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Life Science IO ILES BVolume 4, Number 8 F Metabolomics

Amino acid metabolites for: Natural Product Disease State Biomarkers

Sigma-Aldrich metabolite standards, enzymes, Inborn Error Metabolism HPLC solvents, and separation technologies Stable Isotope-Labeled help you navigate the metabolic pathways to Metabolic Studies biomarker discovery.

BiofilesVol4No8FINAL.indd 1 11/10/2009 12:00:02 PM Life Science

BVolume 4, ioNumber 8 Fi l e s Your gateway to Biochemicals and Reagents for Life Science Research from Sigma® Table of Contents

Introduction 3

An Expanded Set of Analogs for the Ribosomal Translation of Unnatural Peptides 4 Background 4 Methodology/Principal Findings 4 Conclusions/Significance 4 Introduction 4 Aminoacylation Competition Assay 5 Translation Efficiency of Analogs 5 BioFiles Online allows you to: Discussion 5

 Easily navigate the content of the current BioFiles issue Amino Acid Metabolites in Natural  Access any issue of BioFiles Product Biosynthesis 7  Subscribe for: ✓ future issues Amino Acid Metabolites as Biomarkers for the ✓ eBioFiles email notifications Differentiation of Diseased and Healthy Cells 8

 Gain access to Sigma BioBlogs Characteristic Metabolites for Inborn Errors Register today for upcoming issues and eBioFiles announcements at of Amino Acid Metabolism 9 sigma.com/biofiles Altered Amino Acid Metabolites in Aging 10 Metabolomics Online Non-Labeled Amino Acid Metabolites 11 Our Sigma Life Science Metabolomics page is a comprehensive resource for your metabolomic research needs. In addition to our enzymatic based kits and Stable Isotope-Labeled Amino Acid Metabolites 16 enzymes, our alliance with the International Union of Biochemistry and Molecular Biology (IUBMB) enables us to feature the Nicholson Metabolomic Pathway Charts Metabolite Libraries 20 and Animations. Amino Acid Metabolite Library 21 n Enzymatic Kits Metabolite Library 22 n Metabolic Enzymes Carbohydrate Metabolite Library 23 n Metabolic Libraries New Metabolites from Sigma-Aldrich 25 n Metabolic Pathways n And more Drug Discovery 26 DiscoveryCPR: Discover with Custom Packaged Visit us at sigma.com/metabolomics Pharmacologically Active Compounds and Metabolites 26 Metabolomic MetaFind Contest LOPAC®1280: Library of Pharmacologically Active Compounds 27 Win one of two Garmin nüvi 855W GPS Street Navigators! Sigma-Aldrich has been there Metabolite Chromatographic Analysis 28 to help you navigate the pathways of metabolism Ascentis® Express HILIC from Supelco® 28 for over 50 years. Now, we’ll help two sharp-eyed CHROMASOLV® Solvents 29 researchers navigate their own journeys!

Find all of the metabolomic-related signs incorporated into the front cover, then correctly fill out the reply card in this issue or go online to register to win. Everyone who enters can receive a free Metabolic Pathways Poster. To register online, visit sigma.com/metafind

2 Introduction Roland Wohlgemuth [email protected] Introduction The metabolic pathways around the to the amino acid, protein and energy metabolism. Amino acid 20 common α-amino acids are unique metabolism is therefore influenced by a variety of factors, which for each amino acid, but also central can be investigated directly at the amino acid level or at the related to all living organisms. Plants and metabolite level in the corresponding amino acid pathway. microorganisms can produce their own The introduction of non-radioactive and stable isotope tracer amino acids, whereas mammals/humans methods has enabled safe investigations of protein and amino can do this only partially. They need to digest proteins in order to acid metabolism from microorganisms, plants, animals or humans. obtain several of their amino acids. Selective inhibition of amino Nutritional and pathological conditions can influence protein acid biosynthesis is therefore of high interest in the agrochemical deficiencies leading to amino acid limitations or on the other hand and pharmaceutical industry as a strategy to destroy undesired can lead to a surplus of amino acids in metabolic diseases. As a plants or pathogens without affecting mammals/humans. correct level of amino acids is vital, the biosynthesis of amino acids The metabolic breakdown of the common α-amino acids starts with is regulated by a variety of mechanisms at the DNA, RNA or protein the removal of the α-amino group as either ammonia or aspartate, level. In the biosynthesis of amino acids, induction or repression which can directly be excreted to the surroundings by fish and other of enzymes are not the most important regulation mechanisms. aquatic animals. Terrestrial organisms however must convert the Different amino acid riboswitches have been discovered which ammonia into a non-toxic compound like (mammals) or uric act on the RNA level by selectively sensing the corresponding acid (birds and reptiles). The remaining amino acid carbon skeleton, amino acid. The most important regulatory mechanism is feedback which often is an α-keto acid, is then converted into an intermediate regulation at the level of enzyme action and enzyme synthesis. capable of entering the . The diversity of natural amino acid metabolic pathways and their The tasks within the metabolic pathways to synthesize the common connections show the importance of a balanced and robust supply 20 amino acids as building blocks for proteins are distributed of these molecules for a healthy state of biological cells. Therefore, differently in the biosphere. Humans are able to synthesize it is not surprising that L-amino acids are among the most 11 out of the 20 amino acids, while the other 9 amino acids are only important industrial central metabolites, manufactured at 100 to synthesized in plants or microorganisms and must therefore be 1,500,000 ton scale for the cosmetic, food, feed and nutraceutical taken up by humans and other higher organisms through nutrition. industries. The experience in the optimization of amino acid Genetics, birth, development and adaptation, health and production levels in industry has clearly shown that detailed disease, stage of life and environment can bring in major shifts quantitative knowledge of the metabolism is required in order to design superior production strains.

+ H NH3 + + O O H NH3 H NH3 2- O3PO HO - COO - - - COO- COO COO COO L- Pyruvate 3-Phospho-L- L-Serine Pyruvate O

COO- Pyruvate O HO H

+ 2- O H NH3 2- O PO O3PO 3 O - C COO- COO - - OOC H2N COO COO- 3-Phospho-Hydroxypyruvate 3-Phospho-D-Glycerate L- Oxaloacetate

+ + H NH3 + H NH3 H NH3 O -OOC 2- O3PO - - COO - COO COO COO- L-Aspartate H OH O Phospho-L-Homoserine L- Pyruvate -OOC -OOC COO- COO-

Oxaloacetate Fumarate

+ H NH3 + NH3 O HO + H NH3 COO- H2C HO - - COO L-Homoserine COO- COO Pyruvate L-Serine

O

C H COO- Glyoxalate

Our Innovation, Your Research — Shaping the Future of Life Science 3 An Expanded Set of Amino Acid Analogs for the Ribosomal Translation of Unnatural Peptides An excerpt taken from PLoS ONE 2(10): e972. doi:10.1371/ Introduction journal.pone.0000972. The complete reference and accompanying citations are available online at plosone.org The recent development of translation systems reconstituted entirely from purified components [1-4] has enabled the ribosomal Matthew C. T. Hartman, Kristopher Josephson, Chi-Wang Lin, synthesis of peptides composed primarily of unnatural (i.e. non- Jack W. Szostak proteinogenic) amino acids. The major roadblock to the ribosomal Howard Hughes Medical Institute, Department of Molecular synthesis of highly modified drug-like peptides is the limited Biology, Center for Computational and Integrative Biology, number of unnatural building blocks known to be compatible with Simches Research Center, Massachusetts General Hospital, Boston, the translation apparatus. This dearth of unnatural building blocks Massachusetts, United States of America results in part from difficulties in loading unnatural amino acids Copyright: © 2009 Matthew C. T. et al. This is an open-access onto tRNA, the key first step in translation. Several techniques for article distributed under the terms of the Creative Commons charging tRNAs with unnatural amino acids have been developed Attribution License, which permits unrestricted use, distribution, such as chemoenzymatic tRNA acylation [5-7], ribozyme and reproduction in any medium, provided the original author and acylation [8], chemical acylation using PNA thioesters [9], and source are credited. the use of engineered aminoacyl-tRNA synthetases (AARSs) [10]. Unfortunately all of these approaches require specialized reagents and/or multistep syntheses. In contrast, an all-enzymatic system Background using the wild-type AARSs would be as convenient as a standard The application of in vitro translation to the synthesis of unnatural translation experiment using the twenty proteinogenic amino peptides may allow the production of extremely large libraries acids. To this end we have recently developed a MALDI-TOF MS of highly modified peptides, which are a potential source of lead screening assay [11] that has uncovered over 90 unnatural compounds in the search for new pharmaceutical agents. The building blocks that are AARS substrates. The incorporation specificity of the translation apparatus, however, limits the diversity of these amino acids into peptides, however, depends on of unnatural amino acids that can be incorporated into peptides the efficiency of aminoacylation, and on whether or not they by ribosomal translation. We have previously shown that over are compatible with the translational steps subsequent to 90 unnatural amino acids can be enzymatically loaded onto tRNA. aminoacylation. The specificity of many of these steps with respect to unnatural amino acids is unknown. It is clear; however, that the ribosome does not tolerate certain very sterically demanding Methodology/Principal Findings aminoacyl-tRNAs [12,13], and recent studies suggest that a We have now used a competition assay to assess the efficiency of threshold EF-Tu affinity is required for aminoacyl-tRNAs to enter the tRNA-aminoacylation of these analogs. We have also used a series of A-site of the ribosome [14]. Particular types of backbone analogs peptide translation assays to measure the efficiency with which these also seem to be excluded during these translational steps [15],

