASNNaEx Transport, Extracellular 0.00 100000.00 (Ala-L in) L-alanine/L-cysteine Na-dependent exchange ALACYSNaEx Transport, Extracellular 0.00 100000.00 (Ala-L in) ALADGLYexR D-alanine/glycine reversible exchange Transport, Extracellular -100000.00 100000.00 L-alanine/L-glutamine Na-dependent exchange ALAGLNNaEx Transport, Extracellular 0.00 100000.00 (Ala-L in) ALAGLYexR L-alanine/glycine reversible exchange Transport, Extracellular -100000.00 100000.00 Alanine and Aspartate ALAR alanine racemase 0.00 503.32 Metabolism L-alanine/L-serine Na-dependent exchange (Ala- ALASERNaEx Transport, Extracellular 0.00 100000.00 L in) Glycine, Serine, and ALASm 5-aminolevulinate synthase 0.00 145.31 Threonine Metabolism ALATA_L L-alanine transaminase Glutamate metabolism -403.32 110.00 L-alanine/L-threonine Na-dependent exchange ALATHRNaEx Transport, Extracellular 0.00 100000.00 (Ala-L in) ALAt4 Alanine-Sodium symporter Transport, Extracellular 0.00 100000.00

ALCD1_r alcohol dehydrogenase (methanol) Miscellaneous 0.00 175.79

ALCD21_D alcohol dehydrogenase (D-1,2-propanediol) Pyruvate Metabolism 0.00 100000.00

ALCD21_L alcohol dehydrogenase (L-1,2-propanediol) Pyruvate Metabolism 0.00 276.73 aldehyde dehydrogenase (phenylacetaldehyde, ALDD19x(P) Phenylalanine metabolism 0.00 10.00 NADP) aldehyde dehydrogenase (indole-3- ALDD20x Tryptophan metabolism 0.10 12.00 acetaldehyde, NAD) ALOX12 Arachidonate 12-lipoxygenase Eicosanoid Metabolism 0.00 195.29 Glycine, Serine, and ALR Aldose reductase 0.00 276.73 Threonine Metabolism ALR2 aldose reductase (methylglyoxal) Pyruvate Metabolism 0.00 276.73

ALR3 aldose reductase (acetol) Pyruvate Metabolism 0.00 276.73

AMPDA Adenosine monophosphate deaminase Nucleotides 0.00 354.91

AMPTASECGe alanyl aminopeptidase (cys-gly) (e) Glutathione Metabolism 0.00 224.11

ARACHDCOAtx_r fatty acid intracellular transport Transport, Peroxisomal 0.00 39.96

ARACHDt2 fatty acid transport via diffusion Transport, Extracellular -100000.00 100000.00 Transport, Endoplasmic ARACHDtr intracellular transport 0.00 49.95 Reticular Urea cycle/amino group ARGN arginase 0.00 153.05 metabolism Alanine and Aspartate ARGSL argininosuccinate lyase 0.00 151.05 Metabolism Alanine and Aspartate ARGSS argininosuccinate synthase 0.00 151.05 Metabolism L-arginine transport via diffusion (extracellular to ARGtiDF Transport, Extracellular 0.00 2.00 cytosol) Ascorbate and Aldarate ASCBOX ascorbic acid oxidase 0.00 199.80 Metabolism

Table A1. continued lower upper Abbreviation Name subSystem bound bound ASCBt L-ascorbate transport via facilitated diffusion Transport, Extracellular -100000.00 100000.00

ASCBt4 L-ascorbate transport via proton symport Transport, Extracellular -100000.00 100000.00 L-alanine/L-asparagine Na-dependent exchange ASNALANaEx Transport, Extracellular 0.00 100000.00 (Asn-L in) L-cysteine/L-asparagine Na-dependent exchange ASNCYSNaEx Transport, Extracellular 0.00 100000.00 (Asn-L in) L-glutamine/L-asparagine Na-dependent ASNGLNNaEx Transport, Extracellular 0.00 100000.00 exchange (Asn-L in) Alanine and Aspartate ASNNm L-asparaginase (mitochondrial) 0.00 186.75 Metabolism L-serine/L-asparagine Na-dependent exchange ASNSERNaEx Transport, Extracellular 0.00 100000.00 (Asn-L in) L-threonine/L-asparagine Na-dependent ASNTHRNaEx Transport, Extracellular 0.00 100000.00 exchange (Asn-L in) ASNtm L-asparagine transport, mitochondrial Transport, Mitochondrial 0.00 186.75

ASPCTr aspartate carbamoyltransferase (reversible) Pyrimidine Biosynthesis 0.00 121.33

ASPGLUm aspartate-glutamate mitochondrial shuttle Transport, Mitochondrial -1650.43 1305.08 Alanine and Aspartate ASPTA aspartate transaminase -1650.43 1305.08 Metabolism Alanine and Aspartate ASPTAm aspartate transaminase -1302.58 1650.43 Metabolism ATPS4m ATP synthase (four protons for one ATP) Oxidative Phosphorylation 0.00 1393.92

ATPtm ADP/ATP transporter, mitochondrial Transport, Mitochondrial 0.00 100000.00

BDHm (R)-3-Hydroxybutanoate:NAD+ oxidoreductase Butanoate Metabolism -217.58 10.00 (R)-3-Hydroxybutanoate transport via H+ BHBt Transport, Extracellular -217.58 10.00 symport (R)-3-Hydroxybutanoate mitochondrial transport BHBtm Transport, Mitochondrial -217.58 10.00 via H+ symport BILIRED Nad(p)h biliverdin reductase Heme Degradation 0.00 18.16 bilirubin transport via bicarbonate BILIRUBt2_r Transport, Extracellular 0.00 18.16 countertransport BPNT 3,5-bisphosphate nucleotidase Nucleotides 0.00 242.83

C110CPT2m C110 transport into the mitochondria Fatty Acid Metabolism 0.00 100000.00

C160CPT1 carnitine O-palmitoyltransferase Carnitine shuttle 0.00 50.62

C160CPT2 C160 transport into the mitochondria Carnitine shuttle 0.00 50.62

C160CRNt C160 transport into the mitochondria Carnitine shuttle 0.00 50.62

C204CPT1 carnitine C20:4 transferase Carnitine shuttle 0.00 49.12

C204CPT2 arachidonic acid transport into the mitochondria Carnitine shuttle 0.00 49.12

C204CRNt arachidonic acid transport into the mitochondria Carnitine shuttle 0.00 49.12

CAATPS Ca ATPase Transport, Extracellular 0.00 511.44

CAMPt cAMP transport (ATP-dependent) Transport, Extracellular 0.00 54.19

CATm catalase ROS Detoxification 0.00 299.80

CATp catalase A, peroxisomal Miscellaneous 0.00 299.80

CAt7r calcium / sodium antiporter (1:3), reversible Transport, Extracellular -100000.00 100000.00 carbamoyl-phosphate synthase (glutamine- CBPS Pyrimidine Biosynthesis 0.00 121.33 hydrolysing) carbamoyl-phosphate synthase (ammonia) CBPSam Glutamate metabolism 0.00 151.05 (mitochondria phosphatidylinositol synthase (Homo sapiens, CDIPTr_18_0_20_4 0.00 209.30 C18:0,20:4) CDS_18_0_20_4 phosphatidate cytidylyltransferase (C18:0,C20:4) 0.00 209.30

CEPTC_16_0_18_0 choline phosphotransferase (C16:0, C18:0) 0.00 89.70

Table A1. continued lower upper Abbreviation Name subSystem bound bound CEPTC_16_0_18_1 choline phosphotransferase (C16:0, C18:1) 0.00 89.70

CEPTC_18_0_20_4 choline phosphotransferase (C18:0, C20:4) 0.00 313.95

CEPTE_18_0_20_4 ethanolamine phosphotransferase (C18:0, C20:4) 0.00 313.95

Glycerophospholipid CHLPCTD choline phosphate cytididyltransferase 0.00 313.95 Metabolism CHOLK Choline kinase Glycerophospholipid 0.00 627.59 citrulline mitochondrial transport via proton CITRtm Transport, Mitochondrial -100000.00 100000.00 antiport CITtam_r citrate transport, mitochondrial Transport, Mitochondrial 0.00 1570.76

CITtbm citrate transport, mitochondrial Transport, Mitochondrial 0.00 1568.99

CO2t CO2 transporter via diffusion Transport, Extracellular -598.72 100.00

CO2tm CO2 transport (diffusion), mitochondrial Transport, Mitochondrial -563.37 1381.36

COAtm CoA transporter Transport, Mitochondrial -261.62 627.89

COAtp_r coenzyme A transport, peroxisomal Transport, Peroxisomal 0.00 672.67

COt CO transporter via diffusion Transport, Extracellular 0.00 18.16

CPPPGO coproporphyrinogen oxidase (O2 required) Heme Biosynthesis 0.00 18.16

CRNCARtp carnitine-acetylcarnitine carrier, peroxisomal Transport, Peroxisomal 0.00 672.67 L-carnitine transport out of mitochondria via CRNtim Transport, Mitochondrial 0.00 1046.49 diffusion CRVNCtr fatty acid transport via diffusion Transport, Extracellular -100000.00 100000.00 chondroitin sulfate D proteoglycan protease, Chondroitin sulfate CSDPASEly 0.00 5.00 lysosome (endosome) degradation CSNAT carnitine O-acetyltransferase 0.00 100000.00

carnitine O-acetyltransferase, reverse direction, CSNATp Fatty Acid Metabolism 0.00 672.67 peroxisomal CSNATr carnitine O-acetyltransferase Carnitine shuttle -100000.00 1046.49 chondroitin sulfate D transport, extracellular to CSPG_Dtly Transport, Lysosomal 0.00 5.00 lysosome CSm citrate synthase Citric Acid Cycle 0.00 755.80

CTPS1 CTP synthase (NH3) Nucleotides 0.00 313.80

CYOOm2 cytochrome c oxidase, mitochondrial Complex IV Oxidative Phosphorylation 0.00 99.90

CYOR-u10m ubiquinol-6 cytochrome c reductase, Complex III Oxidative Phosphorylation 0.00 199.80 L-alanine/L-cysteine Na-dependent exchange CYSALANaEx Transport, Extracellular 0.00 100000.00 (Cys-L in) L-cysteine/L-asparagine Na-dependent exchange CYSASNNaEx Transport, Extracellular 0.00 100000.00 (Cys-L in) L-cysteine/L-glutamine Na-dependent exchange CYSGLNNaEx Transport, Extracellular 0.00 100000.00 (Cys-L in) CYSGLYex L-cysteine/glycine exchanger Transport, Extracellular 0.00 100000.00

CYSGLYexR L-cysteine/glycine reversible exchanger Transport, Extracellular -100000.00 100000.00 L-serine/L-cysteine Na-dependent exchange CYSSERNaEx Transport, Extracellular 0.00 100000.00 (Cys-L in) CYSTA cysteine transaminase Cysteine Metabolism 0.00 5.00

CYSTGL cystathionine g-lyase Cysteine Metabolism 0.00 10.00 L-cysteine/L-threonine Na-dependent exchange CYSTHRNaEx Transport, Extracellular 0.00 100000.00 (Cys-L in) CYSTS cystathionine beta-synthase Methionine Metabolism 0.00 10.00

CYTDK1 cytidine kinase (ATP) Nucleotides 0.00 627.59

CYTDt_r cytidine facilated transport in cytosol Transport, Extracellular 0.00 100000.00

Table A1. continued lower upper Abbreviation Name subSystem bound bound CYTK1 cytidylate kinase (CMP) Nucleotides -100000.00 100000.00

CYTK10 cytidylate kinase (CMP,dGTP) Nucleotides -100000.00 100000.00

CYTK11 cytidylate kinase (dCMP,dGTP) Nucleotides -100000.00 100000.00

CYTK12 cytidylate kinase (dCMP,dCTP) Nucleotides -100000.00 100000.00

CYTK13 cytidylate kinase (dCMP,dATP) Nucleotides -100000.00 100000.00

CYTK14 cytidylate kinase (dCMP,UTP) Nucleotides -100000.00 100000.00

CYTK2 cytidylate kinase (dCMP) Nucleotides -100000.00 100000.00

CYTK5 cytidylate kinase (dCMP) Nucleotides -100000.00 100000.00

CYTK6 cytidylate kinase (CMP,CTP) Nucleotides -100000.00 100000.00

CYTK7 cytidylate kinase (CMP,UTP) Nucleotides -100000.00 100000.00

CYTK8 cytidylate kinase (CMP,dATP) Nucleotides -100000.00 100000.00

CYTK9 cytidylate kinase (CMP,dCTP) Nucleotides -100000.00 100000.00

D-LACt2_r D-lactate transport via proton symport Transport, Extracellular 0.00 326.53

DADA Deoxyadenosine deaminase Nucleotides 0.00 188.94

DADAe Deoxyadenosine deaminase, extracellular Nucleotides 0.00 189.15

DADNt4_r deoxyadenosine transport via diffusion Transport, Extracellular 0.00 189.15 Diacylglycerol phosphate kinase (homo DAGK_hs_18_0_20_4 -390.23 209.30 sapiens,C18:0, C20:4) DALAOXx D-Alanine Oxidase (x) D-alanine metabolism 0.00 199.80

DALAxt D-Alanine transport to perixosome D-alanine metabolism 0.00 199.80

DCMPDA dCMP deaminase Pyrimidine Catabolism -627.59 146.56

DCSPTN1COAtx_r fatty acid intracellular transport Transport, Peroxisomal 0.00 45.62

DCSPTN1CPT1 carnitine O-palmitoyltransferase Carnitine shuttle 0.00 27.63

DCSPTN1CPT2 carnitine transferase Carnitine shuttle 0.00 27.63

DCSPTN1CRNt transport into the mitochondria (carnitine) Carnitine shuttle 0.00 27.63

DCSPTN1t_r fatty acid transport via diffusion Transport, Extracellular 0.00 45.62

DCYTt_r deoxycytidine transport via diffusion Transport, Extracellular 0.00 80.92 fatty acyl-CoA desaturase (n-C22:4CoA -> n- DESAT22_1p Fatty acid elongation 0.00 48.51 C22:5CoA) DGK1_r deoxyguanylate kinase (dGMP:ATP) Nucleotides 0.00 157.33 Pentose and Glucuronate DGULND dehydro-L-gulonate decarboxylase 0.00 176.84 Interconversions DHFR dihydrofolate reductase Folate Metabolism 0.00 110.16

DHORD9 dihydoorotic acid dehydrogenase (quinone10) Pyrimidine Biosynthesis 0.00 121.33

DHORTS_r dihydroorotase Pyrimidine Biosynthesis 0.00 121.33

DINt deoxyinosine transport via diffusion Transport, Extracellular -67.00 189.15 2,3-diketo-5-methylthio-1-phosphopentane Arginine and Proline DKMPPD 0.00 65.76 degradation reaction Metabolism DMNONCRNCPT2_r DMNON carnitine transferase 0.00 100000.00

DNDPt1m dATP transport via ADP antiport Transport, Mitochondrial 0.00 71.79

DNDPt39m dUTP transport via dGDP antiport Transport, Mitochondrial 0.00 100000.00

DNDPt47m dTTP transport via dTDP antiport Transport, Mitochondrial 0.00 100000.00

Table A1. continued lower upper Abbreviation Name subSystem bound bound DNDPt60m dGTP transport via dUDP antiport Transport, Mitochondrial 0.00 100000.00

DNDPt62m dGTP transport via dGDP antiport Transport, Mitochondrial 0.00 100000.00 Dolichyl beta-D-glucosyl phosphate flippase DOLGLCP_Lter N-Glycan Biosynthesis 0.00 313.95 (liver) Dolichyl beta-D-glucosyl phosphate flippase DOLGLCP_Uter N-Glycan Biosynthesis 0.00 313.95 (uterus) Dolichyl-beta-D-glucosyl-phosphate DOLGPP_Ler N-Glycan Biosynthesis 0.00 313.95 dolichylphosphohydrolase (liver) Dolichyl-beta-D-glucosyl-phosphate DOLGPP_Uer N-Glycan Biosynthesis 0.00 313.95 dolichylphosphohydrolase (uterus) DOLICHOL_Lter dolichol diffusion, human (liver) N-Glycan Biosynthesis 0.00 209.30

DOLICHOL_Uter dolichol diffusion, human (uterus) N-Glycan Biosynthesis 0.00 209.30