An Expanded Set of Amino Acid Analogs for the Ribosomal Translation of Unnatural Peptides Translation the Ribosomal Analogs for An Expanded Set of Amino Acid analogs are incorporated into peptides. The translation apparatus although exactly how they are rejected is not well-understood. Our tolerates most side chain derivatives, a few α,α-disubstituted, newly defined pool of AARS substrates is ideal for addressing these N-methyl- and α-hydroxy-derivatives, but no β-amino acids. We show specificity questions because it contains a diverse collection of side that over 50 unnatural amino acids can be incorporated into peptides chain, N-methyl-, α,α-disubstituted and β-aminoacyl-tRNAs. Here by ribosomal translation. Using a set of analogs that are efficiently we describe a straight forward means of determining whether an charged and translated we were able to prepare individual peptides enzymatically charged unnatural amino acid can be effectively containing up to 13 different unnatural amino acids. incorporated into a peptide. The results of these experiments have allowed us to identify over 50 unnatural amino acids that can be incorporated at a single defined position in a peptide with high Conclusions/Significance efficiency using an all-enzymatic translation system. Our work Our results demonstrate that a diverse array of unnatural building identifies building blocks that can be combined to prepare highly blocks can be translationally incorporated into peptides. These modified peptides that contain multiple unnatural amino acids. building blocks provide new opportunities for in vitro selections We also identify many cases where the engineering of synthetases, with highly modified druglike peptides. EF-Tu or the ribosome itself may be required to enable efficient incorporation of interesting analogs.

4 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Aminoacylation Competition Assay acid, by comparison of the peptide radioactivity for the all-natural peptide with that containing the unnatural analog. To verify that The MALDI-TOF MS assay that we used to identify unnatural amino the translated peptide contained the unnatural amino acid, the acids that are AARS substrates [11] does not provide a quantitative mass of the peptide was determined by MALDI-MS. For unnatural measure of tRNA charging efficiency. The rate of synthesis of amino acids that differed in mass by +/–1 amu from their natural aminoacylated tRNA, and the degree to which an analog competes counterparts, we verified incorporation using templates requiring of Amino AcidAn Expanded Set Analogs for the Ribosomal Translation of Unnatural Peptides effectively against traces of contamination with the natural amino multiple (4-7) incorporations. For instance, incorporation of the acid, can greatly affect the yield and purity of analog-containing analog A18 was tested using a template with peptides synthesized by in vitro translation. However, detailed 4 tryptophan codons (see supporting information Figure S1) and kinetic analysis of large numbers of analogs is not feasible. We was unambiguously identified due to its +4 mass difference from therefore devised an AARS competitive inhibition assay in which the the tryptophan containing peptide. We grouped the amino acid charging of a natural amino acid in the presence and absence of an analogs that we studied into three classes based on translation analog could be quantitatively compared by MS through the use of efficiency and specificity. Class I monomers resulted in a peptide an isotopically labeled derivatizing reagent [11]. In order to compare yield that was >75% of that obtained with the corresponding natural analog inhibition among different AARSs, we set the natural amino amino acid, and the translated peptide was homogeneous by acid at roughly 2x its Km and then added the unnatural amino acid MALDI-MS analysis. Class II monomers were translated less efficiently, analog at 1000-fold higher concentration. As an example, the with a peptide yield ranging from 25% to 75% of that obtained assays for the inhibition measurement of valine analog 3-fluoro- with the natural amino acid, but the translated peptide was still valine (N15) are shown in Figure 1. For each assay an identical homogeneous. Class III monomers were either poorly translated amount of nonisotopically derivatized Val-AMP was added as an (<25% peptide yield) and/or led to a heterogeneous mixture of internal standard, and experiments in the presence or absence peptides. In many cases inefficient translation correlated with poor of the analog were performed using the deuterium (d15) labeled aminoacylation, suggesting that the synthesis of aminoacylated derivatizing reagent [11]. The presence of competing N15 clearly tRNA may have limited peptide yield. Peptide heterogeneity was led to a strong decrease in the intensity of the d15-Val-AMP most often due to the misincorporation of natural amino acids in peak (Figure 1B) when compared to the assay with valine alone place of the desired analog. We discuss these analogs in groups (Figure 1A). Comparison of the ratio of Val-AMP to d15-Val-AMP in the based on their side chain and backbone compositions. We used the presence and absence of the analog allowed determination of the same amino acid abbreviations used in our previous paper [11] % inhibition value. The inhibition data for the analogs is presented (C = Charged, P= Polar, A =Aromatic, N= Nonpolar, α = α,α in Table 1. As expected, different analogs vary widely in their disubstituted, β = beta amino acid, M= N-methyl). Since our first ability to competitively inhibit the aminoacylation of the natural report we have found two additional unnatural amino acids that are amino acids. In general, we expect good competitive inhibitors efficiently aminoacylated and translated; these compounds to be good substrates, although this correlation need not always ('Photo-Leu', N25; 'Photo-Met', N26) are also discussed below. Finally, hold. Nevertheless, as discussed below, analogs that are good we have described the translation results for twelve of these analogs competitive inhibitors tend to be translated more efficiently than in a preliminary report [1]; because these analogs are included in the analogs that are poor competitors, supporting the idea that the other experiments described herein, we have included them here. synthesis of high levels of aminoacylated tRNA during a translation reaction facilitates the synthesis of analog-bearing peptides. Discussion Translation Efficiency of Analogs Correlation Between Aminoacylation We have previously defined a set of 90 amino acid analogs that can and Translation Assay be enzymatically charged onto tRNA [11]. To determine which of A scatter plot comparing inhibition of the AARS reaction containing these could be incorporated into peptides, we used an assay based the cognate, natural amino acid and translation yield (single on the translation of short peptides containing a single unnatural incorporation in templates a-e) is shown in Figure 10. Analogs that amino acid. We prepared 5 separate mRNA templates containing a are efficient AARS competitors are located in the top half of the plot, C-terminal FLAG or His6 tag for purification; this set of templates is and analogs that are translated efficiently appear on the right. From similar to but more complete than that previously described [1]. the plot it is clear that there is a correlation between competition Each template was designed to test analogs of 4 of the natural with the natural AA for the AARS and translation efficiency—there amino acids (Figure 2, a-e). The translation reactions were then are no highly efficient AARS competitors that translate poorly carried out in the PURE translation system [1,4] with 35S- and thus would appear in the upper left quadrant of the plot. as the N-terminal radiolabel, except for Met analogs which were There are, on the other hand, a few analogs that translate well, tested using 3H-His and template e. In each test, one of the natural but are inefficient AARS competitors and appear in lower right amino acids was omitted and a corresponding analog added in quadrant. These include A19, A21-A25, C9, C11, N11, N20, and P1. its place; thus synthesis of radiolabeled tagged peptide required Several of these (A24, A25, C11, 11, N20, and P1) were among the readthrough of the codon assigned to the unnatural amino acid [1]. more inefficient analogs with the 20 AA template experiments. The peptide yield for each unnatural amino acid was determined Thus it seems reasonable to conclude that for these analogs relative to the peptide yield for the corresponding natural amino the inefficiency is occurring during the AARS charging step. The synthetases (LeuRS and TrpRS) activating the remaining analogs in

Our Innovation, Your Research — Shaping the Future of Life Science 5 the lower right quadrant of the graph (A19, A21-23 and C9) have peptides in our assays of 13 α-hydroxy acids, either the synthetases

especially low Kms (1.5 μM [59] and 12 μM [60] respectively) for their or EF-Tu must discriminate against the other α-hydroxy acids. Given cognate AAs. This might allow them to compensate for their relative that many α-hydroxy acids are common metabolites (e.g. glycolate, inefficiencies of charging since the analogs were tested in these lactate, glycerate, malate) while others may be generated at low particular translation experiments at 400 μM. levels in cells by hydrolysis of acyl-CoA intermediates or reduction of α-keto acids, it would not be surprising if many synthetases Specificity of the Translation Apparatus and perhaps EF-Tu have evolved the ability to discriminate As a step towards the synthesis of large libraries of NRP-like against α-hydroxy acids. If this is the case, it will be necessary to molecules using an in vitro translation system, we have studied engineer modified synthetases and perhaps EF-Tu to enable the the tolerance of the translation apparatus to a wide variety of efficient enzymatic incorporation of α-hydroxy acids into peptides. amino acid analogs. The translation experiments are summarized Similar synthetase engineering may be needed for the N-methyl by analog class in Table 2. Most side chain analogs are efficiently amino acids, which, except for N-methyl His and Asp were poorly incorporated into peptides, but the backbone analogs are for the incorporated into peptides in our experiments and were poor AARS most part poorly translated. Of the 71 analogs tested, 41 side chain competitors as well. Previous experiments show that chemically analogs are efficiently translated with high fidelity along with the generated N-methyl aminoacyl-tRNAs can be used to generate other 19 AAs, and another 8 side chain and 2 backbone analogs methylated peptides with reasonable efficiency [15,63], suggesting should be efficiently translated if contamination of the translation that the main block to incorporation is not at the level of EF-Tu or system with natural, cognate AAs can be removed. The remaining the ribosome. By default, poor efficiency of tRNA charging may be analogs (mostly backbone), although AARS substrates, are poorly the limiting factor. In contrast, the β-amino acids are likely to be incorporated into peptides during translation. Considering the side discriminated against by the active site of the peptidyl transferase chain analogs as a class, poor charging onto tRNA appears to be center, possibly due to a higher pKa of the amino group [53]. the most common explanation for inefficient translation. This is supported by the correlation between competitive aminoacylation 140 inhibition (a surrogate for aminoacylation activity) and translation

efficiency (peptide yield and homogeneity) (Figure 10). For 120 certain side chain analogs this explanation is certainly correct because they have been incorporated into peptides with good 100 efficiency using stop codon suppression systems. For example, p-nitrophenylalanine (A14) has been efficiently incorporated 80 into proteins in E. coli using an engineered AARS [61]. Similarly e inhibition β-cyclopentyl alanine (N19) [51] and L-C-propargyl glycine (N9) [3] have been efficiently added using E. coli in vitro translation systems. 60 The correlation between charging efficiency and translatability suggests that enzyme engineering of the AARSs to better 40 recognize certain analogs will be an important step to improve % AARS competitiv

translation yield. Alternatively, enzymatic pre-charging of the tRNAs 20 at high enzyme and amino acid concentrations prior to addition An Expanded Set of Amino Acid Analogs for the Ribosomal Translation of Unnatural Peptides Translation the Ribosomal Analogs for An Expanded Set of Amino Acid to the translation mixture may improve yields while minimizing 0 product heterogeneity due to competition from efficiently acylated contaminating natural amino acids. -20 For the backbone analogs, the relative importance of 0 20 40 60 80 100 aminoacylation efficiency vs. later steps in translation varies with the % Translation Yield

type of backbone modification. In the case of the α-hydroxy acids, Figure 10. Comparison of % AARS competition and % translation yield for all we cannot detect tRNA acylation directly. However, the ribosomes of the analogs shown in Table 1. The symbols are as follows: blue circles-side from E. coli are known to be able to generate linked products chain analogs, green squares-α,α disubstituted amino acids, black open triangles-N-methyl amino acids, red diamonds-β-amino acids. Translation yields for the α-hydroxy analogs of Phe, Leu, Ile, Ala, [15,51,57,62] and for analogs that gave multiple peaks in the translation experiment were set to now Met. Since only α-hydroxy methionine was incorporated into zero for this graph.

6 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Amino Acid Metabolites in Natural Product Biosynthesis

The biosynthesis of natural products can also utilize amino acids which differ from the proteinogenic amino acids required for the ribosomal machinery. Several hundred other Starting a new lab? Amino Acid in Natural Product Metabolites Biosynthesis building blocks, in addition to the the twenty standard amino acids found in proteins, can be incorporated into the final products of non-ribosomal peptide synthesis. Beside the pathways dependent on nonribosomal peptide synthetases (NRPS), complex natural products are also formed by NRPS-independent pathways. Non-proteinogenic amino acids like 3-amino-5-hydroxy-benzoic acid for the biosynthesis of ansamycin or 3,5-dihydroxyphenylglycine for and biosynthesis offer interesting building blocks for a diversity of natural products.

Name Cat. No. l-2-Aminoadipic acid, O HNH2 A7275-100MG OH ≥98% (TLC) HO A7275-250MG O A7275-1G A7275-5G

H 7-Aminocephalo- H2N S 191140-1G sporanic acid, 98% 191140-5G N O CH3 O O O OH

3-Amino-5- O 05881 ® HO Let Sigma-Aldrich help you get it done on time, hydroxybenzoic OH acid hydrochloride, • HCl on the spot and on the money.

≥97.0% (HPLC) NH2

N-(p-Coumaroyl)-l- O 07077-50MG Moving to a new location? O homoserine lactone, N H O ≥94% (HPLC) HO Make a good first impression – choose high-quality l-2,3-Diamino- O 33270-1G-F products at competitive prices from Sigma-Aldrich. OH propionic acid H2N hydrochloride, H HCl Received your first research grant? ≥97.0% H2N

(S)-3,5-Dihydroxy- NH2 D3689-5MG Focus on your discoveries – not your expenses. phenylglycine HO OH D3689-10MG hydrate, ≥98% (HPLC) O Let Sigma-Aldrich help you make the most of your OH • xH2O research dollars. H 4-Hydroxy-l- NH2 56160-10G phenylglycine, O 56160-50G Easy & Economical Sigma-Aldrich New Lab puriss., ≥99.0% (NT) OH HO Start-Up Program! 4-Hydroxy- O 114286-1G phenylpyruvic OH 114286-5G  Over 100,000 quality biochemical and organic acid, 98% O HO chemical products Indole-3-pyruvic acid O I7017-1G  Savings of up to 70% OH I7017-5G O N  Additional savings as your order value increases H d-, HNH2 P4875-1G H3C OH Join the Sigma-Aldrich New Lab Start-Up program – 98-101% HS P4875-5G CH3 O P4875-25G contact your local sales representative for more information. d-Pipecolinic 268062-100MG OH acid, 99% N H O sigma-aldrich.com Porphobilinogen HN O P1134-1MG H2N OH P1134-5MG OH P1134-10MG O P1134-50MG

2,3-Pyridine- O P63204-25G dicarboxylic OH P63204-100G OH acid, 99% N O

Tryptamine, ≥99% NH2 T2891-10MG T2891-250MG N H T2891-1G

Tyramine NH2 T2879-10MG hydrochloride, ≥98% HCl T2879-1G T2879-5G T2879-25G

OH T2879-100G

Our Innovation, Your Research — Shaping the Future of Life Science 7 Amino Acid Metabolites as Biomarkers for the Differentiation of Diseased and Healthy Cells

Changes from healthy states of biological cells to pathogenic Name Cat. No.

forms and conditions can be described in terms of important d-, O O 27505-500MG-F

≥99.0% (NT) H2N N OH H high molecular weight constituents of cells like nucleic acids, NH2

proteins, , glycocompounds as well as in terms of small Creatinine, O C4255-10MG NH anhydrous C4255-10G molecular weight compounds. The search for meaningful small NH N C4255-25G molecules as biomarkers in urine or blood for diseases is highly CH3 C4255-100G attractive due to the established world-wide track record of C4255-1KG 3,4-Dihydroxy-l- HO D9628-5G metabolite analysis in routine clinical chemistry analysis. The focus HNH2 phenylalanine OH D9628-25G HO thereby is however restricted to a small number of metabolites O D9628-100G D9628-500G for which the corresponding rapid analytical methods have been Dopamine NH2 H8502-5G highly automated. hydrochloride H8502-10G • HCl H8502-25G

The development of new methodologies in metabolomics OH H8502-100G research allowing now the simultaneous analysis of a large number OH Kynurenic acid, ≥98% OH K3375-250MG of metabolites opens the way for the discovery of disease-related K3375-1G OH metabolites. This identification of biomarkers in biological samples N K3375-5G is simplified by the availability of the corresponding metabolites O in pure form, as demonstrated by the increasing number of l-Kynurenine O K8625-25MG OH K8625-100MG correlations between changes in metabolism and diseases states, NH2 O NH2 K8625-500MG K8625-1G not only in metabolic diseases but also in certain cancers like e.g. 3-Nitro-l- O N7389-5G O N the identification of as a biomarker for the presence and 2 OH N7389-10G NH2 N7389-25G progression of prostate cancer. HO l-Pipecolic acid, 99% P2519-100MG OH Metabolic profiling experiments have been of great use to (titration) N P2519-250MG H researchers in the search for small molecular weight biomarkers of O P2519-1G O Sarcosine, SigmaUltra H S7672-10MG diseased cells, tissues or toxicity issues, but also for the assessment N H3C OH S7672-25G of the influence of a new drug candidate on metabolic processes S7672-100G and its metabolic stability.