DOLK_L Dolichol kinase, human (liver) N-Glycan Biosynthesis 0.00 209.30

DOLK_U Dolichol kinase, human (uterus) N-Glycan Biosynthesis 0.00 209.30 Dolichol-phosphate phosphohydrolase, human DOLPH_Ler N-Glycan Biosynthesis 0.00 209.30 (liver) Dolichol-phosphate phosphohydrolase, human DOLPH_Uer N-Glycan Biosynthesis 0.00 209.30 (uterus) DOLP_Lter dolichol phosphate flippase (liver) N-Glycan Biosynthesis 0.00 313.95

DOLP_Uter dolichol phosphate flippase (uterus) N-Glycan Biosynthesis 0.00 313.95

DOPABMO dopamine beta-monooxygenase Tyrosine metabolism 0.00 22.00

DOPAMT Dopamine:amet O-methyltransferase Tyrosine metabolism 0.00 22.00

DOPASFt Dopamine 3-0-sulfate transport (diffusion) Transport, Extracellular 0.00 22.00

DOPASULT Dopamine Sulfotransferase Tyrosine metabolism 0.00 22.00 Dopamine secretion via secretory vesicle (ATP DOPAVESSEC Transport, Extracellular 0.00 313.80 driven) DOPAtu Dopamine uniport Transport, Extracellular 0.10 941.49

DPCOAPP pyrophasphatase (dephospho-CoA) CoA Catabolism 0.00 313.95

DPGM Diphosphoglyceromutase Glycolysis/Gluconeogenesis 0.00 627.59

DPGase Diphosphoglycerate phosphatase Glycolysis/Gluconeogenesis 0.00 627.59

DRIBt_r deoxyribose transport via diffusion Transport, Extracellular 0.00 103.27

DURIt_r deoxyuridine transport via diffusion Transport, Extracellular 0.00 74.94

DUTPDPm dUTP diphosphatase Nucleotides 0.00 392.25

ENO enolase Glycolysis/Gluconeogenesis -282.23 416.51

ETF electron transfer flavoprotein Fatty acid oxidation 0.00 199.80 Electron transfer flavoprotein-ubiquinone ETFQO Fatty acid oxidation 0.00 199.80 oxidoreductase Glycerophospholipid ETHAK Ethanolamine kinase 0.00 627.59 Metabolism FA160ACPH fatty-acyl-ACP hydrolase Fatty Acid Metabolism -68.06 436.11

FACOAL160i C160 fatty acid activation Fatty acid activation 0.00 194.58

FACOAL180i C180 fatty acid activation Fatty acid activation 0.00 160.49

FACOAL181i C181 fatty acid activation Fatty acid activation 0.00 125.58

FACOAL191 fatty-acid--CoA ligase Fatty acid activation 0.00 313.95

FACOAL204 fatty-acid--CoA ligase Fatty acid activation -100000.00 156.97

FACOAL204i arachidonic acid activation Fatty acid activation 0.00 100000.00

FACOAL205_r fatty-acid--CoA ligase Fatty acid activation 0.00 39.96

Table A1. continued lower upper Abbreviation Name subSystem bound bound FACOAL224_r fatty-acid--CoA ligase Fatty acid activation 0.00 99.90

FACOAL2251_r fatty-acid--CoA ligase Fatty acid activation 0.00 45.62

FACOAL226_r fatty-acid--CoA ligase Fatty acid activation 0.00 100000.00

FACOAL226i C226 fatty acid activation Fatty acid activation 0.00 100000.00 FAEL204 fatty-acyl-CoA elongation (n-C20:4CoA) Fatty acid elongation 0.00 99.90

FALDH formaldehyde dehydrogenase Tyrosine metabolism -65.76 50.64 formaldehyde transport via diffusion FALDtly Transport, Lysosomal 0.00 149.90 (lysosomall) FAOXC160 Beta oxidation of long chain fatty acid Fatty acid oxidation 0.00 50.62

FAOXC16080m Beta oxidation of long chain fatty acid Fatty acid oxidation 0.00 50.62 Fatty acid oxidation, FAOXC16080x Beta oxidation of long chain fatty acid 0.00 15.89 peroxisome Fatty acid oxidation, FAOXC180x Beta oxidation of long chain fatty acid 0.00 63.58 peroxisome FAOXC183806m Beta oxidation of fatty acid Fatty acid oxidation 0.00 26.38 Fatty acid oxidation, FAOXC183806x Beta oxidation of long chain fatty acid 0.00 10.37 peroxisome FAOXC18480m Beta oxidation of fatty acid Fatty acid oxidation 0.00 31.21 Fatty acid oxidation, FAOXC18480x Beta oxidation of long chain fatty acid 0.00 10.37 peroxisome FAOXC204 Beta oxidation of long chain fatty acid Fatty acid oxidation 0.00 49.12

FAOXC2051843m Beta oxidation of fatty acid Fatty acid oxidation 0.00 31.21 Fatty acid oxidation, FAOXC2051843x Beta oxidation of long chain fatty acid 0.00 10.37 peroxisome Fatty acid oxidation, FAOXC2242046x Beta oxidation of long chain fatty acid 0.00 39.96 peroxisome FAOXC2251836m Beta oxidation of fatty acid Fatty acid oxidation 0.00 26.38 Fatty acid oxidation, FAOXC2251836x Beta oxidation of long chain fatty acid 0.00 10.37 peroxisome FAOXC2252053m Beta oxidation of long chain fatty acid Fatty acid oxidation 0.00 27.63 Fatty acid oxidation, FAOXC2252053x Beta oxidation of long chain fatty acid 0.00 39.96 peroxisome FAOXC80 Beta oxidation of med/long chain fatty acid Fatty acid oxidation 0.00 93.18

FAS100COA fatty acyl-CoA synthase (n-C10:0CoA) Fatty acid elongation 0.00 58.38

FAS120COA fatty-acyl-CoA synthase (n-C12:0CoA) Fatty acid elongation 0.00 58.38

FAS140COA fatty-acyl-CoA synthase (n-C14:0CoA) Fatty acid elongation 0.00 58.38

FAS160COA fatty-acyl-CoA synthase (n-C16:0CoA) Fatty acid elongation 0.00 56.31

FAS180COA fatty-acyl-CoA synthase (n-C18:0CoA) Fatty acid elongation 0.00 121.59 fatty acyl-CoA synthase (n-C8:0CoA), lumped FAS80COA_L Fatty acid elongation 0.00 93.18 reaction FATP1t fatty acid electroneutral transport Transport, Extracellular -100000.00 100000.00

FATP2t fatty acid electroneutral transport Transport, Extracellular -100000.00 100000.00

FATP3t fatty acid electroneutral transport Transport, Extracellular -100000.00 100000.00

FATP6t fatty acid electroneutral transport Transport, Extracellular -100000.00 100000.00

FATP7t fatty acid electroneutral transport Transport, Extracellular -100000.00 100000.00

FATP8t fatty acid electroneutral transport Transport, Extracellular -100000.00 100000.00

FATP9t fatty acid electroneutral transport Transport, Extracellular -100000.00 100000.00

FBA fructose-bisphosphate aldolase Glycolysis/Gluconeogenesis -312.13 52.49

Table A1. continued lower upper Abbreviation Name subSystem bound bound FBP fructose-bisphosphatase Glycolysis/Gluconeogenesis 0.00 627.59 Fructose and Mannose FBP26 Fructose-2,6-bisphosphate 2-phosphatase 0.00 627.59 Metabolism FCLTm Ferrochelatase, mitochondrial Heme Biosynthesis 0.00 18.16

FE2tm iron (II) transport Transport, Mitochondrial 0.00 18.16

FKYNH N-Formyl-L-kynurenine amidohydrolase Tryptophan metabolism 0.00 10.00

FRUt1r D-fructose transport in via uniport Transport, Extracellular -100000.00 100000.00

FTHFDH formyltetrahydrofolate dehydrogenase Folate Metabolism 0.00 154.15

FTHFL formate-tetrahydrofolate ligase Folate Metabolism 0.00 61.37

FUM fumarase Citric Acid Cycle -100000.00 100000.00

FUMm fumarase, mitochondrial Citric Acid Cycle -100000.00 100000.00

FUMtm fumarate transport, mitochondrial Transport, Mitochondrial -100000.00 100000.00 Glycerophospholipid G3PD1 glycerol-3-phosphate dehydrogenase (NAD) -369.14 302.53 Metabolism glycerol-3-phosphate dehydrogenase (FAD), G3PD2m Glycolysis/Gluconeogenesis 0.00 482.10 mitochondrial L-glutamate 5-semialdehyde dehydratase, Arginine and Proline G5SADrm 0.00 830.68 reversible, mitochondrial Metabolism G6PDA glucosamine-6-phosphate deaminase Aminosugar Metabolism 0.00 627.59

G6PDH2r glucose 6-phosphate dehydrogenase Pentose Phosphate Pathway 0.00 214.15 glucose-6-phosphate phosphatase, edoplasmic G6PPer Glycolysis/Gluconeogenesis 0.00 627.59 reticular glucose 6-phosphate endoplasmic reticular Transport, Endoplasmic G6Pter 0.00 627.59 transport via diffusion Reticular GABAVESSEC GABA secretion via secretory vesicle (ATP driven) Transport, Extracellular 0.00 627.59

GALK galactokinase Galactose metabolism 0.10 25.94

GALT galactose-1-phosphate uridylyltransferase Galactose metabolism -99999.90 100000.00

GALU UTP-glucose-1-phosphate uridylyltransferase Galactose metabolism -100000.00 100000.00

GALt1r galactose transport (uniport) Transport, Extracellular 0.10 2.00

GALtly galactose efflux from lysosome Transport, Lysosomal 0.00 23.94

GAPD glyceraldehyde-3-phosphate dehydrogenase Glycolysis/Gluconeogenesis -206.14 315.53

GCHOLAt3 ABC bile acid transporter Transport, Extracellular 0.00 627.59

GCHOLAte bile acid intracellular transport Transport, Extracellular -100000.00 100000.00

GF6PTA glutamine-fructose-6-phosphate transaminase Aminosugar Metabolism 0.00 627.59 Starch and Sucrose GGNG glycogenin self-glucosylation 0.00 33.05 Metabolism GGT5r Gamma-glutamyltransferase 5 Eicosanoid Metabolism 0.00 10.00

GGT6 Gamma-glutamyltransferase Eicosanoid Metabolism 0.00 10.00 Glycine, Serine, and GHMT2r glycine hydroxymethyltransferase, reversible -122.12 184.78 Threonine Metabolism GK1 guanylate kinase (GMP:ATP) Nucleotides 0.00 313.95 D-glucurono-6,3-lactone transport, endoplasmic Transport, Endoplasmic GLACter_r 0.00 100000.00 reticulum Reticular 1,4-alpha-glucan branching enzyme (glygn1 -> Starch and Sucrose GLBRAN 0.00 33.05 glygn2) Metabolism GLCAASE1ly beta-glucuronidase, lysosomal Heparan sulfate degradation 0.00 7.86 Chondroitin sulfate GLCAASE6ly beta-glucuronidase, lysosomal 0.00 5.00 degradation GLCAASE8ly beta-glucuronidase, lysosomal Hyaluronan Metabolism 0.00 57.07

Table A1. continued lower upper Abbreviation Name subSystem bound bound GLCAASE9ly beta-glucuronidase, lysosomal Hyaluronan Metabolism 0.00 57.07

GLCMter glucose transport via membrane vesicle Transport, Extracellular 0.00 99999.90

GLCNACASE1ly alpha-N-acetylglucosaminidase, lysosomal Heparan sulfate degradation 0.00 7.86

GLCNACASE2ly alpha-N-acetylglucosaminidase, lysosomal Heparan sulfate degradation 0.00 7.86

GLCNACASE3ly alpha-N-acetylglucosaminidase, lysosomal Heparan sulfate degradation 0.00 7.86

GLCNACASE4ly alpha-N-acetylglucosaminidase, lysosomal Heparan sulfate degradation 0.00 7.86

GLCNACASE5ly alpha-N-acetylglucosaminidase, lysosomal Heparan sulfate degradation 0.00 7.86 Transport, Endoplasmic GLCURter glucuronate endoplasmic reticular transport 0.00 176.84 Reticular GLCURtly_r glucuronate transport into lysososme Transport, Lysosomal 0.00 136.69

GLCt1r glucose transport (uniport) Transport, Extracellular 0.10 100000.00 Transport, Endoplasmic GLCter glucose transport, endoplasmic reticulum -627.59 99999.90 Reticular Starch and Sucrose GLDBRAN glycogen debranching enzyme 0.00 33.05 Metabolism Starch and Sucrose GLGNS1 glycogen synthase (ggn -> glygn1) 0.00 33.05 Metabolism L-alanine/L-glutamine Na-dependent exchange GLNALANaEx Transport, Extracellular 0.00 100000.00 (Gln-L in) L-glutamine/L-asparagine Na-dependent GLNASNNaEx Transport, Extracellular 0.00 100000.00 exchange (Gln-L in) L-cysteine/L-glutamine Na-dependent exchange GLNCYSNaEx Transport, Extracellular 0.00 100000.00 (Gln-L in) Ascorbate and Aldarate GLNLASEer_r gluconolactonase, endoplasmic reticulum 0.00 100000.00 Metabolism GLNS glutamine synthetase Glutamate metabolism 0.00 644.76 L-serine/L-glutamine Na-dependent exchange GLNSERNaEx Transport, Extracellular 0.00 100000.00 (Gln-L in) L-threonine/L-glutamine Na-dependent GLNTHRNaEx Transport, Extracellular 0.00 100000.00 exchange (Gln-L in) L-glutamine transport via electroneutral GLNtm Transport, Mitochondrial 0.00 363.00 transporter Starch and Sucrose GLPASE1 glycogen phosphorylase (glygn2 -> dxtrn) 0.00 33.05 Metabolism Starch and Sucrose GLPASE2 glycogen phosphorylase (amyls -> glc-D) 0.00 33.05 Metabolism Ascorbate and Aldarate GLRASE_r glucuronolactone reductase 0.00 100000.00 Metabolism GLUCYS gamma-glutamylcysteine synthetase Glutathione Metabolism 0.00 224.13

GLUDC Glutamate Decarboxylase Glutamate metabolism 0.00 214.21

GLUDxm glutamate dehydrogenase (NAD) (mitochondrial) Glutamate metabolism -413.58 126.69

GLUNm glutaminase (mitochondrial) Glutamate metabolism 0.00 363.00 L-glutamate reversible transport via proton GLUt2m Transport, Mitochondrial -799.14 100000.00 symport, mitochondrial Glutamate transport via Na, H symport and K GLUt6 Transport, Extracellular 0.10 629.59 antiport Transport, Endoplasmic GLUtr_r intracellular transport 0.00 10.00 Reticular GLYC-St L-glycerate export Transport, Extracellular 0.00 151.44 Glyoxylate and Dicarboxylate GLYCK2 glycerate kinase 0.00 199.80 Metabolism GLYCt glycerol transport via channel Transport, Extracellular -10.00 160.40 Glycerophospholipid GLYK glycerol kinase 0.00 311.09 Metabolism GLYOX hydroxyacylglutathione hydrolase Pyruvate Metabolism 0.00 276.73

Table A1. continued lower upper Abbreviation Name subSystem bound bound Glycine, Serine, and GLYOp glycine oxidase, perixosomal 0.00 199.80 Threonine Metabolism Glycine secretion via secretory vesicle (ATP GLYVESSEC Transport, Extracellular 0.00 627.59 driven) GLYtm glycine passive transport to mitochondria Transport, Mitochondrial -189.51 189.48

GND phosphogluconate dehydrogenase Pentose Phosphate Pathway 0.00 214.15

GPAM_hs_16_0 glycerol-3-phosphate acyltransferase (C16:0) 0.00 125.58

GPAM_hs_18_0 glycerol-3-phosphate acyltransferase (C18:0) 0.00 156.97

Glycerophosphodiester phosphodiesterase Glycerophospholipid GPDDA1 0.00 301.09 (Glycerophosphocholine) Metabolism Glutathione dehydrogenase (dehydroascorbate Ascorbate and Aldarate GTHDH 0.00 199.80 reductase) Metabolism GTHO glutathione oxidoreductase Glutamate metabolism 0.00 149.90

GTHOm glutathione oxidoreductase Glutamate metabolism 0.00 149.90

GTHP glutathione peroxidase Glutathione Metabolism -199.80 100.00

GTHPm glutathione peroxidase, mitochondria Glutathione Metabolism 0.00 149.90 Transport, Endoplasmic GTHRDtr glutathione transport via diffusion 0.00 10.00 Reticular GTHS glutathione synthetase Glutathione Metabolism 0.00 224.13