Amino Acid Metabolites as Biomarkers for the Differentiation of Diseased and Healthy Cells of Diseased and Healthy Metabolites as Biomarkers the Differentiation Amino Acid for Visit the Enzyme Explorer Assay Library

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8 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Characteristic Metabolites for Inborn Errors of Amino Acid Metabolism

Inborn errors of metabolism are caused by changes in specific Urinary excretion of the branched chain amino acids leucine, Errors of Amino Acid for Metabolites Metabolism Characteristic Inborn enzymatic reactions and hundreds of different such alterations, valine and isoleucine is an indicator for maple syrup urine which affect about 1 of every 5000 newborns, have been disease, N-acetylaspartic acid for Canavan disease and tyrosine characterized. The first inborn errors of metabolism, which have and N-acetyltyrosine for tyrosinemia type I. The identification of been described in the beginning of the 20th century by Sir Archibald new amino acid biomarkers for metabolic disorders is of major Garrod, dealt with alkaptonuria, pentosuria, cystinuria and albinism. importance to biomedical research, and a generic approach for the Infants and children with treatable errors of metabolism can be large-scale prediction of specific biomarkers has been described. identified by screening newborns for meaningful metabolite Newborns are not typically screened for other metabolic disorders biomarkers. Several classic inborn errors of metabolism can be and as a result, these disorders are often only detected in infants detected by the accumulation of certain amino acids as metabolites and children after damage has occurred and effects such as in body fluids like serum and urine. Phenylketonuria (PKU) is an developmental delay and mental retardation become apparent. inherited metabolic disorder. Individuals having phenylketonuria do Early detection involving a blood sample analysis for a metabolic not have the ability to further metabolize phenylalanine. Fortunately marker can reduce such consequences by nutritional adaptations this metabolic disorder can be analyzed by the urinary excretion of and dietary restriction. Simultaneous enzyme and metabolite tests phenylalanine and individuals with this metabolic disorder can be from a single patient sample are needed for the efficient diagnosis successfully treated by dietary restriction. of inborn errors of metabolism in an individual.

Name Cat. No. Name Cat. No.

N-Acetyl-l-aspartic O 00920-5G l-Homocystine, O NH2 H6010-100MG HO S O acid, puriss., OH 00920-25G ≥98% (TLC) HO S H6010-500MG ≥99.0% (T) O HN CH3 NH2 OH H6010-1G O Homogentisic acid O H0751-100MG N-Acetyl-l-tyrosine, O 01527-10G OH H0751-500MG OH ≥98.0% (T) OH H0751-1G

HN CH3 HO HO O 3-Hydroxy-3-methyl- O O H4392-100MG γ-Aminobutyric acid, O A5835-10MG glutaric acid, ≥95% HO OH H4392-1G H N HO CH3 SigmaUltra, ≥99% 2 OH A5835-10G A5835-25G l-Isoleucine, CH3 O 58879-10G H C A5835-100G ≥99.5% (NT) 3 OH 58879-50G NH Argininosuccinic NH A5707-10MG 2 58879-250G acid disodium salt H2N CH2CH2CH2NHCNH A5707-50MG CH O CH2COO Isovaleric acid, 99% 3 129542-100ML hydrate, ≥80% H H A5707-250MG Na OOC HOOC Na H3C OH 129542-500ML l-Citrulline, ≥98% (TLC) O O C7629-10MG l-Leucine, ≥99.5% (NT) O 61819-25G H3C H2N N OH C7629-1G OH 61819-100G H CH NH NH2 C7629-5G 3 2 61819-500G C7629-25G Melanin - M8631-100MG C7629-100G M8631-250MG C7629-500G M8631-1G C7629-1KG Methylmalonic O O M54058-5G l-Cystathionine, NH2 O C7505-10MG HO S acid, 99% HO OH M54058-25G ~90% (TLC) OH C7505-50MG CH3 O NH2 C7505-250MG l-Phenylalanine, O 78019 , purum, O 47910-1KG HO ≥99.0% (NT) OH ≥99.0% (T) OH NH2 O l-Tyrosine, ≥99.0% (NT) O 93829-25G Glutaric acid, 99% O O G3407-25G OH 93829-100G HO OH G3407-100G NH2 G3407-500G HO d l -, O H4628-10MG l-Valine, ≥99.5% (NT) CH3 O 94619-25G HS ≥95% (titration) OH H4628-1G H3C OH 94619-100G NH NH2 H4628-5G 2 94619-500G H4628-25G

Our Innovation, Your Research — Shaping the Future of Life Science 9 Altered Amino Acid Metabolites in Aging

Muscle loss with aging is associated with significant changes in Name Cat. No. amino acid metabolism. Nutritional changes in the daily protein γ-Aminobutyric acid, O A5835-10MG H N SigmaUltra, ≥99% 2 OH A5835-10G intake, provision of excess leucine or exercise may improve A5835-25G activation of translation initiation and muscle protein synthesis. A A5835-100G 2-Aminoisobutyric O 850993-25G significant portion of the aged population may not be receiving H3C acid, 98% OH 850993-100G H3C sufficient sulphur amino acids, which are present between 3% NH2 and 6% in proteins. From the two sulphur-containing amino acids d l -3-Aminoisobutyric O 217794-1G

acid, 98% H2N OH 217794-5G only is synthesized by us and requires a steady supply of CH3

sulphur, while methionine cannot be synthesized by humans and l-, NH O 11009-25G-F

≥99.5% (NT) H2N N OH 11009-100G-F has to be supplied by our food. On the other hand, homocysteine, H NH2 11009-500G-F a sulphur-containing amino acid playing a role in one-carbon l-, O 11189-100G HO metabolism, may be involved in geriatric multisystem problems ≥99.5% (T) OH 11189-500G O NH and therefore research in monitoring and lowering homocysteine 2 11189-1KG l-Carnitine inner salt, CH3 OH O C0158-1G H C N is of interest. Efforts to assess excitatory amino acid metabolism synthetic, ≥98% 3 O C0158-5G CH3 in a variety of neurodegenerative disorders may be useful for the C0158-25G C0158-100G development of new neuroprotective pharmaceuticals. chloride, NH2 D9439-1VL HO O OH Altered Amino Acid Metabolites in Aging Amino Acid Altered from bovine, D9439-2VL 99.5%±0.2% O NH2

HO + - NH2 N Cl NH2 O OH

O

d l -Homocysteine, O H4628-10MG HS ≥95% (titration) OH H4628-1G Imagine a tool that gives you the power NH2 H4628-5G H4628-25G Homovanillic acid O H1252-100MG OH H1252-250MG to navigate a comprehensive universe H1252-1G OCH3 OH

d l -p-Hydroxy- O H3253-100MG phenyllactic acid, OH H3253-500MG ~98% (HPLC) OH H3253-1G of continually curated biological data HO Melatonin, ≥98% (TLC) H M5250-250MG N CH3 H3CO M5250-1G O N M5250-5G H M5250-10G

and interactive genetic networks, l-, 83160-25G OH O N puriss., ≥99.0% (T) H 83160-100G O 83160-500G Taurine, ≥99.5% (T) O 86329-25G HO S NH 86329-500G all with a single, simple click. O 2

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Sigma and Sigma-Aldrich are registered trademarks belonging to Sigma-Aldrich Co. and its affiliate Sigma-Aldrich Biotechnology, L.P. The red cube symbol is a trademark belonging to Sigma-Aldrich Co. and its affiliate Sigma-Aldrich Biotechnology, L.P. Ingenuity is a registered trademark belonging to Ingenuity Systems.

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10 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Non-Labeled Amino Acid Metabolites

The pathways for the biosynthesis and degradation of the Name Cat. No. 20 common amino acids as well as for selected other amino β-Alanine, puriss. O 05160-50G

p.a., ≥99.0% (NT) H2N OH 05160-250G Non-Labeled Amino Acid Metabolites acids are key to cellular life. In order to investigate these pathways 05160-1KG

Sigma-Aldrich offers a broad variety of metabolites. l-Alanine, ≥98.5%, O A7469-10MG H C from non-animal 3 OH A7469-25G source NH2 A7469-100G Name Cat. No. A7469-1KG Acetyl coenzyme A NH2 A2056-1MG l O N -Alanine, 05129-25G salt, ≥93% H C CH O O N A2056-5MG H3C 3 3 ≥99.5% (NT) OH 05129-100G (HPLC) HO O N A2056-10MG P O P O N NH2 05129-500G O A2056-25MG O NH OH OH O O A2056-100MG l-2-Aminoadipic HNH2 A7275-100MG • xNa O OH OH NH acid, ≥98% (TLC) HO A7275-250MG HO P O H3C S O OH A7275-1G O A7275-5G

N-Acetyl-d l - - A8875-25G γ-Aminobutyric acid, O A5835-10MG H N SigmaUltra, ≥99% 2 OH A5835-10G A5835-25G N-Acetyl-5- H A1824-100MG HO N CH3 A5835-100G hydroxytryptamine, A1824-250MG O ≥99% (TLC) N A1824-1G 1-Aminocyclo- O A3903-100MG H propanecarboxylic OH A3903-250MG NH O CH 2 Nα-Acetyl-l- 3 A2010-100MG acid, ≥98% (TLC) A3903-1G HNH A2010-500MG d l -3-Aminoisobutyric O 217794-1G OH H2N A2010-1G acid, 98% H2N OH 217794-5G O CH3 O Nε-Acetyl-l-lysine H2N H A4021-1G O OH 5- A3785-500MG H3C N A4021-5G H2N OH • HCl H hydrochloride, ~98% A3785-1G O O A3785-5G O Nα-Acetyl-l- A3626-500MG 5-Aminolevulinic O 08340-250MG H2N OH A3626-1G acid hydrochloride, H2N OH • HCl 08340-1G H C NH 3 ≥97.0% (AT) O 08340-5G O 2-Aminophenol, 99% OH A71301-5G N-Acetyl-d- O A3876-1G A71301-100G NH2 phenylalanine, OH A3876-5G A71301-500G Sigma Grade HN CH3 Ammonium (NH4)2S2O8 A7460-100G O persulfate, A7460-500G N-Acetyl-l- O 857459-1G SigmaUltra, ≥98.0% phenylalanine, 99% OH 857459-5G Angiotensin II - A9525-1MG HN CH3 human, A9525-5X1MG O ≥93% (HPLC) A9525-5MG N-Acetylputrescine O A8784-25MG A9525-10MG H2N hydrochloride, N CH3 • HCl A8784-100MG A9525-50MG H ≥98% (TLC) A8784-500MG l-Anserine O A1131-100MG C CH2CH2NH2 d l nitrate salt A1131-250MG N-Acetyl- -serine - A2638-1G N NH O A2638-10G CH CH C OH N 2 HNO S-(5′-Adenosyl)-l- NH2 A9384-10MG CH3 3 homocysteine N A9384-25MG N Anthranilic acid, O A89855-25G H S N N A9384-50MG H2N O reagent grade, ≥98% OH A89855-100G HO A9384-100MG NH A89855-500G O 2 HO OH A89855-2KG

NH O S-(5′-Adenosyl)-l- NH2 A7007-5MG l-Arginine, A8094-10MG N methionine chloride, Cl– N A7007-25MG 98.5-101.0%, from H2N N OH A8094-25G CH3 H H S+ non-animal source NH2 A8094-100G ≥80%, from yeast N N A7007-100MG H2N O l A8094-1KG ( -Methionine HO A7007-500MG enriched) O A7007-1G HO OH l-Arginine, NH O 11009-25G-F

≥99.5% (NT) H2N N OH 11009-100G-F S-(5 -Adenosyl)-l- NH2 A4377-5MG H ′ NH2 11009-500G-F methionine iodide, N N A4377-25MG NH O O I CH3 l-Arginine 11039-100G from yeast, ≥80% N N A4377-100MG S monohydrochloride, H2N N OH • HCl 11039-500G (HPLC), ≥80% HO O H NH (spectrophotometric NH2 ≥99.5% (AT) 2 OH OH assay) Argininosuccinic NH A5707-10MG

O OH acid disodium salt H2N CH2CH2CH2NHCNH A5707-50MG Adenylosuccinic O A5028-25MG CH2COO acid, ~96% (HPLC) A5028-100MG hydrate, ≥80% H H A5707-250MG HO NH Na OOC HOOC Na

N N l-Asparagine, O HNH2 11149-25G-F O OH N N ≥99.5% (NT) H N 11149-100G-F HO P O 2 O OH O 11149-500G-F

OH OH d-Aspartic acid, 99% O 219096-25G HO OH 219096-100G

Adenylosuccinic - A4778-100MG O NH2 acid sodium salt, ~96% (HPLC) l-Aspartic acid, O 11189-100G HO ≥99.5% (T) OH 11189-500G sulfate NH H2SO4 A7127-1G O NH2 11189-1KG salt, ≥97% H2NCNHCH2CH2CH2CH2NH2 A7127-5G

Our Innovation, Your Research — Shaping the Future of Life Science 11 Name Cat. No. Name Cat. No. Betaine, ≥99.0% (NT) O 61962-50G 2,5-Dihydroxybenzoic O 85707-10MG-F CH3 - HO H3C N O 61962-250G acid, puriss. p.a., OH 85707-250MG-F CH 3 matrix substance OH 85707-1G-F for MALDI-MS, Betaine aldehyde O B3650-2MG CH3 >99.0% (HPLC) + chloride H3C N H Cl B3650-10MG CH3 B3650-100MG d l -3,4-Dihydroxy- OH 151610-500MG mandelic acid, 98% OH O Carbamyl phosphate O C4135-1G O HO disodium salt, ≥80% H2N O P ONa OH ONa OH O 3,4-Dihydroxy- 850217-1G l-Carnosine, ~99% H C9625-10MG H2N N phenylacetic O 850217-5G OH C9625-5G HO O C9625-25G acid, 98% OH N NH C9625-100G 3,4-Dihydroxy-d- O D9378-250MG H OH chloride, CH3 26978-25G phenylalanine, ≥98% D9378-1G Cl H N ≥99.0% (AT) HO NCH3 26978-100G 2 CH3

O trans-Cinnamic C80857-5G HO OH acid, ≥99% OH C80857-250G 3,4-Dihydroxy-l- HO D9628-5G HNH2 phenylalanine OH D9628-25G (R)-(−)-Citramalic O HO CH3 329142-1G HO OH O D9628-100G acid, 98% HO 329142-5G D9628-500G O 3,5-Diiodo-l-tyrosine OH D0754-10G p-Coumaric acid, HO O C9008-1G dihydrate I I

Non-Labeled Amino Acid Metabolites Non-Labeled Amino Acid ≥98.0% (HPLC) C9008-5G C9008-10G O C9008-25G OH NH2 OH N,N-Dimethylglycine, CH3 O D1156-10MG CH3 O N Creatine, anhydrous C0780-10MG ≥99% H3C OH D1156-5G H N N 2 OH C0780-50G D1156-10G NH C0780-100G D1156-25G C0780-500G N,N-Dimethylglycine CH3 O D6382-5G CH O N Creatine 3 • H O C3630-100G hydrochloride H C OH • HCl D6382-25G HN N 2 3 monohydrate, ≥98% OH C3630-1KG NH2 N,N-Dimethylglycine CH3 O 40380-50G N hydrochloride, H C OH • HCl Creatinine, O C4255-10MG 3 NH puriss., ≥99.0% (AT) anhydrous C4255-10G NH N C4255-25G Dopamine NH2 H8502-5G CH3 C4255-100G hydrochloride H8502-10G C4255-1KG • HCl H8502-25G

OH H8502-100G l-Cystathionine, NH2 O C7505-10MG HO S OH ~90% (TLC) OH C7505-50MG O NH 2 C7505-250MG N-Formyl-l- O F3377-10MG H CS methionine 3 OH F3377-250MG l-Cysteic acid O HNH2 30170-10G monohydrate, HO S OH • H2O 30170-50G H NH F3377-1G O ≥99.0% (T) O O

d-Cysteine, puriss., O 30095-100MG Fumaric acid, purum, O 47910-1KG HO ≥99.0% (RT) HS OH 30095-1G ≥99.0% (T) OH O NH2

O l-Cysteine, ≥98%, O C7352-10MG Gentisic acid sodium G5129-10G HO from non-animal HS OH C7352-25G salt hydrate ONa G5129-50G • xH O source NH2 C7352-100G OH 2 C7352-1KG NH O l- 2 H 49740-1G O HO N OH l-Cysteine, 30089-25G oxidized, ≥99.0% N 49740-5G H ≥98.5% (RT) HS OH 30089-100G O O O (HPLC, sum of S NH 2 30089-500G enantiomers) S O O O H NH2 O N l-, C7602-10MG HO N OH HO S H 98.5-101.0%, from S OH C7602-25G O NH2 non-animal source O NH2 C7602-100G NH O C7602-1KG l-Glutathione 2 H G6654-250MG HO N OH oxidized, N G6654-500MG NH O H l-Cystine, ≥99.5% (T) 2 30199-25G O O O HO S SigmaUltra, ≥98% S G6654-1G S OH 30199-100G S G6654-5G O O O O NH2 30199-500G H N HO N OH 1,4-Diaminobutane, NH2 D13208-25G H H2N O NH2 99% D13208-100G SH D13208-500G l-Glutathione O O O G6529-1G H reduced, SigmaUltra, N G6529-5G O O HO N OH 2,6-Diaminopimelic 33240-1G H ≥98.0% NH O G6529-25G acid, purum, HO OH 33240-5G 2

NH2 NH2 ≥97.0% (NT) d-(+)-Glyceric acid O G8766-25MG 2+ 2,6-Diaminopimelic O O D1377-5G hemicalcium salt, HO O Ca G8766-100MG OH acid, ≥98% (TLC) HO OH D1377-10G 99.9% (GC) 2 G8766-250MG

NH2 NH2 G8766-1G

O 1,3-Diaminopropane, H2NCH2CH2CH2NH2 D23602-25G Glycine, for 50046-50G H N 99% D23602-500G molecular biology, 2 OH 50046-250G D23602-3KG ≥99.0% (NT) 50046-1KG Dihydrouracil O D7628-5G Glyoxylic acid O G10601-10G H • H2O NH monohydrate, 98% OH G10601-25G O G10601-100G N O H

12 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Name Cat. No. Name Cat. No.