GTMLTe g-glutamyltransferase (e) Glutathione Metabolism 0.00 224.11

GUACYC guanylate cyclase Nucleotides 0.00 313.95

GUAPRT guanine phosphoribosyltransferase Salvage Pathway 0.00 313.95 Transport, Endoplasmic GULLACter gulonolactone endoplasmic reticular transport 0.00 100000.00 Reticular Pentose and Glucuronate GULN3D L-gulonate 3-dehydrogenase 0.00 176.84 Interconversions Pentose and Glucuronate GULNDer gulonate dehydrogenase, endoplasmic reticulum -100000.00 176.84 Interconversions Transport, Endoplasmic GULNter L-gulonate endoplasmic reticular export 0.00 176.84 Reticular Pentose and Glucuronate GUR1PP Glucuronate 1-phosphate phosphatase 0.00 131.24 Interconversions H2CO3D carboxylic acid dissociation Miscellaneous 0.00 666.50

H2CO3D2_r carboxylic acid dissociation Miscellaneous 0.00 666.50

H2O2t hydrogen peroxide transport via diffusion Transport, Extracellular -149.90 199.80 hydrogen peroxide lysosomal transport via H2O2tly Transport, Lysosomal 0.00 149.90 diffusion H2O2tm hydrogen peroxide mitochondrial transport Transport, Mitochondrial -199.80 599.60 hydrogen peroxide peroxisomal transport via H2O2tp Transport, Peroxisomal -199.80 599.60 diffusion Transport, Endoplasmic H2Oter H2O endoplasmic reticulum transport -199.80 627.79 Reticular H2Otly H2O transport, lysosomal Transport, Lysosomal -299.80 656.35

H2Otp H2O transport, peroxisomal Transport, Peroxisomal -599.60 325.48

HAS1 hyaluronan synthase Hyaluronan Metabolism 0.00 65.62

HAS2 hyaluronan synthase Hyaluronan Metabolism 0.00 57.07

HAtly hyaluronan transport, extracellular to lysosome Transport, Lysosomal 0.00 57.07 Urea cycle/amino group HCO3Em HCO3 equilibration reaction -100000.00 100000.00 metabolism HCO3_CLt bicarbonate transport (Cl-/HCO3- exchange) Transport, Extracellular -100000.00 100000.00

HCO3_NAt bicarbonate transport (Na/HCO3 cotransport) Transport, Extracellular -100000.00 100000.00

HDCAtr fatty acid transport via diffusion Transport, Extracellular -100000.00 100000.00

Table A1. continued lower upper Abbreviation Name subSystem bound bound HEX1 hexokinase (D-glucose:ATP) Glycolysis/Gluconeogenesis 0.00 629.59 Fructose and Mannose HEX7 hexokinase (D-fructose:ATP) 0.00 629.59 Metabolism HKYNH 3-Hydroxy-L-kynurenine hydrolase Tryptophan metabolism 0.00 10.00

HMBS hydroxymethylbilane synthase Heme Biosynthesis 0.00 18.16

HMGCOASi Hydroxymethylglutaryl CoA synthase (ir) Cholesterol Metabolism 0.00 313.95 Hydroxymethylglutaryl-CoA reversible HMGCOAtm Transport, Mitochondrial -627.89 261.62 mitochondrial transport Hydroxymethylglutaryl-CoA reversible HMGCOAtx Transport, Peroxisomal 0.00 672.67 peroxisomal transport HMGLm hydroxymethylglutaryl-CoA lyase Cholesterol Metabolism 0.00 784.49

HMGLx hydroxymethylglutaryl-CoA lyase Cholesterol Metabolism 0.00 672.67

HOXG Heme oxygenase 1 Heme Degradation 0.00 18.16

HPACtr hydroxyphenylacetate transport via diffusion Transport, Extracellular 0.00 22.00

HPETOX 12-HPET oxidoreductase 0.00 195.29 Glyoxylate and Dicarboxylate HPYRR2x hydroxypyruvate reductase (NADH) 0.00 151.44 Metabolism Glyoxylate and Dicarboxylate HPYRRy Hydroxypyruvate reductase (NADPH) 0.00 199.80 Metabolism HPYRtp_r hydroxypyruate transport, peroxisomal Transport, Peroxisomal 0.00 199.80

HS1ly heparan-N-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

HS2ly heparan-N-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

HS3ly heparan-N-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

HS4ly heparan-N-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86 heparan-glucosaminide N-acetyltransferase, HSAT1ly Heparan sulfate degradation 0.00 7.86 lysosomal heparan-glucosaminide N-acetyltransferase, HSAT2ly Heparan sulfate degradation 0.00 7.86 lysosomal heparan-glucosaminide N-acetyltransferase, HSAT3ly Heparan sulfate degradation 0.00 7.86 lysosomal heparan-glucosaminide N-acetyltransferase, HSAT4ly Heparan sulfate degradation 0.00 7.86 lysosomal heparan sulfate proteoglycan protease, HSPASEly Heparan sulfate degradation 0.00 7.86 lysosome (endosome) heparan sulfate transport, extracellular to HSPGtly Transport, Lysosomal 0.00 7.86 lysosome HXANtx hypoxanthine diffusion in peroxisome Transport, Peroxisomal 0.00 54.65 hypoxanthine phosphoribosyltransferase HXPRT Salvage Pathway 0.00 313.95 (Hypoxanthine) HYXNt_r Hypoxanthine transport Transport, Extracellular 0.00 89.69 Transport, Endoplasmic Htr H transporter, endoplasmic reticulum -627.79 100000.00 Reticular Htx H transporter, peroxisome Transport, Peroxisomal -313.95 399.60

ICDHy isocitrate dehydrogenase (NADP) Citric Acid Cycle 0.00 1391.39

ICDHyrm Isocitrate dehydrogenase (NADP+) Citric Acid Cycle -100000.00 443.30

IDOAASE1ly alpha-L-iduronidase, lysosomal Heparan sulfate degradation 0.00 7.86

IDOAASE2ly alpha-L-iduronidase, lysosomal Heparan sulfate degradation 0.00 7.86

IDOAASE3ly alpha-L-iduronidase, lysosomal Heparan sulfate degradation 0.00 7.86 Valine, Leucine, and ILETA isoleucine transaminase 0.00 100000.00 Isoleucine Metabolism Valine, Leucine, and ILETAm_r isoleucine transaminase, mitochondrial 0.00 100000.00 Isoleucine Metabolism

Table A1. continued lower upper Abbreviation Name subSystem bound bound ILEt5m_r Isoleucine mitochondrial transport Transport, Mitochondrial 0.00 100000.00

INSt Inosine transport (diffusion) Transport, Extracellular -100000.00 189.15

KAS8 b-ketoacyl synthetase (palmitate, n-C16:0) Fatty acid elongation 0.00 63.90

KCC2t K+-Cl- cotransporter (NH4+) Transport, Extracellular -100000.00 100000.00

KCCt K+-Cl- cotransport Transport, Extracellular -100000.00 100000.00 2-keto-3deoxy-D-glycero-D-galactononic acid KDNH Aminosugar Metabolism 0.00 68.57 phosphohydrolase KYN3OX kynurenine 3-monooxygenase Tryptophan metabolism 0.00 10.00 L-Lactate dehydrogenase, L-LACDcm Pyruvate Metabolism 0.00 199.80 cytosolic/mitochondrial L-LACt2r_r L-lactate reversible transport via proton symport Transport, Extracellular 0.00 1526.25

L-LACt4r L-lactate reversible transport via sodium symport Transport, Extracellular 0.00 1526.25 L-lactate transport via diffusion (cytosol to L-LACtcm Transport, Mitochondrial 0.00 1735.09 mitochondria) LALDO2 D-Lactaldehyde:NADP+ 1-oxidoreductase Pyruvate Metabolism 0.00 276.73

LALDO2x D-Lactaldehyde:NAD+ 1-oxidoreductase Pyruvate Metabolism 0.00 276.73

LCADi lactaldehyde dehydrogenase Pyruvate Metabolism 0.00 276.73

LCADi_D lactaldehyde dehydrogenase Pyruvate Metabolism 0.00 276.73

LDH_L L-lactate dehydrogenase Glycolysis/Gluconeogenesis -1735.09 198.83

LDH_Lm L-lactate dehydrogenase Pyruvate Metabolism 0.00 1735.09 leukotriene A4 transmembrane (homo sapiens) LEUKTRA4t -99.90 10.00 transport Transport, Endoplasmic LEUKTRA4tr leukotriene intracellular transport 0.00 10.00 Reticular leukotriene B4 transmembrane (homo sapiens) LEUKTRB4t_r 0.00 109.90 transport leukotriene D4 transmembrane (homo sapiens) LEUKTRD4t_r 0.00 10.00 transport Transport, Endoplasmic LEUKTRD4tr_r leukotriene intracellular transport 0.00 10.00 Reticular leukotriene E4 transmembrane (homo sapiens) LEUKTRE4t_r 0.00 10.00 transport leukotrieneF4 transmembrane (homo sapiens) LEUKTRF4t_r 0.00 10.00 transport Valine, Leucine, and LEUTA leucine transaminase 0.00 100000.00 Isoleucine Metabolism Valine, Leucine, and LEUTAm leucine transaminase, mitochondrial -100000.00 100.00 Isoleucine Metabolism LEUt4 L-leucine transport in via sodium symport Transport, Extracellular 0.00 100000.00

LEUt5m leucine mitochondrial transport Transport, Mitochondrial -100000.00 100.00

LGNCt fatty acid transport via diffusion Transport, Extracellular -100000.00 100000.00

LGTHL lactoylglutathione lyase Pyruvate Metabolism 0.00 276.73 degradation of proteoglycan linkage region, LINKDEG1ly Heparan sulfate degradation 0.00 7.86 lysosomal degradation of proteoglycan linkage region, Chondroitin sulfate LINKDEG3ly 0.00 5.00 lysosomal degradation LPASE_16_0 lysophospholipase (C16:0) 0.00 89.70

LPASE_18_0 lysophospholipase (C18:0) 0.00 301.09

LPS2_hs_16_0_18_0 lipase (homo sapiensC16:0, C18:0) 0.00 125.58

LPS2_hs_16_0_18_1 lipase (homo sapiensC16:0, C18:1) 0.00 125.58

LPS2_hs_18_0_20_4 lipase (homo sapiens C18:0, C20:4) 0.00 301.09

LPS3_hs_18_0 lipase(homo sapiens C18:0) 0.00 125.58

Table A1. continued lower upper Abbreviation Name subSystem bound bound LPS3_hs_18_1 lipase(homo sapiens C18:1) 0.00 125.58

LPS3_hs_20_4 lipase(homo sapiens C20:4) 0.00 301.09

LSOProd Lumped superoxide production 0.00 399.60

LTA4H Leukotriene A-4 hydrolase Eicosanoid Metabolism 0.00 109.90

LTC4Sr Leukotriene C4 synthase Eicosanoid Metabolism 0.00 10.00

LTD4DP Leukotriene D4 dipeptidase Eicosanoid Metabolism 0.00 10.00

MALtm malate transport, mitochondrial Transport, Mitochondrial -100000.00 100000.00 Fructose and Mannose MAN6PI_r mannose-6-phosphate isomerase 0.00 68.57 Metabolism MCITS 2-methylcitrate synthase Propanoate Metabolism 0.00 10.00

MCLACCYSR 3-mercaptolactate:cysteine reductase Cysteine Metabolism 0.00 5.00

MCLOR_r 3-Mercaptolactate:NAD+ oxidoreductase Cysteine Metabolism 0.00 5.00

MDH malate dehydrogenase Citric Acid Cycle -1305.08 1649.66

MDHm malate dehydrogenase, mitochondrial Citric Acid Cycle -1699.73 1241.86 5-Methylthio-5-deoxy-D-ribulose 1-phosphate Arginine and Proline MDRPD 0.00 65.76 dehydratase Metabolism ME1m malic enzyme (NAD), mitochondrial Pyruvate Metabolism 0.00 784.49

ME2m malic enzyme (NADP), mitochondrial Pyruvate Metabolism 0.00 784.49

MEOHt2_r Methanol diffusion Transport, Extracellular 0.00 66.33

MEOHtly Methanol transporter, lysosome Transport, Lysosomal 0.00 149.90 3-mercaptolactate-cysteine disulfide transport, MERCPLACCYSt Transport, Extracellular 0.00 5.00 extracellular METAT methionine adenosyltransferase Methionine Metabolism 0.10 196.13

METLEUex Methionine/Leucine exchange (Met in) Transport, Extracellular 0.00 100000.00

MGSA methylglyoxal synthase Pyruvate Metabolism 0.00 296.54

MGSA2 methyglyoxylate synthase 2 (from g3p) Pyruvate Metabolism 0.00 296.54 Inositol Phosphate MI1345PP inositol-1,3,4,5-trisphosphate 5-phosphatase 0.00 104.65 Metabolism Inositol Phosphate MI134P4P inositol-1,3,4-trisphosphate 4-phosphatase 0.00 104.65 Metabolism Inositol Phosphate MI13PP inositol-1,3-bisphosphate 3-phosphatase 0.00 104.65 Metabolism Inositol Phosphate MI145PK inositol-1,4,5-trisphosphate 3-kinase 0.00 104.65 Metabolism Inositol Phosphate MI145PP inositol-1,4,5-trisphosphate 5-phosphatase 0.00 125.58 Metabolism Inositol Phosphate MI14P4P inositol-1,4-bisphosphate 4-phosphatase 0.00 156.97 Metabolism Inositol Phosphate MI1PP myo-inositol 1-phosphatase 0.00 209.30 Metabolism Arginine and Proline MTAP 5-methylthioadenosine phosphorylase 0.00 65.76 Metabolism MTHFC methenyltetrahydrofolate cyclohydrolase Folate Metabolism -242.51 179.00 methylenetetrahydrofolate dehydrogenase MTHFD Folate Metabolism -100000.00 100000.00 (NADP) methylenetetrahydrofolate dehydrogenase MTHFD2m Folate Metabolism -100000.00 833.04 (NAD), mitochondrial methylenetetrahydrofolate dehydrogenase MTHFDm Folate Metabolism -782.99 100000.00 (NADP), mitochondrial MTHGXLt Methylglyoxal transport (cytosol to extracellular) Transport, Extracellular 0.00 289.03 Arginine and Proline MTRI 5-methylthioribose-1-phosphate isomerase 0.00 65.76 Metabolism NACHEX27ly beta-N-acetylhexosaminidase, lysosomal Hyaluronan Metabolism 0.00 57.07

Table A1. continued lower upper Abbreviation Name subSystem bound bound Chondroitin sulfate NACHEX6ly beta-N-acetylhexosaminidase, lysosomal 0.00 5.00 degradation Chondroitin sulfate NACHEX7ly beta-N-acetylhexosaminidase, lysosomal 0.00 5.00 degradation NADH2-u10m NADH dehydrogenase, mitochondrial Oxidative Phosphorylation 0.00 199.80

NADHtpu NADH transporter, peroxisome Transport, Peroxisomal 0.00 100000.00

NADN NAD nucleosidase NAD Metabolism 0.00 209.30 Transport, Endoplasmic NADPHtru NADPH transporter, endoplasmic reticulum 0.00 100000.00 Reticular Transport, Endoplasmic NADPtru NADP transporter, endoplasmic reticulum 0.00 100000.00 Reticular NADS2 NAD synthase (glutamine-hydrolysing) NAD Metabolism 0.00 10.00

NADtpu NAD transporter, peroxisome Transport, Peroxisomal 0.00 100000.00

NAt5 sodium/ammonium proton antiporter Transport, Extracellular -100000.00 100000.00

NDP6 nucleoside-diphosphatase (dCDP) Nucleotides 0.00 627.59

NDP8 nucleoside-diphosphatase (dUDP) Nucleotides 0.00 149.51

NDPK1 nucleoside-diphosphate kinase (ATP:GDP) Nucleotides -100000.00 100000.00

NDPK2 nucleoside-diphosphate kinase (ATP:UDP) Nucleotides -100000.00 100000.00

NDPK3 nucleoside-diphosphate kinase (ATP:CDP) Nucleotides -100000.00 100000.00

NDPK4 nucleoside-diphosphate kinase (ATP:dTDP) Nucleotides 0.00 100000.00 nucleoside-diphosphate kinase (ATP:dTDP), NDPK4m Nucleotides -100000.00 68.10 mitochondrial NDPK5 nucleoside-diphosphate kinase (ATP:dGDP) Nucleotides -100000.00 100000.00 nucleoside-diphosphate kinase (ATP:dGDP), NDPK5m Nucleotides -100000.00 49.22 mitochondrial NDPK6 nucleoside-diphosphate kinase (ATP:dUDP) Nucleotides 0.00 100000.00 nucleoside-diphosphate kinase (ATP:dUDP), NDPK6m Nucleotides -100000.00 392.25 mitochondrial NDPK7 nucleoside-diphosphate kinase (ATP:dCDP) Nucleotides -100000.00 100000.00