O O 4-Guanidinobutyric H G6503-1G 5-Hydroxy-l- H9772-100MG H N N acid, ≥98% 2 OH G6503-5G tryptophan HO OH H9772-250MG

NH NH2 N H9772-1G H H9772-5G Histamine H2N H7250-10MG N H9772-25G dihydrochloride, • 2HCl H7250-5G N H NaO ≥99% (TLC) H7250-10G Imidazole-4-acetic N I7013-500MG Non-Labeled Amino Acid Metabolites H7250-25G acid sodium salt O I7013-1G N H H N I7013-5G Histamine 2 N 53300-1G dihydrochloride, • 2HCl 53300-5G O N 4-Imidazoleacrylic 859796-5G ≥99.0% (AT) H 53300-25G acid, 99% HO N 859796-25G 859796-100G l O N -, 53319-25G H ≥99.5% (NT) N OH 53319-100G NH O N 2 Indole-3- I1000-25MG H acetaldehyde– S ONa I1000-100MG HO O sodium bisulfite N l-Histidine O 53369-25G H addition compound monohydrochloride N OH 53369-100G NH2 OH monohydrate, N 53369-500G 3-Indoleacetic acid I2886-5G H • HCl • H2O ≥99.5% (AT) O I2886-25G N H I2886-100G d l -Homocysteine, O H4628-10MG HS ≥95% (titration) OH H4628-1G Indole-3-acetic acid ONa I5148-2G NH2 H4628-5G sodium salt, ≥98% O I5148-10G N H4628-25G H O NH l-Homocystine, 2 H6010-100MG O S O Indole-3-pyruvic acid I7017-1G ≥98% (TLC) HO S H6010-500MG OH I7017-5G NH OH 2 H6010-1G O N Homogentisic acid O H0751-100MG H OH H0751-500MG HO 3-Iodo-l-tyrosine NH I8250-1G OH H 2 H0751-1G OH I8250-5G I HO O I8250-25G l-Homoserine HNH2 H6515-10MG l-Isoleucine, CH3 O 58879-10G OH H C HO H6515-250MG ≥99.5% (NT) 3 OH 58879-50G O H6515-1G NH2 58879-250G H6515-5G α-Ketoglutaric acid, O O K1750-100G 3-Hydroxyanthranilic O OH H9391-5G ≥98.5% (titration, HO OH K1750-1KG O acid NH2 NaOH)

OH α-Ketoglutaric O O K3752-5G • 2H O acid disodium salt NaO ONa 2 K3752-100G O OH 4-Hydroxybenzoic H20059-100G dihydrate, ~95% O K3752-1KG acid, 99% H20059-500G H20059-1KG α-Ketoglutaric acid O O K2000-5G potassium salt, HO OK K2000-25G OH ≥98% (enzymatic) O K2000-100G O O K2000-1KG 3-Hydroxy-d l - NH2 NH2 H1771-25MG kynurenine HO C CH2 CH C OH H1771-100MG α-Ketoglutaric O O K2010-5G H1771-250MG acid sodium salt, HO ONa K2010-25G SigmaUltra O K2010-100G 6-Hydroxymelatonin H H0627-50MG N CH3 H3CO Kynurenic acid, ≥98% OH K3375-250MG O HO N K3375-1G H OH N K3375-5G d l -3-Hydroxy-3- NH2 H6132-5MG O N methylglutaryl O O N H6132-10MG O H3C CH3 l-Kynurenine O K8625-25MG coenzyme A sodium O P O P O N N • xNa H6132-25MG HN O OH K8625-100MG salt, ≥90% (HPLC) OH OH OH • 3H2O NH2 O NH2 K8625-500MG O O OH K8625-1G O N P OH H S OH OH l-Kynurenine O NH2 K3750-500MG OH O O HO CH3O sulfate salt • HO S OH K3750-1G O O K3750-5G NH2 4-Hydroxy- OH H50004-5G phenylacetic O H50004-25G d l -β-Leucine, purum, NH2 O 17988-1G-F HO H C acid, 98% H50004-100G ≥98.0% (NT) 3 OH

CH3 d l -p-Hydroxy- O H3253-100MG phenyllactic acid, OH H3253-500MG l-Leucine, ≥99.5% (NT) O 61819-25G OH H3C ~98% (HPLC) HO H3253-1G OH 61819-100G CH3 NH2 61819-500G 4-Hydroxy- O 114286-1G O O phenylpyruvic OH 114286-5G Lithium acetoacetate, 00478-250MG-F O ≥90% (CH) H3C OLi 00478-1G-F acid, 98% HO O O HO Lithium carbamoyl- OLi C5625-10MG cis-4-Hydroxy-d- H5877-250MG P phosphate dibasic H2N O OLi C5625-1G OH H5877-1G N H5877-10G hydrate, ≥85% C5625-5G H O C5625-25G trans-4-Hydroxy-l- HO H54409-2.5G Lithium O 54913-1G-F proline, ≥99% OH H54409-10G β-hydroxypyruvate HO OLi • xH2O 54913-5G-F N H54409-25G hydrate, purum, O H O H54409-100G ≥97.0% (NT, calc. β-Hydroxypyruvic - 06372-5MG-F based on dry acid, ≥95.0% 06372-25MG-F substance) (T, dry substance) l-Lysine O 62929-100G-F H N monohydrochloride, 2 OH • HCl ≥99.5% (AT) NH2

Our Innovation, Your Research — Shaping the Future of Life Science 13 Name Cat. No. Name Cat. No.

Malonyl coenzyme A NH2 M4263-5MG 2-Oxoadipic acid, O O 75447-100MG HO lithium salt, ≥90% N N M4263-10MG ≥95.0% (HPLC) OH 75447-500MG O O OH (HPLC) H H O O N M4263-25MG O N N N HO S O P O P O M4263-100MG CH3 O d-Pantothenic acid H3C CH3 O O P5710-25G O O H3C OH OH HO O hemicalcium salt, N O Ca2+ P5710-100G HO P O H • xLi OH SigmaUltra OH 2 OH

d-Pantothenic acid H3C CH3 O O 21210-25G-F O Mandelic acid, 99% M2101-250G HO 2+ HO hemicalcium salt, N O Ca 21210-100G-F OH M2101-500G H puriss., ≥99.0% (T) OH 2 21210-500G-F Phenol, for OH 77608-100G molecular biology, 77608-500G (R)-(−)-Mandelic OH M2209-25G ≥99.5% (GC) acid, 98% OH O O Phenylacetaldehyde, 107395-25ML ≥90% H 107395-100ML Melatonin, ≥98% (TLC) H M5250-250MG 107395-500ML N CH3 H3CO M5250-1G O N M5250-5G H M5250-10G Phenylacetic acid, 99% O P16621-5G OH P16621-100G l-Methionine O O M1126-1G S P16621-500G sulfoxide H3C OH M1126-5G NH2 d-Phenylalanine, O P1751-5G 3-Methoxytyramine NH2 M4251-100MG ≥98% (TLC) OH P1751-25G hydrochloride, ≥95.5% HCl M4251-1G NH2 P1751-100G

Non-Labeled Amino Acid Metabolites Non-Labeled Amino Acid l-Phenylalanine, O P2126-100G OCH3 OH reagent grade, ≥98% OH P2126-500G NH2 P2126-1KG NH 1-Methylhistamine N 2 M4910-25MG dihydrochloride, M4910-100MG l-Phenylalanine, O P5482-10MG N ≥98% (TLC) • 2HCl 98.5-101.0%, from OH P5482-25G CH3 non-animal source NH2 P5482-100G 3-Methylhistamine N M7780-50MG P5482-1KG • 2HCl dihydrochloride H N N 2 2-Phenylethylamine NH2 P6513-25G CH3 hydrochloride, ≥98% • HCl P6513-100G 1-Methyl-l-histidine, O 67520-50MG d l -3-Phenyllactic acid O P7251-1G purum, ≥98.0% (TLC) N OH 67520-250MG OH P7251-10G NH2 N OH CH3 O CH O Phosphocreatine H 3 P7936-10MG H Nω-Methyl-5- O M1514-100MG NaO P N N • xH2O HO N disodium salt OH P7936-1G CH3 OH ONa hydroxy­trypt­amine • HO M1514-500MG hydrate, ~98% NH P7936-5G oxalate salt, ≥98% N O H P7936-25G (alkalimetric) Phosphocreatine HO NH2 OH O CH O P1937-500MG OH H 3 1-Methyl-4- N M9265-10MG di(tris) salt, ~98% HO P N N P1937-1G OH imidazoleacetic acid O M9265-250MG (enzymatic) OH OH P1937-5G N 2 NH hydrochloride • HCl CH3 O O d-(−)-3- Na+ -O P8877-10MG O O P Methylmalonic M54058-5G O O- Na+ Phosphoglyceric HO P8877-1G acid, 99% HO OH M54058-25G acid disodium OH P8877-5G CH3 salt, ≥93% CH O (±)-3-Methyl-2- 3 K7125-5G O-Phospho-l-serine O O P0878-10MG H C HO oxovaleric acid 3 ONa P HO O OH P0878-1G O sodium salt NH2 P0878-5G 4-Methyl-2- O 68255-1G P0878-25G H C oxovaleric acid, 3 OH 68255-5G Potassium O 08075-250MG-F CH O purum, ≥98.0% (T) 3 β-hydroxypyruvate, HO OK 08075-1G-F ≥95.0% (NT) O 7-Methyltryptamine NH2 M8002-100MG M8002-500MG l-Proline, ReagentPlus®, P0380-10MG N OH H M8002-1G ≥99% (TLC) N P0380-100G CH3 H O P0380-1KG H N-ω-Methyl- N 115312-100MG P0380-5KG tryptamine, 99% CH3 115312-1G l-Proline, ≥99.5% (NT) 81709-25G N OH H N 81709-100G H O N′-Nitrosonornicotine, 75285-2MG NH2 N n-Propionyl P5397-5MG analytical standard, N NO coenzyme A N P5397-10MG N O O ≥99.0% (HPLC) O H3C CH3 lithium salt, ≥85% O P O P O N N P5397-25MG HN O • xLi+ (−)-Norepinephrine, HO A7257-500MG OH OH H OH OH ≥98% HO CCH NH A7257-1G O 2 2 S O OH A7257-5G O N CH3 P OH H O OH (+)-Octopine H O O4875 H3C OH 2,3-Pyridine- O P63204-25G HNH H dicarboxylic acid, 99% OH P63204-100G H2N N OH OH NH O N O l-Ornithine O 75469-25G Pyrrole-2-carboxylic P73609-1G monohydrochloride, OH • HCl 75469-500G OH H2N acid, 99% N P73609-5G ≥99.5% (AT) NH2 H O

Oxaloacetic acid, ≥98% O O O4126-1G Pyruvic acid, purum, O 15940-100ML HO H C OH O4126-5G ≥98.0% (T) 3 OH O O4126-25G O O4126-100G

14 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Name Cat. No. Name Cat. No. Rosmarinic acid, 97% HO 536954-5G Spermine H 85605-1G O N NH2 O tetrahydrochloride, • 4HCl 85605-5G HO OH N NH2 H O OH for molecular 85605-25G biology, ≥99.5% (AT) OH , O S3674-100G OH l O O -Saccharopine S1634-10MG SigmaUltra, ≥99.0% HO S3674-250G Non-Labeled Amino Acid Metabolites O HO OH O S1634-25MG S3674-1KG HN S1634-250MG OH Succinyl coenzyme A NH2 S1129-5MG NH2 N sodium salt O O N S1129-25MG O H3C CH3 O O P O P O N N • xNa Sarcosine, SigmaUltra H S7672-10MG HN O N OH OH H C OH S7672-25G OH 3 O O S7672-100G S O OH O N OH P OH H d-Serine, ≥98% (TLC) HNH2 S4250-5G O OH HO OH S4250-25G O O O O-Succinyl-l- S7129-25MG O homoserine HO OH S7129-100MG O l-Serine, ReagentPlus®, S4500-10MG O NH2 ≥99% (TLC) HO OH S4500-1G NH Thiamine O O C8754-1G 2 S4500-100G S pyrophosphate, ≥97% HO P O P O Cl– C8754-5G S4500-1KG OH OH N+ C8754-25G H C l-Serine, ≥99.5% (NT) O 84959-25G 3 NH2 C8754-100G HO OH 84959-100G NN NH2 CH3 Serotonin H9523-25MG HO NH2 l-Thyroxine, I T2376-100MG hydrochloride • HCl H9523-100MG I O ≥98% (HPLC) NH T2376-500MG N H9523-250MG 2 H OH T2376-1G H9523-1G HO I I O T2376-5G O CH O Sodium creatine H 3 27920-1G NaO P N N • 4H2O l-Thyroxine sodium I T2501-1G phosphate dibasic OH 27920-5G ONa I O tetrahydrate, NH salt pentahydrate, NH2 T2501-5G ONa • 5H O ≥98.0% (NT) ≥98% (HPLC) HO I 2 I O (±)-Sodium 2,3- OH 39693 dihydroxyisovalerate H3C ONa 3,3′,5-Triiodo-l- O T2877-100MG H C HO I hydrate, ≥95% (CE) 3 OH O • xH2O thyronine, ≥95% OH T2877-250MG (HPLC) NH2 T2877-500MG Sodium fumarate - F1506-25G I O I T2877-1G dibasic F1506-100G T2877-5G F1506-500G l-Tryptophan, O T8941-10MG Sodium O 06367 ≥99.0%, from OH T8941-25G β-hydroxypyruvate HO ONa non-animal source NH2 T8941-100G O N hydrate, ≥97.0% H T8941-1KG (NT, calc. based on dry substance) l-Tryptophan, O 93659-10G ≥99.5% (NT) OH 93659-50G O O Sodium malonate 63409-100G NH2 N 93659-250G dibasic, purum, NaO ONa 63409-500G H ≥97.0% (NT) Tyramine, 99% NH2 T90344-5G Sodium 4-methyl- O K0629-1G T90344-25G H3C HO 2-oxovalerate ONa K0629-5G CH3 O K0629-25G Tyramine NH2 T2879-10MG Sodium 2- O K0875-5G hydrochloride, ≥98% HCl T2879-1G T2879-5G oxobutyrate H3C ONa K0875-25G O T2879-25G T2879-100G Sodium O P8001-5G OH phenylpyruvate ONa P8001-25G l-Tyrosine, ≥99.0% (NT) O 93829-25G O OH 93829-100G NH Sodium pyruvate, O P8574-5G HO 2 H C SigmaUltra, ≥99% 3 ONa P8574-25G Uracil, ≥99% O U0750-5G O P8574-100G NH U0750-25G O Sodium pyruvate, 15990-25G N O U0750-100G H C purum, ≥99.0% (NT) 3 ONa 15990-100G H U0750-500G O 15990-500G U0750-1KG Sodium succinate O 14170-100G Urea, for molecular O 51456-500G NaO NH2 C NH2 dibasic hexahydrate, ONa • 6H2O 14170-500G biology, ≥99.5% (T) 51456-2.5KG puriss. p.a., O 3-Ureidopropionic O O 94295-1G ≥99.0% (NT) acid, purum, H2N N OH H Spermidine, for NH2 (CH2)3 NH (CH2)4 NH2 85558-1G ≥98.0% (T) molecular biology, 85558-5G l-Valine, ≥99.5% (NT) CH3 O 94619-25G ≥99.5% (GC) H3C OH 94619-100G H NH Spermidine N 85578-1G 2 94619-500G H2N trihydrochloride, NH2 85578-5G OH ≥99.5% (AT) • 3HCl , 96% D120804-1G D120804-5G Spermine dihydrate, H 85588-5G OH N NH2 N H2N N ≥99.5% (GC) H 85588-25G OH O • 2H2O

Our Innovation, Your Research — Shaping the Future of Life Science 15 Stable Isotope-Labeled Amino Acid Metabolites

The safe labeling of amino acids by stable non-radioactive Name Cat. No.

13 O isotopes has been crucial for advancements in the structural l-Asparagine-4- C O 579866-100MG monohydrate, O C H biology of proteins, proteomics, magnetic resonance imaging and 13 13C C 99 atom % C NH2 H2O H2N spectroscopy, nutrition science and metabolomics. The availability H D 13 15 l-Aspartic acid-d7, 673021 of C- and N-labeled amino acids has enabled selective isotope O D N D 98 atom % D, 98% (CP) D O O labeling of proteins by biosynthetic incorporation of a single D D O D type of labeled amino acid, leaving all the others non-labeled. l-Aspartic acid-1-13C,15N, O 586285 13 HO 13C Metabolism can thereby be studied in several dimensions, either in 99 atom % C; OH 15 98 atom % N 15NH the protein metabolism both at the whole-organism level and at O 2 l-Aspartic acid-2-13C,15N, O 607703 the level of individual proteins or in the small molecule pathways 13 HO 99 atom % C; 13C OH 15 O 15 of amino acid conversions. 98 atom % N NH2 For information regarding pricing and availability, l-Aspartic O 579793 13 13 acid-1,2- C2, HO C 13 please contact: 99 atom % 13C C OH O NH2

ISOTEC® Stable Isotopes Customer Service CH D Choline-1,1,2,2-d4 H C 3 D 615552-1G 3 N+ Phone: 800-448-9760 (US & Canada) bromide, H3C OH 98 atom % D D D 937-859-1808 Br-