NDPK8 nucleoside-diphosphate kinase (ATP:dADP) Nucleotides -100000.00 100000.00

NDPK9 nucleoside-diphosphate kinase (ATP:IDP) Nucleotides 0.00 10.00

NH4tp_r ammonia peroxisomal transport Transport, Peroxisomal 0.00 199.80

NKCC2t Na+-K+-Cl- cotransport (NH4+) Transport, Extracellular -100000.00 100000.00

NKCCt Na+-K+-Cl- cotransport Transport, Extracellular -100000.00 100000.00

NNATr nicotinate-nucleotide adenylyltransferase NAD Metabolism -100000.00 313.95 nicotinate-nucleotide diphosphorylase NNDPR NAD Metabolism 0.00 10.00 (carboxylating) NNMT Nicotinamide N-methyltransferase NAD Metabolism 0.00 10.00 Arginine and Proline NOS1 Nitric Oxide Synthase (intermediate forming) 0.00 49.95 Metabolism Arginine and Proline NOS2 Nitric Oxide Synthase (NO forming) 0.00 24.98 Metabolism NOt_r NO transport (diffusion) Transport, Extracellular 0.00 49.95

NRPPHRSFt norepinephrine sulfate transport (diffusion) Transport, Extracellular 0.00 24.00

NRPPHRSULT Norepinephrine Sulfotransferase Tyrosine metabolism 0.00 24.00 Noradrenaline secretion via secretory vesicle NRPPHRVESSEC Transport, Extracellular 0.00 313.80 (ATP driven) NRPPHRtu Norepinephrine uniport Transport, Extracellular 0.10 941.49

NRVNCt fatty acid transport via diffusion Transport, Extracellular -100000.00 100000.00

Table A1. continued lower upper Abbreviation Name subSystem bound bound NTD1 5-nucleotidase (dUMP) Pyrimidine Catabolism 0.00 627.59

NTD11 5-nucleotidase (IMP) Purine Catabolism 0.00 315.35

NTD2 5-nucleotidase (UMP) Pyrimidine Catabolism 0.00 627.59

NTD3 5-nucleotidase (dCMP) Pyrimidine Catabolism 0.00 627.59

NTD4 5-nucleotidase (CMP) Pyrimidine Catabolism 0.00 627.59

NTD5 5-nucleotidase (dTMP) Pyrimidine Catabolism 0.00 627.59

NTD8 5-nucleotidase (dGMP) Nucleotides 0.00 157.33

NTD9 5-nucleotidase (GMP) Nucleotides 0.00 313.95

NaKt Na+/K+ exchanging ATPase Transport, Extracellular 0.00 627.59 superoxide anion transport via diffusion O2St Transport, Extracellular 0.00 399.60 (extracellular) superoxide anion transport via diffusion O2Stm_r Transport, Mitochondrial 0.00 399.60 (mitochondria) superoxide anion transport via diffusion O2Stx Transport, Peroxisomal 0.00 399.60 (peroxisome) O2t o2 transport (diffusion) Transport, Extracellular 0.10 299.80 Transport, Endoplasmic O2ter O2 transport, endoplasmic reticulum 0.00 99.90 Reticular O2tm O2 transport (diffusion) Transport, Mitochondrial -100.00 399.60

O2tp O2 transport, peroxisomal Transport, Peroxisomal -299.80 199.80 Glycine, Serine, and OBDHc 2-Oxobutanoate dehydrogenase, cytosolic 0.00 10.00 Threonine Metabolism Urea cycle/amino group OCBTm ornithine carbamoyltransferase, irreversible 0.00 151.05 metabolism OCCOAtm Octanoyl-CoA transport, diffusion Transport, Mitochondrial 0.00 93.18

OCCOAtx_r fatty acid intracellular transport Transport, Peroxisomal 0.00 15.89

OCDCAtr fatty acid transport via diffusion Transport, Extracellular -100000.00 100000.00

OCDCEAtr fatty acid transport via diffusion Transport, Extracellular -100000.00 100000.00 Valine, Leucine, and OCOAT1m 3-oxoacid CoA-transferase -588.55 728.07 Isoleucine Metabolism OMPDC orotidine-5-phosphate decarboxylase Pyrimidine Biosynthesis 0.00 121.33 Urea cycle/amino group ORNDC Ornithine Decarboxylase 0.00 130.69 metabolism Urea cycle/amino group ORNTArm ornithine transaminase reversible (m) -125.85 12.00 metabolism ornithine mitochondrial transport via proton ORNt3m Transport, Mitochondrial -100000.00 100000.00 antiport ornithine mitochondrial transport exchange with ORNt4m Transport, Mitochondrial -100000.00 100000.00 citruline ornithine transport via diffusion (extracellular to ORNtiDF Transport, Extracellular 0.00 10.00 cytosol) ORPT_r orotate phosphoribosyltransferase Pyrimidine Biosynthesis 0.00 121.33 1-pyrroline-5-carboxylate dehydrogenase, P5CDm Glutamate metabolism 0.00 784.49 mitochondrial Arginine and Proline P5CRxm pyrroline-5-carboxylate reductase (m) 0.00 100000.00 Metabolism PACCOAL phenylacetate-CoA ligase Phenylalanine metabolism 0.00 10.00 choline phosphatase (homo sapiens C18:0, PCHOLP_18_0_20_4 0.00 390.23 C20:4) PCm pyruvate carboxylase Pyruvate Metabolism 0.00 1609.91

PDE1 3,5-cyclic-nucleotide phosphodiesterase Nucleotides 0.00 313.95

PDE4 3,5-cyclic-nucleotide phosphodiesterase Nucleotides 0.00 313.95

PDHm pyruvate dehydrogenase Glycolysis/Gluconeogenesis 0.00 516.34

Table A1. continued lower upper Abbreviation Name subSystem bound bound PEAMNO Phenethylamine oxidase Phenylalanine metabolism 0.00 10.00

PEFLIP phosphatidylethanolamine flippase Transport, Extracellular 0.00 627.59

PEFLIPm phosphatidylethanolamine flippase Transport, Mitochondrial 0.00 627.59

PEPCKm Phosphoenolpyruvate carboxykinase (GTP) Glycolysis/Gluconeogenesis 0.00 1568.99 Glycerophospholipid PETHCT phosphoethanolamine cytidyltransferase 0.00 313.95 Metabolism PE_HStm_r phosphatidylethanolamine scramblase Transport, Mitochondrial 0.00 627.59 phosphatidylethanolamin (homo sapiens) PEt_r 0.00 627.59 transport PFK phosphofructokinase Glycolysis/Gluconeogenesis 0.00 632.93 Fructose and Mannose PFK26 6-phosphofructo-2-kinase 0.00 627.59 Metabolism Glycine, Serine, and PGCD phosphoglycerate dehydrogenase 0.00 308.01 Threonine Metabolism PGDI Prostaglandin-H2 D-isomerase [Precursor] Eicosanoid Metabolism 0.00 49.95

PGI glucose-6-phosphate isomerase Glycolysis/Gluconeogenesis -625.59 4.00

PGK phosphoglycerate kinase Glycolysis/Gluconeogenesis -315.53 546.22

PGL 6-phosphogluconolactonase Pentose Phosphate Pathway 0.00 214.15

PGM phosphoglycerate mutase Glycolysis/Gluconeogenesis -315.53 282.23

PGMT phosphoglucomutase Glycolysis/Gluconeogenesis -311.95 2.00

PGS_COX Prostaglandin G/H synthase (Cyclooxygenase) 0.00 49.95

PGS_PO Prostaglandin G/H synthase (peroxidase) 0.00 49.95

PGSr Prostaglandin G/H synthase Eicosanoid Metabolism 0.00 49.95 Phenylacetyl-CoA:L-glutamine alpha-N- PHACCOAGLNAC Phenylalanine metabolism 0.00 10.00 phenylacetyltransferase L-1-pyrroline-3-hydroxy-5-carboxylate Arginine and Proline PHCDm 0.00 100000.00 dehydrogenase Metabolism L-1-Pyrroline-3-hydroxy-5-carboxylate Arginine and Proline PHCHGSm_r spontaneous conversion to L-4- 0.00 100000.00 Metabolism Hydroxyglutamate semialdehyde, mitochondrial PHEACGLNt PHEACGLN extracellular transport via diffusion Transport, Extracellular 0.00 10.00

PHEMEtm Heme transport to cytosol Transport, Mitochondrial 0.00 18.16

PHEt4 L-phenylalanine transport in via sodium symport Transport, Extracellular 0.00 100000.00

PHYCBOXL L-Phenylalanine carboxy-lyase Phenylalanine metabolism 0.00 10.00 phosphatidylinositol-3,4,5-trisphosphate 3- Inositol Phosphate PI345P3P 0.00 627.59 phosphatase Metabolism phosphatidylinositol-3,4,5-trisphosphate 5- Inositol Phosphate PI345P5P 0.00 627.59 phosphatase Metabolism Inositol Phosphate PI34P5K phosphatidylinositol 3,4-bisphosphate 5-kinase 0.00 627.59 Metabolism Inositol Phosphate PI45P3K phosphatidylinositol 4,5-bisphosphate 3-kinase 0.00 627.59 Metabolism phosphatidylinositol-4,5-bisphosphate 4- Inositol Phosphate PI45P4P 0.00 627.59 phosphatase Metabolism phosphatidylinositol 4,5-bisphosphate PI45PLC_18_0_20_4 0.00 125.58 phospholipase C (C18:0, C20:4) phosphatidylinositol 4-phosphate 5-kinase PI4P5K_18_0_20_4 0.00 125.58 (C18:0,C20:4) phosphatidylinositol 4-phosphate phospholipase PI4PLC_18_0_20_4 0.00 156.97 C (C18:0,C20:4) Inositol Phosphate PI4PP phosphatidylinositol-4-phosphate 4-phosphatase 0.00 627.59 Metabolism Inositol Phosphate PI5P4K phosphatidylinositol-5-phosphate 4-kinase 0.00 627.59 Metabolism Glycerophospholipid PIK4 phosphatidylinositol 4-kinase 0.00 627.59 Metabolism

Table A1. continued lower upper Abbreviation Name subSystem bound bound PIK4_18_0_20_4 phosphatidylinositol 4-kinase (C18:0,C20:4) 0.00 156.97

phosphatidylinositol phospholipase C PIPLC_18_0_20_4 0.00 209.30 (C18:0,C20:4) phosphate mitochondrial transport via proton PIt2m_2 -100000.00 994.95 symport phosphate transport in/out via three Na+ PIt7 Transport, Extracellular -100000.00 100000.00 symporter Transport, Endoplasmic PIter phosphate transport, endoplasmic reticulum 0.00 1046.49 Reticular PLA2_2_16_0_18_0 phospholipase A2 (C16:0,C18:0) 0.00 89.70

PLA2_2_16_0_18_1 phospholipase A2 (C16:0,C18:1) 0.00 89.70

PLA2_2_18_0_20_4 phospholipase A2 (C18:0,C20:4) 0.00 301.09

PMTCOAtx fatty acid intracellular transport Transport, Peroxisomal -63.58 47.41

PPA inorganic diphosphatase Oxidative Phosphorylation 0.00 523.25

PPAP_16_0_18_0 phosphatidic acid phosphatase (C16:0, C18:0) 0.00 125.58

PPAP_16_0_18_1 phosphatidic acid phosphatase (C16:0, C18:1) 0.00 125.58

PPAm inorganic diphosphatase Oxidative Phosphorylation 0.00 392.93

PPBNGS porphobilinogen synthase Heme Biosynthesis 0.00 72.65

PPDOx Propane-1,2-diol:NAD+ 1-oxidoreductase Pyruvate Metabolism 0.00 100000.00

PPDOy Propane-1,2-diol:NADP+ 1-oxidoreductase Pyruvate Metabolism 0.00 100000.00

PPM phosphopentomutase Pentose Phosphate Pathway -216.38 316.01

PPPG9tm protoporphyrinogen IX mitochondrial transport Heme Biosynthesis 0.00 18.16

PPPGOm protoporphyrinogen oxidase, mitochondrial Heme Biosynthesis 0.00 9.08

PRDXl Peroxidase (multiple substrates) Miscellaneous 0.00 149.90

PRISTCOAtx_r pristcoa peroxisomal transport Transport, Peroxisomal 0.00 313.95

PRISTtx prist peroxisomal transport Transport, Peroxisomal 0.00 313.95 prostaglandin transport via bicarbonate PROSTGD2t_r Transport, Extracellular 0.00 49.95 countertransport PROt4(2)r_r Proline transport (sodium symport) (2:1) Transport, Extracellular 0.00 100000.00

PROtm_r L-proline transport, mitochondrial Transport, Mitochondrial 0.00 457.24

PRPPS phosphoribosylpyrophosphate synthetase Pentose Phosphate Pathway 0.00 314.01 Glycine, Serine, and PSERT phosphoserine transaminase 0.00 308.01 Threonine Metabolism PSFLIP phosphatidylserine flippase Transport, Extracellular 0.00 627.59 Glycine, Serine, and PSP_L phosphoserine phosphatase (L-serine) 0.00 308.01 Threonine Metabolism Phosphatidylserine synthase (homo sapiens PSSA1_hs_18_0_20_4 -390.23 10.00 C18:0, C20:4) Phosphatidylserine synthase (homo sapiens PSSA2_hs_18_0_20_4 0.00 313.95 C18:0, C20:4) PSt3_r phosphatidylserine (homo sapiens) transport 0.00 627.59

PTE3x peroxisomal acyl-CoA thioesterase Fatty Acid Metabolism 0.00 313.95

PTPAT pantetheine-phosphate adenylyltransferase CoA Biosynthesis 0.00 313.95 Arginine and Proline PTRCOX1 Putrescine:oxygen oxidoreductase (deaminating) 0.00 130.69 Metabolism PUNP1 purine-nucleoside phosphorylase (Adenosine) Nucleotides -183.81 316.01 purine-nucleoside phosphorylase PUNP2 Purine Catabolism -189.15 182.51 (Deoxyadenosine) PUNP3 purine-nucleoside phosphorylase (Guanosine) Purine Catabolism -44.96 313.95

Table A1. continued lower upper Abbreviation Name subSystem bound bound purine-nucleoside phosphorylase PUNP4 Purine Catabolism -50.13 146.56 (Deoxyguanosine) PUNP5 purine-nucleoside phosphorylase (Inosine) Purine Catabolism -60.08 317.35

PUNP6 purine-nucleoside phosphorylase (Deoxyinosine) Purine Catabolism -67.00 189.15

PYK pyruvate kinase Glycolysis/Gluconeogenesis 0.00 1660.39 pyruvate peroxisomal transport via proton PYRt2p_r D-alanine metabolism 0.00 199.80 symport PYRt2r_r pyruvate reversible transport via proton symport Transport, Extracellular 0.00 325.30

QUILSYN Quinolinate Synthase (Eukaryotic) Tryptophan metabolism 0.00 10.00

RADH retinal dehydrogenase Vitamin A Metabolism -100000.00 100000.00

RADH2 retinal dehydrogenase (NADPH) Vitamin A Metabolism 0.00 100000.00

RADH3 retinal dehydrogenase Vitamin A Metabolism -100000.00 100000.00

RADH4 retinal dehydrogenase (NADPH) Vitamin A Metabolism 0.00 100000.00

RNDR1 ribonucleoside-diphosphate reductase (ADP) Nucleotides 0.00 192.64

RNDR2 ribonucleoside-diphosphate reductase (GDP) Nucleotides 0.00 146.56

RNDR4 ribonucleoside-diphosphate reductase (UDP) Nucleotides 0.00 149.51

RPE ribulose 5-phosphate 3-epimerase Pentose Phosphate Pathway -133.53 143.75

RPI ribose-5-phosphate isomerase Pentose Phosphate Pathway -142.82 1.33

S2TASE1ly iduronate-2-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

S2TASE2ly iduronate-2-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86 Chondroitin sulfate S2TASE4ly glucuronate-2-sulfatase, lysosomal 0.00 5.00 degradation Chondroitin sulfate S2TASE5ly glucuronate-2-sulfatase, lysosomal 0.00 5.00 degradation S3TASE1ly N-acetylglucosamine-3-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

S3TASE2ly N-acetylglucosamine-3-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

S3TASE3ly N-acetylglucosamine-3-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

S6TASE1ly N-acetylglucosamine-6-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

S6TASE2ly N-acetylglucosamine-6-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86

S6TASE3ly N-acetylglucosamine-6-sulfatase, lysosomal Heparan sulfate degradation 0.00 7.86 Chondroitin sulfate S6TASE6ly N-acetylgalactosamine-6-sulfatase, lysosomal 0.00 5.00 degradation Chondroitin sulfate S6TASE7ly N-acetylgalactosamine-6-sulfatase, lysosomal 0.00 5.00 degradation SADT sulfate adenylyltransferase Nucleotides 0.00 242.83 Fructose and Mannose SBTD_D2 D-sorbitol dehydrogenase (D-fructose producing) 0.00 629.59 Metabolism Fructose and Mannose SBTR D-sorbitol reductase 0.00 629.59 Metabolism L-alanine/L-serine Na-dependent exchange (Ser- SERALANaEx Transport, Extracellular 0.00 100000.00 L in) L-serine/L-asparagine Na-dependent exchange SERASNNaEx Transport, Extracellular 0.00 100000.00 (Ser-L in) L-serine/L-cysteine Na-dependent exchange SERCYSNaEx Transport, Extracellular 0.00 100000.00 (Ser-L in) L-serine/L-glutamine Na-dependent exchange SERGLNNaEx Transport, Extracellular 0.00 100000.00 (Ser-L in) SERGLYexR L-Serine/Glycine reversible exchange Transport, Extracellular -100000.00 100000.00 Glycine, Serine, and SERHL L-Serine hydro-lyase 0.00 404.98 Threonine Metabolism L-serine/L-threonine Na-dependent exchange SERTHRNaEx Transport, Extracellular 0.00 100000.00 (Ser-L in)

Table A1. continued lower upper Abbreviation Name subSystem bound bound SERtp L-serine transport, peroxisomal Transport, Peroxisomal 0.00 199.80

SFGTH S-Formylglutathione hydralase Tyrosine metabolism -65.76 50.64 sulfate transport via chloride countertransport SO4CLtex2 Transport, Extracellular 0.00 100000.00 (2:1) SO4t4_2 sulfate transport via sodium symport Transport, Extracellular -100000.00 100000.00

SO4tl sulfate transport intracellular 0.00 108.64

Urea cycle/amino group SPMS spermidine synthase 0.00 36.82 metabolism SPODM superoxide dismutase ROS Detoxification 0.00 199.80

SPODMm superoxide dismutase ROS Detoxification 0.00 199.80

SPODMx superoxide dismutase, peroxisome ROS Detoxification 0.00 199.80 Urea cycle/amino group SPRMS spermine synthase 0.00 32.88 metabolism serine-pyruvate aminotransferase (irreversible), Glycine, Serine, and SPTix 0.00 199.80 peroxisomal Threonine Metabolism Seratonin reversible transport in via sodium SRTNt6(2)r Transport, Extracellular 0.10 2.00 symport/potassium antiport (1:2) succinate-semialdehyde dehydrogenase (NAD) SSALxm Glutamate metabolism 0.00 100.78 reversible (mitochondrial) STCOAtx fatty acid intracellular transport Transport, Peroxisomal 0.00 63.58

SUCCt2m_r succinate transport, mitochondrial Transport, Mitochondrial 0.00 349.82

SUCCt4_3 succinate transport via sodium symport Transport, Extracellular -100000.00 100000.00

SUCD1m succinate dehydrogenase Citric Acid Cycle -348.93 87.82

SUCOASm Succinate--CoA ligase (ADP-forming) Citric Acid Cycle -100000.00 100000.00

TALA transaldolase Pentose Phosphate Pathway -63.55 78.26

TCHOLAt3 ABC bile acid transporter Transport, Extracellular 0.00 627.59

TCHOLAte bile acid intracellular transport Transport, Extracellular -100000.00 100000.00 L-alanine/L-threonine Na-dependent exchange THRALANaEx Transport, Extracellular 0.00 100000.00 (Thr-L in) L-threonine/L-asparagine Na-dependent THRASNNaEx Transport, Extracellular 0.00 100000.00 exchange (Thr-L in) L-cysteine/L-threonine Na-dependent exchange THRCYSNaEx Transport, Extracellular 0.00 100000.00 (Thr-L in) L-threonine/L-glutamine Na-dependent THRGLNNaEx Transport, Extracellular 0.00 100000.00 exchange (Thr-L in) THRGLYexR L-threonine/glycine reversible exchange Transport, Extracellular -100000.00 100000.00 L-serine/L-threonine Na-dependent exchange THRSERNaEx Transport, Extracellular 0.00 100000.00 (Thr-L in) thymine reversible transport via facilated THYMt_r Transport, Extracellular 0.00 110.16 diffusion TKT1 transketolase Pentose Phosphate Pathway -63.55 78.26

TKT2 transketolase Pentose Phosphate Pathway -63.55 78.26

TMDPP thymidine phosphorylase Pyrimidine Catabolism 0.00 110.16

TMDS thymidylate synthase Nucleotides 0.00 110.16

TMNDNCCOAtx_r fatty acid intracellular transport Transport, Peroxisomal 0.00 49.95

TMNDNCt_r fatty acid transport via diffusion Transport, Extracellular 0.00 39.96

TPI triose-phosphate isomerase Glycolysis/Gluconeogenesis -211.85 293.00

TRDR thioredoxin reductase (NADPH) Nucleotides 0.00 192.64 L-Tryptophan:oxygen 2,3-oxidoreductase TRPO2 Tryptophan metabolism 0.00 10.00 (decyclizing) TRPt L-tryptophan transport Transport, Extracellular -100000.00 10.00

Table A1. continued lower upper Abbreviation Name subSystem bound bound Tryptamine:oxygen TRYPTAOX Tryptophan metabolism 0.10 12.00 oxidoreductase(deaminating)(flavin-containing) Tryptamine reversible transport in via sodium TRYPTAt 0.10 2.00 symport/potassium antiport (1:2) Tetradecanoate (n-C14:0) transport in via TTDCAt Transport, Extracellular 0.00 100000.00 uniport TTDCAtr_r fatty acid transport 0.00 100000.00

TXA2te_r thromboxane A2 transport Transport, Extracellular 0.00 49.95 Transport, Endoplasmic TXA2tr_r thromboxane A2 intracellular transport 0.00 49.95 Reticular TXASr Thromboxane-A synthase Eicosanoid Metabolism 0.00 49.95

TXBS Thromboxane-B synthase 0.00 49.95

TYMSFt Tyramine O-sulfate transport (diffusion) Transport, Extracellular 0.00 22.00

TYMSULT Tyramine Sulfotransferase Tyrosine metabolism 0.00 22.00 Tyramine reversible transport in via sodium TYMt 0.10 2.00 symport/potassium antiport (1:2) Tyramine:oxygen TYROXDAc oxidoreductase(deaminating)(flavin-containing) Tyrosine metabolism 0.00 22.00 (cytosol) UAG4E_r UDP-N-acetylglucosamine 4-epimerase Aminosugar Metabolism 0.00 10.00

UAGALDP UDP-N-acetylgalactosamine diphosphorylase Aminosugar Metabolism 0.00 10.00

UAGDP UDP-N-acetylglucosamine diphosphorylase Aminosugar Metabolism 0.00 313.95 UDPglucose:dolichyl-phosphate beta-D- UDPDOLPT_L N-Glycan Biosynthesis 0.00 313.95 glucosyltransferase (liver) UDPglucose:dolichyl-phosphate beta-D- UDPDOLPT_U N-Glycan Biosynthesis 0.00 313.95 glucosyltransferase (uterus) Pentose and Glucuronate UDPG1P UDPglucuronate uridine-monophosphohydrolase 0.00 131.24 Interconversions UDPG4E_r UDPglucose 4-epimerase Galactose metabolism 0.10 25.94 Starch and Sucrose UDPGD UDPglucose 6-dehydrogenase 0.00 166.84 Metabolism Pentose and Glucuronate UDPGNP UDPglucuronate uridine-diphosphohydrolase 0.00 161.16 Interconversions UDPglucose--hexose-1-phosphate UGLT Galactose metabolism -99999.90 100000.00 uridylyltransferase UMPK UMP kinase Nucleotides -100000.00 100000.00

UMPK2 UMP kinase (CTP) Nucleotides -100000.00 100000.00

UMPK3 UMP kinase (UTP) Nucleotides -100000.00 100000.00

UMPK4 UMP kinase (GTP) Nucleotides -100000.00 100000.00

UMPK5 UMP kinase (dATP) Nucleotides -100000.00 100000.00

UMPK6 UMP kinase (dCTP) Nucleotides -100000.00 100000.00

UMPK7 UMP kinase (dGTP) Nucleotides -100000.00 100000.00 Arginine and Proline UNK2 2-keto-4-methylthiobutyrate transamination 0.00 60.92 Metabolism Arginine and Proline UNK3 2-keto-4-methylthiobutyrate transamination 0.00 65.76 Metabolism UPP3S uroporphyrinogen-III synthase Heme Biosynthesis 0.00 18.16 uroporphyrinogen decarboxylase UPPDC1 Heme Biosynthesis 0.00 18.16 (uroporphyrinogen III) URATEt urate export from cytosol Transport, Extracellular 0.00 61.44

URATEtx urate export from peroxisome Transport, Peroxisomal 0.00 61.44

UREAt Urea transport via facilitate diffusion Transport, Extracellular -100000.00 100000.00

UREAt5 urea, water cotransport Transport, Extracellular -100000.00 100000.00

Table A1. continued lower upper Abbreviation Name subSystem bound bound URIDK2m uridylate kinase (dUMP), mitochondrial Nucleotides 0.00 392.25

URIK1 uridine kinase (ATP:Uridine) Pyrimidine Biosynthesis 0.00 627.59

URIt_r uridine facilated transport in cytosol Transport, Extracellular 0.00 100000.00 Ascorbate and Aldarate UROLACer uronolactonase, endoplasmic reticulum 0.00 100000.00 Metabolism VITD3t Vitamin D3 release Transport, Extracellular 0.00 100000.00

VITD3t2 Vitamin D3 uptake Transport, Extracellular 0.00 100000.00

VITD3tm Vitamin D3 transport from mitochondria Transport, Mitochondrial 0.00 100000.00

VITD3tm3 Vitamin D3 transport in mitochondria Transport, Mitochondrial 0.00 100000.00

XAO2x xanthine oxidase Purine Catabolism 0.00 54.65

XAOx xanthine oxidase,peroxisomal Purine Catabolism 0.00 61.44

XYLTt_r Xylitol transport via passive diffusion Transport, Extracellular 0.00 82.06 Pentose and Glucuronate XYLUR xylulose reductase 0.00 176.84 Interconversions XYLt_r D-xylose reversible transport Transport, Extracellular 0.00 11.97

XYLtly Xylose efflux from lysosome Transport, Lysosomal 0.00 11.97

sink_ACP sink_ACP -68.06 436.11

sink_palmACP sink_palmACP -436.11 68.06

sink_ps_hs_18_0_20_4 sink_ps_hs_18_0_20_4 -301.09 10.00

docosa-4,7,10,13,16-pentaenoic acid (n-6) Exchange EX_dcsptn1(e) 0.00 45.62 exchange

Table A2. the list of metabolites and their properties in the human platelet model.

Abbreviation Names Charges Formulas

10fthf[c] 10-Formyltetrahydrofolate -2 C20H21N7O7

12HPET[c] 12-Hydroperoxyeicosa-5,8,10,14-tetraenoate -1 C20H31O4

12harachd[c] 12 hydroxy arachidonic acid -1 C20H31O3

12ppd-R[c] (R)-Propane-1,2-diol 0 C3H8O2

12ppd-S[c] (S)-Propane-1,2-diol 0 C3H8O2

13-cis-retn[c] 13-cis-retinoate -1 C20H27O2

13dpg[c] 3-Phospho-D-glyceroyl phosphate -4 C3H4O10P2

1mncam[c] 1-Methylnicotinamide 1 C7H9N2O

23dpg[c] 2,3-Disphospho-D-glycerate -5 C3H3O10P2

25hvitd2[c] 25-Hydroxyvitamin D2 0 C28H44O2

25hvitd3[c] 25-Hydroxyvitamin D3 0 C27H44O2

2amac[c] 2-Aminoacrylate 0 C3H5NO2

2dr1p[c] 2-Deoxy-D-ribose 1-phosphate -2 C5H9O7P

2hb[c] 2-Hydroxybutyrate -1 C4H7O3

2kmb[c] 2-keto-4-methylthiobutyrate -1 C5H7O3S

2mcit[c] 2-Methylcitrate -3 C7H7O7

2obut[c] 2-Oxobutanoate -1 C4H5O3

2pg[c] D-Glycerate 2-phosphate -3 C3H4O7P

34dhmald[c] 3,4-Dihydroxymandelaldehyde 0 C8H8O4

34dhoxpeg[c] 3,4-Dihydroxyphenylethyleneglycol 0 C8H10O4

34dhpac[c] 3,4-Dihydroxyphenylacetaldehyde 0 C8H8O3

34dhpha[c] 3,4-Dihydroxyphenylacetate -1 C8H7O4

35cgmp[c] 3,5-Cyclic GMP -1 C10H11N5O7P

3dhguln[c] 3-Dehydro-L-gulonate -1 C6H9O7

3hanthrn[c] 3-Hydroxyanthranilate 0 C7H7NO3

3mop[c] (S)-3-Methyl-2-oxopentanoate -1 C6H9O3

3mox4hpac[c] 3-Methoxy-4-hydroxyphenylacetaldehyde 0 C9H10O3

3moxtyr[c] 3-Methoxytyramine 1 C9H14NO2

3pg[c] 3-Phospho-D-glycerate -3 C3H4O7P

3php[c] 3-Phosphohydroxypyruvate -3 C3H2O7P

4abut[c] 4-Aminobutanoate 0 C4H9NO2

4abutn[c] 4-Aminobutanal 1 C4H10NO

4hoxpacd[c] 4-Hydroxyphenylacetaldehyde 0 C8H8O2

4hphac[c] 4-Hydroxyphenylacetate -1 C8H7O3

4mop[c] 4-Methyl-2-oxopentanoate -1 C6H9O3

4nph[c] 4-Nitrophenol 0 C6H5NO3

4nphsf[c] 4-Nitrophenyl sulfate -1 C6H4NO6S

ametam[c] S-Adenosylmethioninamine 2 C14H24N6O3S

cytd[c] Cytidine 0 C9H13N3O5

Table A2. continued

Abbreviation Names Charges Formulas

5aop[c] 5-Amino-4-oxopentanoate 0 C5H9NO3

5hoxindact[c] 5-Hydroxyindoleacetaldehyde 0 C10H9NO2

5hoxindoa[c] 5-Hydroxyindoleacetate -1 C10H8NO3

5mdr1p[c] 5-Methylthio-5-deoxy-D-ribose 1-phosphate -2 C6H11O7PS

5mdru1p[c] 5-Methylthio-5-deoxy-D-ribulose 1-phosphate -2 C6H11O7PS

5moxact[c] 5-Methoxyindoleacetate -1 C11H10NO3

5mta[c] 5-Methylthioadenosine 0 C11H15N5O3S

6pgc[c] 6-Phospho-D-gluconate -3 C6H10O10P

6pgl[c] 6-phospho-D-glucono-1,5-lactone -2 C6H9O9P

ACP[c] acyl carrier protein -1 C11H21N2O7PRS

Lfmkynr[c] L-Formylkynurenine 0 C11H12N2O4

Lkynr[c] L-Kynurenine 0 C10H12N2O3

Sfglutth[c] S-Formylglutathione -1 C11H16N3O7S Tyr-194 of apo-glycogenin protein (primer for glycogen Tyr-ggn[c] 0 XOH synthesis) aacoa[c] Acetoacetyl-CoA -4 C25H36N7O18P3S

abt[c] L-Arabinitol 0 C5H12O5

ac[c] Acetate -1 C2H3O2

acac[c] Acetoacetate -1 C4H5O3

accoa[c] Acetyl-CoA -4 C23H34N7O17P3S

acetol[c] Acetol 0 C3H6O2

acgal[c] N-Acetyl-D-galactosamine 0 C8H15NO6

acgal1p[c] N-Acetyl-D-galactosamine 1-phosphate -2 C8H14NO9P

acgam[c] N-Acetyl-D-glucosamine 0 C8H15NO6

acgam1p[c] N-Acetyl-D-glucosamine 1-phosphate -2 C8H14NO9P

acgam6p[c] N-Acetyl-D-glucosamine 6-phosphate -2 C8H14NO9P

acrn[c] O-Acetylcarnitine 0 C9H17NO4

ade[c] Adenine 0 C5H5N5

adn[c] Adenosine 0 C10H13N5O4

adp[c] ADP -3 C10H12N5O10P2

adprib[c] ADPribose -2 C15H21N5O14P2

adrn[c] adrenic acid -1 C22H35O2

adrncoa[c] adrenyl coenzyme A -4 C43H66N7O17P3S

ahcys[c] S-Adenosyl-L-homocysteine 0 C14H20N6O5S

akg[c] 2-Oxoglutarate -2 C5H4O5

ala-D[c] D-Alanine 0 C3H7NO2

ala-L[c] L-Alanine 0 C3H7NO2

alpa_hs_16_0[c] lysophosphatidic acid (homo sapiens, C16:0) -2 C19H39O7P

alpa_hs_18_0[c] lysophosphatidic acid (homo sapiens, C18:0) -2 C21H41O7P

amet[c] S-Adenosyl-L-methionine 1 C15H23N6O5S

Table A2. continued

Abbreviation Names Charges Formulas

amp[c] AMP -2 C10H12N5O7P

aps[c] Adenosine 5-phosphosulfate -2 C10H12N5O10PS

arachd[c] arachidonic acid -1 C20H31O2

arachdcoa[c] C20:4-CoA -4 C41H62N7O17P3S

arachdcrn[c] C20:4 carnitine 0 C27H45NO4

arg-L[c] L-Arginine 1 C6H15N4O2

argsuc[c] N(omega)-(L-Arginino)succinate -1 C10H17N4O6

ascb-L[c] L-Ascorbate 0 C6H8O6

asn-L[c] L-Asparagine 0 C4H8N2O3

asp-L[c] L-Aspartate -1 C4H6NO4

atp[c] ATP -4 C10H12N5O13P3

bhb[c] (R)-3-Hydroxybutanoate -1 C4H7O3

bilirub[c] Bilirubin -2 C33H34N4O6

biliverd[c] Biliverdin -2 C33H32N4O6

c226coa[c] cervonyl coenzyme A -4 C43H62N7O17P3S

ca2[c] Calcium 2 Ca

camp[c] cAMP -1 C10H11N5O6P

cbasp[c] N-Carbamoyl-L-aspartate -2 C5H6N2O5

cbp[c] Carbamoyl phosphate -2 CH2NO5P

cdp[c] CDP -3 C9H12N3O11P2

cdpchol[c] CDPcholine -1 C14H25N4O11P2 cdpdag_hs_18_0_20_4[ diacylglycerol (homo sapiens, C18:0, C20:4) -2 C50H83N3O15P2 c] cdpea[c] CDPethanolamine -1 C11H19N4O11P2

chol[c] Choline 1 C5H14NO

cholp[c] Choline phosphate -1 C5H13NO4P

cit[c] Citrate -3 C6H5O7

citr-L[c] L-Citrulline 0 C6H13N3O3

cl[c] Chloride -1 Cl

cmp[c] CMP -2 C9H12N3O8P

cmusa[c] 2-Amino-3-carboxymuconate semialdehyde -1 C7H6NO5

co[c] Carbon monoxide 0 CO

co2[c] CO2 0 CO2

coa[c] Coenzyme A -4 C21H32N7O16P3S

cpppg3[c] Coproporphyrinogen III -4 C36H40N4O8

crn[c] L-Carnitine 0 C7H15NO3

crvnc[c] cervonic acid, C22:6 n-3 -1 C22H31O2

ctp[c] CTP -4 C9H12N3O14P3

cys-L[c] L-Cysteine 0 C3H7NO2S

cyst-L[c] L-Cystathionine 0 C7H14N2O4S

Table A2. continued

Abbreviation Names Charges Formulas

dad-2[c] Deoxyadenosine 0 C10H13N5O3

dadp[c] dADP -3 C10H12N5O9P2

dag_hs_16_0_18_0[c] diacylglycerol (homo sapiens, C16:0, C18:0) 0 C37H72O5

dag_hs_16_0_18_1[c] diacylglycerol (homo sapiens, C16:0, C18:1) 0 C37H70O5

dag_hs_18_0_20_4[c] diacylglycerol (homo sapiens, C18:0, C20:4) 0 C41H72O5

datp[c] dATP -4 C10H12N5O12P3

dcacoa[c] Decanoyl-CoA (n-C10:0CoA) -4 C31H50N7O17P3S

dcamp[c] N6-(1,2-Dicarboxyethyl)-AMP -4 C14H14N5O11P

dcdp[c] dCDP -3 C9H12N3O10P2

dcmp[c] dCMP -2 C9H12N3O7P

dcsptn1[c] docosa-4,7,10,13,16-pentaenoic acid (n-6) -1 C22H33O2

dcsptn1coa[c] docosa-4,7,10,13,16-pentaenoyl coenzyme A -4 C43H64N7O17P3S

dcsptn1crn[c] docosa-4,7,10,13,16-pentaenoyl carnitine 0 C29H47NO4

dctp[c] dCTP -4 C9H12N3O13P3

dcyt[c] Deoxycytidine 0 C9H13N3O4

ddcacoa[c] Dodecanoyl-CoA (n-C12:0CoA) -4 C33H54N7O17P3S

dgdp[c] dGDP -3 C10H12N5O10P2

dgmp[c] dGMP -2 C10H12N5O7P

dgsn[c] Deoxyguanosine 0 C10H13N5O4

dgtp[c] dGTP -4 C10H12N5O13P3

dhap[c] Dihydroxyacetone phosphate -2 C3H5O6P

dhdascb[c] Dehydroascorbate 0 C6H6O6

dhf[c] 7,8-Dihydrofolate -2 C19H19N7O6

dhor-S[c] (S)-Dihydroorotate -1 C5H5N2O4

din[c] Deoxyinosine 0 C10H12N4O4

dkmpp[c] 2,3-diketo-5-methylthio-1-phosphopentane -2 C6H9O6PS

dnad[c] Deamino-NAD+ -2 C21H24N6O15P2

dolglcp_L[c] Dolichyl beta-D-glucosyl phosphate, human liver homolog -10 C1140H1868O90P10

dolglcp_U[c] Dolichyl beta-D-glucosyl phosphate, human uterine homolog -10 C1085H1780O90P10

dolichol_L[c] Dolichol, human liver homolog 0 C1080H1768O10

dolichol_U[c] Dolichol, human uterine homolog 0 C1025H1680O10

dolp_L[c] Dolichol phosphate, human liver homolog -20 C1080H1758O40P10

dolp_U[c] Dolichol phosphate, human uterine homolog -20 C1025H1670O40P10

dopa[c] Dopamine 1 C8H12NO2

dopasf[c] Dopamine 3-O-sulfate 0 C8H11NO5S

dpcoa[c] Dephospho-CoA -2 C21H33N7O13P2S

drib[c] Deoxyribose 0 C5H10O4

dtdp[c] dTDP -3 C10H13N2O11P2

dtmp[c] dTMP -2 C10H13N2O8P

Table A2. continued.

Abbreviation Names Charges Formulas

dttp[c] dTTP -4 C10H13N2O14P3

dudp[c] dUDP -3 C9H11N2O11P2

dump[c] dUMP -2 C9H11N2O8P

duri[c] Deoxyuridine 0 C9H12N2O5

dutp[c] dUTP -4 C9H11N2O14P3 phosphorylase-limit dextrin (glycogenin-1,6{4[1,4-Glc], 4[1,4- dxtrn[c] 0 C48H81O41X Glc]}) e4p[c] D-Erythrose 4-phosphate -2 C4H7O7P

etha[c] Ethanolamine 1 C2H8NO

ethamp[c] Ethanolamine phosphate -1 C2H7NO4P

f26bp[c] D-Fructose 2,6-bisphosphate -4 C6H10O12P2

f6p[c] D-Fructose 6-phosphate -2 C6H11O9P

fald[c] Formaldehyde 0 CH2O

fdp[c] D-Fructose 1,6-bisphosphate -4 C6H10O12P2

fe2[c] Fe2+ 2 Fe

for[c] Formate -1 CH1O2

fru[c] D-Fructose 0 C6H12O6

fum[c] Fumarate -2 C4H2O4

g1p[c] D-Glucose 1-phosphate -2 C6H11O9P

g3p[c] Glyceraldehyde 3-phosphate -2 C3H5O6P

g3pc[c] sn-Glycero-3-phosphocholine 0 C8H20NO6P

g6p[c] D-Glucose 6-phosphate -2 C6H11O9P

gal[c] D-Galactose 0 C6H12O6

gal1p[c] alpha-D-Galactose 1-phosphate -2 C6H11O9P

gam6p[c] D-Glucosamine 6-phosphate -1 C6H13NO8P

gchola[c] glycocholate 0 C26H43NO6

gdp[c] GDP -3 C10H12N5O11P2

ggn[c] primed glycogenin (glycogenin-8[1,4-Glc]) 0 C48H81O41X

glac[c] D-glucurono-6,3-lactone 0 C6H8O6

glc-D[c] D-Glucose 0 C6H12O6

glcur[c] D-Glucuronate -1 C6H9O7

glcur1p[c] D-Glucuronate 1-phosphate -3 C6H8O10P

gln-L[c] L-Glutamine 0 C5H10N2O3

glu-L[c] L-Glutamate -1 C5H8NO4

glucys[c] gamma-L-Glutamyl-L-cysteine -1 C8H13N2O5S

gly[c] Glycine 0 C2H5NO2

glyc[c] Glycerol 0 C3H8O3

glyc-R[c] (R)-Glycerate -1 C3H5O4

glyc-S[c] (S)-Glycerate -1 C3H5O4

glyc3p[c] Glycerol 3-phosphate -2 C3H7O6P

Table A2. continued

Abbreviation Names Charges Formulas

glygn1[c] glycogen, structure 1 (glycogenin-11[1,4-Glc]) 0 C66H111O56X

glygn2[c] glycogen, structure 2 (glycogenin-1,6-{7[1,4-Glc], 4[1,4-Glc]}) 0 C66H111O56X

glygn3[c] glycogen, structure 3 (glycogenin-7[1,4-Glc]) 0 C42H71O36X

gmp[c] GMP -2 C10H12N5O8P

gsn[c] Guanosine 0 C10H13N5O5

gthox[c] Oxidized glutathione -2 C20H30N6O12S2

gthrd[c] Reduced glutathione -1 C10H16N3O6S

gtp[c] GTP -4 C10H12N5O14P3

gua[c] Guanine 0 C5H5N5O

gullac[c] L-Gulono-1,4-lactone 0 C6H10O6

guln[c] L-Gulonate -1 C6H11O7

h[c] H+ 1 H

h2co3[c] carbonic acid 0 H2CO3

h2o[c] H2O 0 H2O

h2o2[c] Hydrogen peroxide 0 H2O2

hLkynr[c] 3-Hydroxy-L-kynurenine 0 C10H12N2O4

hco3[c] Bicarbonate -1 CHO3

hcys-L[c] L-Homocysteine 0 C4H9NO2S

hdca[c] Hexadecanoate (n-C16:0) -1 C16H31O2

hmbil[c] Hydroxymethylbilane -8 C40H38N4O17

hmgcoa[c] Hydroxymethylglutaryl-CoA -5 C27H39N7O20P3S

homoval[c] Homovanillate -1 C9H9O4

hpyr[c] Hydroxypyruvate -1 C3H3O4

hxan[c] Hypoxanthine 0 C5H4N4O

icit[c] Isocitrate -3 C6H5O7

id3acald[c] Indole-3-acetaldehyde 0 C10H9NO

idp[c] IDP -3 C10H11N4O11P2

ile-L[c] L-Isoleucine 0 C6H13NO2

imp[c] IMP -2 C10H11N4O8P

ind3ac[c] Indole-3-acetate -1 C10H8NO2

inost[c] myo-Inositol 0 C6H12O6

ins[c] Inosine 0 C10H12N4O5

itp[c] ITP -4 C10H11N4O14P3

k[c] potassium 1 K

kdn[c] 2-keto-3-deoxy-D-glycero-D-galactononic acid -1 C9H15O9

kdnp[c] 2-keto-3-deoxy-D-glycero-D-galactononic acid 9-phosphate -3 C9H14O12P

lac-D[c] D-Lactate -1 C3H5O3

lac-L[c] L-Lactate -1 C3H5O3 lald-D[c] D-Lactaldehyde 0 C3H6O2

Table A2. continued

Abbreviation Names Charges Formulas

lald-L[c] L-Lactaldehyde 0 C3H6O2

leu-L[c] L-Leucine 0 C6H13NO2

leuktrA4[c] Leukotriene A4 -1 C20H29O3

leuktrB4[c] Leukotriene B4 -1 C20H31O4

leuktrD4[c] Leukotriene D4 -1 C25H39N2O6S

leuktrE4[c] leukotriene E4 -1 C23H36NO5S

leuktrF4[c] leukotriene F4 -2 C28H42N2O8S

lgnc[c] lignoceric acid -1 C24H47O2

lgt-S[c] (R)-S-Lactoylglutathione -1 C13H20N3O8S

lpchol_hs_16_0[c] lysophosphatidylcholine (homo sapiens, C16:0) 0 C24H50NO7P

lpchol_hs_18_0[c] lysophosphatidylcholine (homo sapiens, C18:0) 0 C26H54NO7P

mag_hs_18_0[c] monoacylglycerol 2 (homo sapiens C18:0) 0 C21H42O4

mag_hs_18_1[c] monoacylglycerol 2(homo sapiens C18:1) 0 C21H40O4

mag_hs_20_4[c] monoglycerol 2 (homo sapiens C20:4) 0 C23H38O4

mal-L[c] L-Malate -2 C4H4O5

malcoa[c] Malonyl-CoA -5 C24H33N7O19P3S

man6p[c] D-Mannose 6-phosphate -2 C6H11O9P

meoh[c] Methanol 0 CH4O1

mercplac[c] 3-Mercaptolactate -1 C3H5O3S

mercplaccys[c] 3-mercaptolactate-cysteine disulfide -1 C6H10O5S2N

mercppyr[c] Mercaptopyruvate -1 C3H3O3S

met-L[c] L-Methionine 0 C5H11NO2S

methf[c] 5,10-Methenyltetrahydrofolate -1 C20H20N7O6

mi1345p[c] 1D-myo-Inositol 1,3,4,5-tetrakisphosphate -8 C6H8O18P4

mi134p[c] 1D-myo-Inositol 1,3,4-trisphosphate -6 C6H9O15P3

mi13p[c] 1D-myo-Inositol 1,3-bisphosphate -4 C6H10O12P2

mi145p[c] 1D-myo-Inositol 1,4,5-trisphosphate -6 C6H9O15P3

mi14p[c] 1D-myo-Inositol 1,4-bisphosphate -4 C6H10O12P2

mi1p-D[c] 1D-myo-Inositol 1-phosphate -2 C6H11O9P

mlthf[c] 5,10-Methylenetetrahydrofolate -2 C20H21N7O6

mthgxl[c] Methylglyoxal 0 C3H4O2

na1[c] Sodium 1 Na

nad[c] Nicotinamide adenine dinucleotide -1 C21H26N7O14P2

nadh[c] Nicotinamide adenine dinucleotide - reduced -2 C21H27N7O14P2

nadp[c] Nicotinamide adenine dinucleotide phosphate -3 C21H25N7O17P3

nadph[c] Nicotinamide adenine dinucleotide phosphate - reduced -4 C21H26N7O17P3

ncam[c] Nicotinamide 0 C6H6N2O

nh4[c] Ammonium 1 H4N

nicrnt[c] Nicotinate D-ribonucleotide -2 C11H12NO9P

Table A2. continued

Abbreviation Names Charges Formulas

no[c] Nitric oxide 0 NO

nrpphr[c] Norepinephrine 1 C8H12NO3 nrpphrsf[c] Sulfate derivative of norepinephrine 0 C8H11NO6S

nrvnc[c] nervonic acid -1 C24H45O2

nwharg[c] N-(omega)-Hydroxyarginine 1 C6H15N4O3

o2[c] O2 0 O2

o2s[c] Superoxide anion -1 O2

oaa[c] Oxaloacetate -2 C4H2O5

occoa[c] Octanoyl-CoA (n-C8:0CoA) -4 C29H46N7O17P3S

ocdca[c] octadecanoate (n-C18:0) -1 C18H35O2

ocdcea[c] octadecenoate (n-C18:1) -1 C18H33O2

odecoa[c] Octadecenoyl-CoA (n-C18:1CoA) -4 C39H64N7O17P3S

orn[c] Ornithine 1 C5H13N2O2

orot[c] Orotate -1 C5H3N2O4

orot5p[c] Orotidine 5-phosphate -3 C10H10N2O11P

pa_hs_16_0_18_0[c] phosphatidic acid (homo sapiens, C16:0, C18:0) -2 C37H73O8P

pa_hs_16_0_18_1[c] phosphatidic acid (homo sapiens, C16:0, C18:1) -2 C37H71O8P

pa_hs_18_0_20_4[c] phosphatidic acid (homo sapiens, C18:0, C20:4) -2 C41H71O8P

pac[c] Phenylacetic acid -1 C8H7O2

pacald[c] Phenylacetaldehyde 0 C8H8O C9H13O18P4FULLRCO2FULLR2CO pail345p_hs[c] phosphatidylinositol-3,4,5-trisphosphate (Homo sapiens) -7 2 C9H14O15P3FULLRCO2FULLR2CO pail34p_hs[c] phosphatidylinositol-3,4-bisphosphate (Homo sapiens) -5 2 C9H14O15P3FULLRCO2FULLR2CO pail45p_hs[c] phosphatidylinositol 4,5-bisphosphate (Homo sapiens) -5 2 pail45p_hs_18_0_20_4[ phosphatidylinositol 4,5-bisphosphate (homo sapiens, C18:0, -5 C47H80O19P3 c] C20:4) C9H15O12P2FULLRCO2FULLR2CO pail4p_hs[c] 1-Phosphatidyl-1D-myo-inositol 4-phosphate (Homo sapiens) -3 2 pail4p_hs_18_0_20_4[c 1-Phosphatidyl-1D-myo-inositol 4-phosphate (homo sapiens, -3 C47H81O16P2 ] C18:0, C20:4) C9H15O12P2FULLRCO2FULLR2CO pail5p_hs[c] 1-Phosphatidyl-1D-myo-inositol 5-phosphate (Homo sapiens) -3 2 pail_hs[c] phosphatidylinositol (homo sapiens) -1 C9H16O9PFULLRCO2FULLR2CO2

pail_hs_18_0_20_4[c] phosphatidylinositol (homo sapiens, C18:0, C20:4) -1 C47H82O13P

palmACP[c] Palmitoyl-ACP (n-C16:0ACP) -1 C27H51N2O8PRS

pan4p[c] Pantetheine 4-phosphate -2 C11H21N2O7PS

pap[c] Adenosine 3,5-bisphosphate -4 C10H11N5O10P2

paps[c] 3-Phosphoadenylyl sulfate -4 C10H11N5O13P2S

pchol_hs_16_0_18_0[c] phosphatidylcholine (homo sapiens, C16:0, C18:0) 0 C42H84NO8P

pchol_hs_16_0_18_1[c] phosphatidylcholine (homo sapiens, C16:0, C18:1) 0 C42H82NO8P

pchol_hs_18_0_20_4[c] phosphatidylcholine (homo sapiens, C18:0, C20:4) 0 C46H84NO8P C5H12NO4PFULLRCO2FULLR2CO pe_hs[c] phosphatidylethanolamine (homo sapiens) 0 2 pe_hs_18_0_20_4[c] phosphatidylethanolamine (homo sapiens, C18:0, C20:4) 0 C43H78NO8P

Table A2. continued

Abbreviation Names Charges Formulas

peamn[c] Phenethylamine 1 C8H12N

pep[c] Phosphoenolpyruvate -3 C3H2O6P

phaccoa[c] Phenylacetyl-CoA -4 C29H38N7O17P3S

phe-L[c] L-Phenylalanine 0 C9H11NO2

pheacgln[c] alpha-N-Phenylacetyl-L-glutamine 0 C13H16N2O4

pheme[c] Protoheme -2 C34H30FeN4O4

pi[c] Phosphate -2 HO4P

pmtcoa[c] Palmitoyl-CoA (n-C16:0CoA) -4 C37H62N7O17P3S

pmtcrn[c] L-Palmitoylcarnitine 0 C23H45NO4

ppbng[c] Porphobilinogen -1 C10H13N2O4

ppcoa[c] Propanoyl-CoA -4 C24H36N7O17P3S

ppi[c] Diphosphate -3 HO7P2

pppg9[c] Protoporphyrinogen IX -2 C34H38N4O4

prist[c] pristanic acid -1 C19H37O2

pristcoa[c] pristanoyl coa -4 C40H68N7O17P3S

pro-L[c] L-Proline 0 C5H9NO2

prostgd2[c] Prostaglandin D2 -1 C20H31O5

prostgg2[c] prostaglandin G2 0 C20H32O6

prostgh2[c] Prostaglandin H2 -1 C20H31O5

prpp[c] 5-Phospho-alpha-D-ribose 1-diphosphate -5 C5H8O14P3 C6H11NO6PFULLRCO2FULLR2CO ps_hs[c] phosphatidylserine (homo sapiens) -1 2 ps_hs_18_0_20_4[c] phosphatidylserine (homo sapiens, C18:0, C20:4) -1 C44H77NO10P

pser-L[c] O-Phospho-L-serine -2 C3H6NO6P

ptrc[c] Putrescine 2 C4H14N2

pyr[c] Pyruvate -1 C3H3O3

quln[c] Quinolinate -2 C7H3NO4

r1p[c] alpha-D-Ribose 1-phosphate -2 C5H9O8P

r5p[c] alpha-D-Ribose 5-phosphate -2 C5H9O8P

retinal[c] Retinal 0 C20H28O

retinal-cis-13[c] cis-13-retinal 0 C20H28O

retn[c] Retinoate -1 C20H27O2

ru5p-D[c] D-Ribulose 5-phosphate -2 C5H9O8P

s7p[c] Sedoheptulose 7-phosphate -2 C7H13O10P

sbt-D[c] D-Sorbitol 0 C6H14O6

ser-L[c] L-Serine 0 C3H7NO3

so4[c] Sulfate -2 O4S

spmd[c] Spermidine 3 C7H22N3

sprm[c] Spermine 4 C10H30N4

srtn[c] Serotonin 1 C10H13N2O

Table A2. continued

Abbreviation Names Charges Formulas

stcoa[c] Stearoyl-CoA (n-C18:0CoA) -4 C39H66N7O17P3S

succ[c] Succinate -2 C4H4O4

tchola[c] taurocholic acid 0 C26H45NO7S

tdcoa[c] Tetradecanoyl-CoA (n-C14:0CoA) -4 C35H58N7O17P3S thf[c] 5,6,7,8-Tetrahydrofolate -2 C19H21N7O6

thr-L[c] L-Threonine 0 C4H9NO3

thym[c] Thymine 0 C5H6N2O2

thymd[c] Thymidine 0 C10H14N2O5

tmndnc[c] timnodonic acid C20:5, n-3 -1 C20H29O2

tmndnccoa[c] timnodonyl coenzyme A -4 C41H60N7O17P3S

trdox[c] Oxidized thioredoxin 0 X

trdrd[c] Reduced thioredoxin 0 XH2

trp-L[c] L-Tryptophan 0 C11H12N2O2

trypta[c] Tryptamine 1 C10H13N2

ttdca[c] tetradecanoate (n-C14:0) -1 C14H27O2

txa2[c] Thromboxane A2 -1 C20H31O5

txb2[c] Thromboxane B2 0 C20H34O6

tym[c] Tyramine 1 C8H12NO

tymsf[c] Tyramine O-sulfate 0 C8H11NO4S

uacgam[c] UDP-N-acetyl-D-glucosamine -2 C17H25N3O17P2

udp[c] UDP -3 C9H11N2O12P2

udpacgal[c] UDP-N-acetyl-D-galactosamine -2 C17H25N3O17P2

udpg[c] UDPglucose -2 C15H22N2O17P2

udpgal[c] UDPgalactose -2 C15H22N2O17P2

udpglcur[c] UDP-D-glucuronate -3 C15H19N2O18P2

ump[c] UMP -2 C9H11N2O9P

uppg3[c] Uroporphyrinogen III -8 C40H36N4O16

urate[c] Urate 0 C5H4N4O3

urea[c] Urea 0 CH4N2O

uri[c] Uridine 0 C9H12N2O6

utp[c] UTP -4 C9H11N2O15P3

vitd3[c] Vitamin D3 0 C27H44O

xu5p-D[c] D-Xylulose 5-phosphate -2 C5H9O8P

xyl-D[c] D-Xylose 0 C5H10O5

xylt[c] Xylitol 0 C5H12O5

xylu-L[c] L-Xylulose 0 C5H10O5

1mncam[e] 1-Methylnicotinamide 1 C7H9N2O

25hvitd2[e] 25-Hydroxyvitamin D2 0 C28H44O2

25hvitd3[e] 25-Hydroxyvitamin D3 0 C27H44O2

Table A2. continued

Abbreviation Names Charges Formulas

2hb[e] 2-Hydroxybutyrate -1 C4H7O3

2mcit[e] 2-Methylcitrate -3 C7H7O7

34dhoxpeg[e] 3,4-Dihydroxyphenylethyleneglycol 0 C8H10O4

4abut[e] 4-Aminobutanoate 0 C4H9NO2

4hphac[e] 4-Hydroxyphenylacetate -1 C8H7O3

4nph[e] 4-Nitrophenol 0 C6H5NO3

4nphsf[e] 4-Nitrophenyl sulfate -1 C6H4NO6S abt[e] L-Arabinitol 0 C5H12O5

ac[e] Acetate -1 C2H3O2

acac[e] Acetoacetate -1 C4H5O3

ade[e] Adenine 0 C5H5N5

adn[e] Adenosine 0 C10H13N5O4

adrn[e] adrenic acid -1 C22H35O2

akg[e] 2-Oxoglutarate -2 C5H4O5

ala-D[e] D-Alanine 0 C3H7NO2

ala-L[e] L-Alanine 0 C3H7NO2

arachd[e] arachidonic acid -1 C20H31O2

arg-L[e] L-Arginine 1 C6H15N4O2

ascb-L[e] L-Ascorbate 0 C6H8O6

asn-L[e] L-Asparagine 0 C4H8N2O3

bhb[e] (R)-3-Hydroxybutanoate -1 C4H7O3

bilirub[e] Bilirubin -2 C33H34N4O6

ca2[e] Calcium 2 Ca

camp[e] cAMP -1 C10H11N5O6P

cgly[e] Cys-Gly 0 C5H10N2O3S

cl[e] Chloride -1 Cl

co[e] Carbon monoxide 0 CO

co2[e] CO2 0 CO2

crvnc[e] cervonic acid, C22:6 n-3 -1 C22H31O2

cspg_d[e] chondroitin sulfate D (GlcNAc6S-GlcA2S) proteoglycan -7 C45H64N2O51S5X

cys-L[e] L-Cysteine 0 C3H7NO2S

cytd[e] Cytidine 0 C9H13N3O5

dad-2[e] Deoxyadenosine 0 C10H13N5O3

dcsptn1[e] docosa-4,7,10,13,16-pentaenoic acid (n-6) -1 C22H33O2

dcyt[e] Deoxycytidine 0 C9H13N3O4

din[e] Deoxyinosine 0 C10H12N4O4

dopa[e] Dopamine 1 C8H12NO2

dopasf[e] Dopamine 3-O-sulfate 0 C8H11NO5S

drib[e] Deoxyribose 0 C5H10O4

Table A2. continued

Abbreviation Names Charges Formulas

duri[e] Deoxyuridine 0 C9H12N2O5

fru[e] D-Fructose 0 C6H12O6

gal[e] D-Galactose 0 C6H12O6

gchola[e] glycocholate 0 C26H43NO6

glc-D[e] D-Glucose 0 C6H12O6

gln-L[e] L-Glutamine 0 C5H10N2O3

glu-L[e] L-Glutamate -1 C5H8NO4

gluala[e] 5-L-Glutamyl-L-alanine -1 C8H13N2O5 gly[e] Glycine 0 C2H5NO2

glyc[e] Glycerol 0 C3H8O3

glyc-S[e] (S)-Glycerate -1 C3H5O4

h[e] H+ 1 H

h2o[e] H2O 0 H2O

h2o2[e] Hydrogen peroxide 0 H2O2

ha[e] hyaluronan -2 C28H40N2O22

ha_pre1[e] hyaluronan biosynthesis, precursor 1 -1 C14H20NO11

hco3[e] Bicarbonate -1 CHO3

hdca[e] Hexadecanoate (n-C16:0) -1 C16H31O2

hspg[e] heparan sulfate proteoglycan -13 C79H113N5O101S12X

hxan[e] Hypoxanthine 0 C5H4N4O

ins[e] Inosine 0 C10H12N4O5

k[e] potassium 1 K

lac-D[e] D-Lactate -1 C3H5O3

lac-L[e] L-Lactate -1 C3H5O3

leu-L[e] L-Leucine 0 C6H13NO2

leuktrA4[e] Leukotriene A4 -1 C20H29O3

leuktrB4[e] Leukotriene B4 -1 C20H31O4

leuktrD4[e] Leukotriene D4 -1 C25H39N2O6S

leuktrE4[e] leukotriene E4 -1 C23H36NO5S

leuktrF4[e] leukotriene F4 -2 C28H42N2O8S

lgnc[e] lignoceric acid -1 C24H47O2

meoh[e] Methanol 0 CH4O1

mercplaccys[e] 3-mercaptolactate-cysteine disulfide -1 C6H10O5S2N

met-L[e] L-Methionine 0 C5H11NO2S

mthgxl[e] Methylglyoxal 0 C3H4O2

na1[e] Sodium 1 Na

nh4[e] Ammonium 1 H4N

no[e] Nitric oxide 0 NO

nrpphr[e] Norepinephrine 1 C8H12NO3

Table A2. continued

Abbreviation Names Charges Formulas

nrpphrsf[e] Sulfate derivative of norepinephrine 0 C8H11NO6S

nrvnc[e] nervonic acid -1 C24H45O2

o2[e] O2 0 O2

o2s[e] Superoxide anion -1 O2

ocdca[e] octadecanoate (n-C18:0) -1 C18H35O2

ocdcea[e] octadecenoate (n-C18:1) -1 C18H33O2

orn[e] Ornithine 1 C5H13N2O2 C5H12NO4PFULLRCO2FULLR2CO pe_hs[e] phosphatidylethanolamine (homo sapiens) 0 2 phe-L[e] L-Phenylalanine 0 C9H11NO2 pheacgln[e] alpha-N-Phenylacetyl-L-glutamine 0 C13H16N2O4

pi[e] Phosphate -2 HO4P

pro-L[e] L-Proline 0 C5H9NO2

prostgd2[e] Prostaglandin D2 -1 C20H31O5 C6H11NO6PFULLRCO2FULLR2CO ps_hs[e] phosphatidylserine (homo sapiens) -1 2 pyr[e] Pyruvate -1 C3H3O3

ser-L[e] L-Serine 0 C3H7NO3

so4[e] Sulfate -2 O4S

srtn[e] Serotonin 1 C10H13N2O

succ[e] Succinate -2 C4H4O4

tchola[e] taurocholic acid 0 C26H45NO7S

thr-L[e] L-Threonine 0 C4H9NO3

thym[e] Thymine 0 C5H6N2O2

tmndnc[e] timnodonic acid C20:5, n-3 -1 C20H29O2

trp-L[e] L-Tryptophan 0 C11H12N2O2

trypta[e] Tryptamine 1 C10H13N2

ttdca[e] tetradecanoate (n-C14:0) -1 C14H27O2

txa2[e] Thromboxane A2 -1 C20H31O5

tym[e] Tyramine 1 C8H12NO

tymsf[e] Tyramine O-sulfate 0 C8H11NO4S

urate[e] Urate 0 C5H4N4O3

urea[e] Urea 0 CH4N2O

uri[e] Uridine 0 C9H12N2O6

vitd3[e] Vitamin D3 0 C27H44O

xyl-D[e] D-Xylose 0 C5H10O5

xylt[e] Xylitol 0 C5H12O5 protein-linked serine residue (glycosaminoglycan attachment Ser-Gly/Ala-X-Gly[l] 0 XH site) acgal[l] N-Acetyl-D-galactosamine 0 C8H15NO6

acgam[l] N-Acetyl-D-glucosamine 0 C8H15NO6 chondroitin sulfate C (GalNAc6S-GlcA), degradation product cs_c_deg5[l] -2 C23H36O24S 5

Table A2. continued

Abbreviation Names Charges Formulas

cs_d[l] chondroitin sulfate D (GlcNAc6S-GlcA2S), free chain -7 C45H65N2O52S5 chondroitin sulfate D (GlcNAc6S-GlcA2S), degradation cs_d_deg1[l] -6 C45H66N2O49S4 product 1 chondroitin sulfate D (GlcNAc6S-GlcA2S), degradation cs_d_deg2[l] -6 C37H53NO44S4 product 2 chondroitin sulfate D (GlcNAc6S-GlcA2S), degradation cs_d_deg3[l] -5 C37H54NO41S3 product 3 chondroitin sulfate D (GlcNAc6S-GlcA2S), degradation cs_d_deg4[l] -4 C31H47NO35S3 product 4 chondroitin sulfate D (GlcNAc6S-GlcA2S), degradation cs_d_deg5[l] -3 C31H48NO32S2 product 5 chondroitin sulfate D (GlcNAc6S-GlcA2S), degradation cs_d_deg6[l] -3 C23H35O27S2 product 6 cspg_d[l] chondroitin sulfate D (GlcNAc6S-GlcA2S) proteoglycan -7 C45H64N2O51S5X

fald[l] Formaldehyde 0 CH2O

gal[l] D-Galactose 0 C6H12O6 glcur[l] D-Glucuronate -1 C6H9O7

h[l] H+ 1 H

h2o[l] H2O 0 H2O

h2o2[l] Hydrogen peroxide 0 H2O2

ha[l] hyaluronan -2 C28H40N2O22

ha_deg1[l] hyaluronan degradation product 1 -1 C22H33N2O16

ha_pre1[l] hyaluronan biosynthesis, precursor 1 -1 C14H20NO11

hs[l] heparan sulfate, free chain -13 C79H114N5O102S12

hs_deg1[l] heparan sulfate, degradation product 1 -12 C79H115N5O99S11

hs_deg10[l] heparan sulfate, degradation product 10 -9 C55H80N3O70S8

hs_deg11[l] heparan sulfate, degradation product 11 -8 C55H81N3O67S7

hs_deg12[l] heparan sulfate, degradation product 12 -7 C55H82N3O64S6

hs_deg13[l] heparan sulfate, degradation product 13 -6 C55H83N3O61S5

hs_deg14[l] heparan sulfate, degradation product 14 -7 C57H84N3O62S5

hs_deg15[l] heparan sulfate, degradation product 15 -7 C49H71N2O57S5

hs_deg16[l] heparan sulfate, degradation product 16 -6 C49H72N2O54S4

hs_deg17[l] heparan sulfate, degradation product 17 -5 C43H65N2O48S4

hs_deg18[l] heparan sulfate, degradation product 18 -4 C43H66N2O45S3

hs_deg19[l] heparan sulfate, degradation product 19 -3 C43H67N2O42S2

hs_deg2[l] heparan sulfate, degradation product 2 -11 C79H116N5O96S10

hs_deg20[l] heparan sulfate, degradation product 20 -4 C45H68N2O43S2

hs_deg21[l] heparan sulfate, degradation product 21 -4 C37H55NO38S2

hs_deg22[l] heparan sulfate, degradation product 22 -3 C37H56NO35S

hs_deg23[l] heparan sulfate, degradation product 23 -2 C31H49NO29S

hs_deg24[l] heparan sulfate, degradation product 24 -1 C31H50NO26

hs_deg25[l] heparan sulfate, degradation product 25 -1 C23H37O21

hs_deg3[l] heparan sulfate, degradation product 3 -12 C81H117N5O97S10

hs_deg4[l] heparan sulfate, degradation product 4 -12 C73H104N4O92S10

Table A2. continued

Abbreviation Names Charges Formulas

hs_deg5[l] heparan sulfate, degradation product 5 -11 C67H97N4O86S10

hs_deg6[l] heparan sulfate, degradation product 6 -10 C67H98N4O83S9

hs_deg7[l] heparan sulfate, degradation product 7 -9 C67H99N4O80S8

hs_deg8[l] heparan sulfate, degradation product 8 -10 C69H100N4O81S8

hs_deg9[l] heparan sulfate, degradation product 9 -10 C61H87N3O76S8

hspg[l] heparan sulfate proteoglycan -13 C79H113N5O101S12X

idour[l] L-Iduronate -1 C6H9O7

meoh[l] Methanol 0 CH4O1

so4[l] Sulfate -2 O4S

xyl-D[l] D-Xylose 0 C5H10O5

1p3h5c[m] L-1-Pyrroline-3-hydroxy-5-carboxylate -1 C5H6NO3

1pyr5c[m] 1-Pyrroline-5-carboxylate -1 C5H6NO2 25hvitd2[m] 25-Hydroxyvitamin D2 0 C28H44O2

25hvitd3[m] 25-Hydroxyvitamin D3 0 C27H44O2

3mop[m] (S)-3-Methyl-2-oxopentanoate -1 C6H9O3

4abut[m] 4-Aminobutanoate 0 C4H9NO2

4hglusa[m] L-4-Hydroxyglutamate semialdehyde 0 C5H9NO4

4mop[m] 4-Methyl-2-oxopentanoate -1 C6H9O3

5aop[m] 5-Amino-4-oxopentanoate 0 C5H9NO3

aacoa[m] Acetoacetyl-CoA -4 C25H36N7O18P3S

acac[m] Acetoacetate -1 C4H5O3

accoa[m] Acetyl-CoA -4 C23H34N7O17P3S

adn[m] Adenosine 0 C10H13N5O4

adp[m] ADP -3 C10H12N5O10P2

akg[m] 2-Oxoglutarate -2 C5H4O5

amp[m] AMP -2 C10H12N5O7P

arachdcoa[m] C20:4-CoA -4 C41H62N7O17P3S

arachdcrn[m] C20:4 carnitine 0 C27H45NO4

asn-L[m] L-Asparagine 0 C4H8N2O3

asp-L[m] L-Aspartate -1 C4H6NO4

atp[m] ATP -4 C10H12N5O13P3

bhb[m] (R)-3-Hydroxybutanoate -1 C4H7O3

cbp[m] Carbamoyl phosphate -2 CH2NO5P

cit[m] Citrate -3 C6H5O7

citr-L[m] L-Citrulline 0 C6H13N3O3

co2[m] CO2 0 CO2

coa[m] Coenzyme A -4 C21H32N7O16P3S

crn[m] L-Carnitine 0 C7H15NO3

datp[m] dATP -4 C10H12N5O12P3

Table A2. continued

Abbreviation Names Charges Formulas

dcsptn1coa[m] docosa-4,7,10,13,16-pentaenoyl coenzyme A -4 C43H64N7O17P3S

dcsptn1crn[m] docosa-4,7,10,13,16-pentaenoyl carnitine 0 C29H47NO4

dgdp[m] dGDP -3 C10H12N5O10P2

dgtp[m] dGTP -4 C10H12N5O13P3

dmnoncoa[m] 4,8 dimethylnonanoyl-CoA -4 C32H54N7O17P3S

dmnoncrn[m] 4,8 dimethylnonanoyl carnitine 0 C18H37NO4

dtdp[m] dTDP -3 C10H13N2O11P2

dttp[m] dTTP -4 C10H13N2O14P3

dudp[m] dUDP -3 C9H11N2O11P2

dump[m] dUMP -2 C9H11N2O8P

dutp[m] dUTP -4 C9H11N2O14P3

e4hglu[m] L-erythro-4-Hydroxyglutamate -1 C5H8NO5

etfox[m] Electron transfer flavoprotein oxidized 0 R etfrd[m] Electron transfer flavoprotein reduced 0 RH2

fad[m] Flavin adenine dinucleotide oxidized -2 C27H31N9O15P2

fadh2[m] Flavin adenine dinucleotide reduced -2 C27H33N9O15P2

fe2[m] Fe2+ 2 Fe

ficytC[m] Ferricytochrome c 3 C42H54FeN8O6S2

focytC[m] Ferrocytochrome C 2 C42H54FeN8O6S2

fum[m] Fumarate -2 C4H2O4

gdp[m] GDP -3 C10H12N5O11P2

gln-L[m] L-Glutamine 0 C5H10N2O3

glu-L[m] L-Glutamate -1 C5H8NO4

glu5sa[m] L-Glutamate 5-semialdehyde 0 C5H9NO3

gly[m] Glycine 0 C2H5NO2

gthox[m] Oxidized glutathione -2 C20H30N6O12S2

gthrd[m] Reduced glutathione -1 C10H16N3O6S

gtp[m] GTP -4 C10H12N5O14P3

h[m] H+ 1 H

h2o[m] H2O 0 H2O

h2o2[m] Hydrogen peroxide 0 H2O2

hco3[m] Bicarbonate -1 CHO3

hmgcoa[m] Hydroxymethylglutaryl-CoA -5 C27H39N7O20P3S

icit[m] Isocitrate -3 C6H5O7

ile-L[m] L-Isoleucine 0 C6H13NO2

lac-L[m] L-Lactate -1 C3H5O3

leu-L[m] L-Leucine 0 C6H13NO2

lnlncgcoa[m] gamma-linolenoyl-CoA -4 C39H60N7O17P3S

mal-L[m] L-Malate -2 C4H4O5

Table A2. continued

Abbreviation Names Charges Formulas

methf[m] 5,10-Methenyltetrahydrofolate -1 C20H20N7O6

mlthf[m] 5,10-Methylenetetrahydrofolate -2 C20H21N7O6

nad[m] Nicotinamide adenine dinucleotide -1 C21H26N7O14P2

nadh[m] Nicotinamide adenine dinucleotide - reduced -2 C21H27N7O14P2

nadp[m] Nicotinamide adenine dinucleotide phosphate -3 C21H25N7O17P3

nadph[m] Nicotinamide adenine dinucleotide phosphate - reduced -4 C21H26N7O17P3

nh4[m] Ammonium 1 H4N

o2[m] O2 0 O2

o2s[m] Superoxide anion -1 O2

oaa[m] Oxaloacetate -2 C4H2O5

occoa[m] Octanoyl-CoA (n-C8:0CoA) -4 C29H46N7O17P3S

orn[m] Ornithine 1 C5H13N2O2 C5H12NO4PFULLRCO2FULLR2CO pe_hs[m] phosphatidylethanolamine (homo sapiens) 0 2 pep[m] Phosphoenolpyruvate -3 C3H2O6P pheme[m] Protoheme -2 C34H30FeN4O4

pi[m] Phosphate -2 HO4P

pmtcoa[m] Palmitoyl-CoA (n-C16:0CoA) -4 C37H62N7O17P3S

pmtcrn[m] L-Palmitoylcarnitine 0 C23H45NO4

ppi[m] Diphosphate -3 HO7P2

ppp9[m] Protoporphyrin -2 C34H32N4O4

pppg9[m] Protoporphyrinogen IX -2 C34H38N4O4

pro-L[m] L-Proline 0 C5H9NO2

pyr[m] Pyruvate -1 C3H3O3

q10[m] Ubiquinone-10 0 C59H90O4

q10h2[m] Ubiquinol-10 0 C59H92O4

strdnccoa[m] stearidonyl coenzyme A -4 C39H58N7O17P3S

succ[m] Succinate -2 C4H4O4

succoa[m] Succinyl-CoA -5 C25H35N7O19P3S

sucsal[m] Succinic semialdehyde -1 C4H5O3

tmndnccoa[m] timnodonyl coenzyme A -4 C41H60N7O17P3S

vitd3[m] Vitamin D3 0 C27H44O

arachd[r] arachidonic acid -1 C20H31O2

dolglcp_L[r] Dolichyl beta-D-glucosyl phosphate, human liver homolog -10 C1140H1868O90P10

dolglcp_U[r] Dolichyl beta-D-glucosyl phosphate, human uterine homolog -10 C1085H1780O90P10

dolichol_L[r] Dolichol, human liver homolog 0 C1080H1768O10

dolichol_U[r] Dolichol, human uterine homolog 0 C1025H1680O10

dolp_L[r] Dolichol phosphate, human liver homolog -20 C1080H1758O40P10

dolp_U[r] Dolichol phosphate, human uterine homolog -20 C1025H1670O40P10

g6p[r] D-Glucose 6-phosphate -2 C6H11O9P

Table A2. continued

Abbreviation Names Charges Formulas

glac[r] D-glucurono-6,3-lactone 0 C6H8O6

glc-D[r] D-Glucose 0 C6H12O6

glcur[r] D-Glucuronate -1 C6H9O7

glu-L[r] L-Glutamate -1 C5H8NO4

gthrd[r] Reduced glutathione -1 C10H16N3O6S

gullac[r] L-Gulono-1,4-lactone 0 C6H10O6

guln[r] L-Gulonate -1 C6H11O7

h[r] H+ 1 H

h2o[r] H2O 0 H2O

leuktrA4[r] Leukotriene A4 -1 C20H29O3

leuktrC4[r] Leukotriene C4 -2 C30H45N3O9S

leuktrD4[r] Leukotriene D4 -1 C25H39N2O6S

nadp[r] Nicotinamide adenine dinucleotide phosphate -3 C21H25N7O17P3

nadph[r] Nicotinamide adenine dinucleotide phosphate - reduced -4 C21H26N7O17P3

o2[r] O2 0 O2 pi[r] Phosphate -2 HO4P

prostgh2[r] Prostaglandin H2 -1 C20H31O5

txa2[r] Thromboxane A2 -1 C20H31O5

acac[x] Acetoacetate -1 C4H5O3

accoa[x] Acetyl-CoA -4 C23H34N7O17P3S

acrn[x] O-Acetylcarnitine 0 C9H17NO4

adrncoa[x] adrenyl coenzyme A -4 C43H66N7O17P3S

ala-D[x] D-Alanine 0 C3H7NO2

ala-L[x] L-Alanine 0 C3H7NO2

arachdcoa[x] C20:4-CoA -4 C41H62N7O17P3S

coa[x] Coenzyme A -4 C21H32N7O16P3S

crn[x] L-Carnitine 0 C7H15NO3

dcsptn1coa[x] docosa-4,7,10,13,16-pentaenoyl coenzyme A -4 C43H64N7O17P3S

glx[x] Glyoxylate -1 C2H1O3

gly[x] Glycine 0 C2H5NO2

h[x] H+ 1 H

h2o[x] H2O 0 H2O

h2o2[x] Hydrogen peroxide 0 H2O2

hmgcoa[x] Hydroxymethylglutaryl-CoA -5 C27H39N7O20P3S

hpyr[x] Hydroxypyruvate -1 C3H3O4

hxan[x] Hypoxanthine 0 C5H4N4O

lnlncgcoa[x] gamma-linolenoyl-CoA -4 C39H60N7O17P3S

nad[x] Nicotinamide adenine dinucleotide -1 C21H26N7O14P2

nadh[x] Nicotinamide adenine dinucleotide - reduced -2 C21H27N7O14P2

Table A2. continued

Abbreviation Names Charges Formulas

nh4[x] Ammonium 1 H4N

o2[x] O2 0 O2

o2s[x] Superoxide anion -1 O2

occoa[x] Octanoyl-CoA (n-C8:0CoA) -4 C29H46N7O17P3S

pmtcoa[x] Palmitoyl-CoA (n-C16:0CoA) -4 C37H62N7O17P3S

prist[x] pristanic acid -1 C19H37O2

pristcoa[x] pristanoyl coa -4 C40H68N7O17P3S

pyr[x] Pyruvate -1 C3H3O3

ser-L[x] L-Serine 0 C3H7NO3

stcoa[x] Stearoyl-CoA (n-C18:0CoA) -4 C39H66N7O17P3S

strdnccoa[x] stearidonyl coenzyme A -4 C39H58N7O17P3S

tmndnccoa[x] timnodonyl coenzyme A -4 C41H60N7O17P3S

urate[x] Urate 0 C5H4N4O3

xan[x] Xanthine 0 C5H4N4O2

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