13 Email: [email protected] Choline bromide- CH3 488593-500MG 13 methyl- C1, N HO 99 atom % 13C Br Stable Isotope-Labeled Metabolites Amino Acid Name Cat. No. CD Choline-d13 D D 3 615536 H2N D l-Alanine-2-d, 485861-1G N CD3 Br OH bromide-(N,N,N- HO 98 atom % D CD3 trimethyl-d ,1,1,2,2-d ), D D O 9 4 98 atom % D l H2N H -Alanine-3,3,3-d3 , 489921-1G CD OH Choline bromide- 3 615528-1G 99 atom % D Br D3C trimethyl-d , HO N CD3 O 9 CD 98 atom % D 3 l 13 O -Alanine-1- C, 489867-500MG D CH 13 Choline chloride- 3 615544 13 H3C C D Cl 99 atom % C OH HO NCH3 1,1,2,2-d4, NH CH 2 98 atom % D D D 3 13 O l-Alanine-1- C, 586722 13 CH3 13 Choline chloride-1- C, 13C 605301 D3C C Cl 3,3,3-d3, OH 99 atom % 13C HO N CH3 13 CH3 99 atom % C; NH2 99 atom % D 15 Choline chloride- N, CH3 609269-1G 15 15 l-Alanine-1-13C,15N, O 608025 98 atom % N HO N CH3 13 99 atom % C; H C 13C Cl CH3 3 OH 15 98 atom % N 15NH 2 Choline chloride- CD3 492051-1G trimethyl-d , l-Alanine-2-13C, O 486779-100MG 9 D3CNCD3 • Cl 98 atom % D 99 atom % 13C H3C 13C OH OH

NH CD O 2 Creatine-(methyl-d3) 3 616249-1G H N N • H2O monohydrate, 2 OH l-Alanine-3-13C, O 661511 13 NH 13 H3 C 98 atom % D 99 atom % C OH 13 13 NH2 Creatine-(methyl- C) CH3 O 604925 • H O monohydrate, H2N N 2 13 O OH l-Alanine-2,3- C2, 13 604682 13 H3 C NH 13 99 atom % C 99 atom % C 13C OH O NH2 Creatinine-(methyl-d3), 485446-250MG NH 98 atom % D 13 O NH l-Alanine- C3 , 660760 N 13 CD 99 atom % C 13 13 3 H3 C C 13C OH Creatinine-(methyl-13C), O 488615-500MG 13 NH NH2 99 atom % C N NH 13 O 13 l-Alanine- C3, d4, 666653 CH3 13 13 13 D3 C C 99 atom % C; 13C OH l-Cysteine-1-13C, O 676128 97 atom % D D NH2 13 13C 99 atom % C, HS OH 13 NH O L-Arginine-1,2- C2 711055 98% (CP) NH2 13C • HCl hydrochloride, H2N N 13C OH 99 atom % 13C H l-Cysteine-15N, O 609129-100MG NH 15 2 98 atom % N, HS OH 15NH 15 95% (CP) 2 l-Arginine- NH O 609080-1G 15 15 13 O guanidineimino- N2 H2N N OH • HCl l-Cystine-1,1′- C , 676136 H 2 NH2 hydrochloride, NH2 13 HO 13 99 atom % C, 13 S C 98 atom % 15N C S OH 99% (CP) NH O 2

16 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Name Cat. No. Name Cat. No.

13C NH 13 15 O 1,4-Diamino- 13 2 588784 L-Histidine- C6, N3 707848 H2N C 13 13 13 C C • HCl butane-1,4- C2, hydrochloride 15N 13C 13C OH 13 99 atom % C monohydrate 13 13 15 • H O C C NH2 2 15NH 13 13 1,4-Diamino- H2N C C 593443 13C 13C NH 13 2 15 O butane- C4, l-Histidine-amine- N, 609226 13 15

99 atom % C, 98 atom % N, N OH Amino Acid Metabolites Stable Isotope-Labeled 15 NH2 97% (CP) 98% (CP) N H 13 O O Diethyl glutarate- C5, 655708 13 13 O 99 atom % C 13C 13C 13C l-Isoleucine-1- C, OH 604771 13 13 13 CH3CH2O C C OCH2CH3 13 H C C 99 atom % C 3 OH NH Ethyl 3-keto- O O 604313 2 13 13 H3 C 13C pentanoate-3,4,5- C, 13 C O CH3 2-Ketobutyric O 571342-250MG 13 99 atom % C 13 13 acid-4- C sodium H3 C ONa • xH2O 13 O O Fumaric acid-2,3- C2, 606073 salt hydrate, 13 13 99 atom % C HO 13C 13C OH 99 atom % C, 97% (CP) O O O 13 2-Ketoglutaric 704334 Fumaric acid- C , O 606014 13 4 acid-1-13C, C 13 13 13 HO OH 99 atom % C HO C C 13 13C 13C OH 99 atom % C, O 95% (CP) O 2-Ketopentanedioic O D D O 615390 l-Glutamic O O 691682 13 acid-d6, 98 atom % D DO OD 13 13 C acid- 3,4- C2, HO C OH D D O 13 99 atom % C, NH2 13 13 98% (CP) 2-Keto-3-(methyl- C)- CH3 O 571334-100MG 13 13 butyric acid-4- C CH3 ONa d-Glutamic acid-5-13C, O O 605255 13 sodium salt, O 13 C 99 atom % C HO OH 99 atom % 13C, NH2 97% (CP) 13 l-Glutamic acid-4- C, O O 587672 O 2-Keto-4-(methyl-d3)- 616621-500MG 13 13 D C 99 atom % C HO C OH pentanoic acid sodium 3 ONa NH 2 salt, 98 atom % D CH3 O l-Glutamic O D D O 644560 2-Keto-4-methyl- H H O O 487716-250MG 13 15 13 13 13 13 13 acid- C5, N,d9, C C C H3CC C C C ONa 13 13 pentanoic acid-1- C 13 DO C C OD 99 atom % C; sodium salt, CH3 H D D D 15ND 98 atom % 15N; 2 99 atom % 13C 98 atom % D O l-Lactic acid-3,3,3-d3 616567 13 O D C l--1,2- C2, O 660809 solution, 98 atom % D 3 OH 13 13 99 atom % C C OH H2N 13C OH H O NH2 l-Leucine-4-d1, 615978 H C 99 atom % D 3 OH O O Glutathione- 683620 H3C D NH2 13 15 O glycine- C2, N, HN OH H 13 13C 15 l O 99 atom % C; N SH NH2 -Leucine-5,5,5-d3, 661554 HO 13C D C 15 99 atom % D 3 OH 98 atom % N, O 95% (CP) CH3 NH2

O l 13 O Glycine-d5, 175838-5G -Leucine-1- C, 661538 13 13 H3C C 98 atom % D ND2 99 atom % C OH DO CH NH D D 3 2

13 15 Glycine-1-13C, O 660728 l-Leucine-1- C, N, O 661546 13 13 13 H3C C 99 atom % 13C C NH2 99 atom % C; OH HO 15 15 98 atom % N H3C NH2 Glycine-2-13C, O 279439-250MG l-Leucine-2-13C,15N, O 607657 13 NH 99 atom % C 2 279439-1G 13 H3C HO 13C 99 atom % C; 13C OH 15 H3C 15 98 atom % N NH2 13 O Glycine- C2, 283827-250MG 13 13 13 15 O C NH2 l 99 atom % C 283827-1G -Leucine-3- C, N, 13 608173 HO 13C 13 H3C C 99 atom % C; OH 15 H3C 15 13 15 O 98 atom % N NH2 Glycine- C2, N, 701416 13 99 atom % C; 15 13 H2 N C l-Leucine-2-13C, O 486817 15 13C OH 99 atom % N 13 99 atom % C H3C Glycine-15N, O 660736 13C OH 15 15 98 atom % N NH2 CH NH HO 3 2

13 O 15 D O l-Leucine-1,2- C2, 604909 Glycine- N,d5, 592617 15 13 H C 13C 15 N 99 atom % C 3 13 98 atom % N; D OD C OH

98 atom % D D D CH3 NH2

O 15 Glycocholic acid- CH 605891 l-Leucine- N, O 660825 HO 3 H 13 CH3 N 13C 15 H3C glycyl-1- C, OH 98 atom % N OH 13 H C 15 99 atom % C 3 H H O CH3 NH2 H H l-Lysine-1-13C O 604704 HO OH H H N 13C hydrochloride, 2 OH • HCl 13 99 atom % C, NH2 98% (CP)

Our Innovation, Your Research — Shaping the Future of Life Science 17 Name Cat. No. Name Cat. No.

l-Lysine-1-13C O 660833 d-Proline-1-13C, 654183 OH H N 13C 13 13 hydrochloride, 2 • HCl 99 atom % C N C OH H 13 O 99 atom % C NH2

13 15 O l-Proline-1- C, 661627 l-Lysine-2− N 592900 OH 13 13 H2N 99 atom % C N C dihydrochloride, OH H 15 15 O 98 atom % N, NH2 98% (CP) Pyruvic-1-13C acid O 677175 13 H3C C l-Lysine-2-15N O 660868 (free acid), OH H N 13 O hydrochloride, 2 OH • HCl 99 atom % C, 15 15 98 atom % N NH2 95% (CP) 13 O l-Methionine- O 660876 Pyruvic-2- C acid 692670 H3C 13 carboxy-13C, S 13C (free acid), C OH D3C OH 99 atom % 13C, O methyl-d3, H NH2 99 atom % 13C; 95% (CP) 13 O 98 atom % D Sarcosine-methyl- C, H 605247 13 13 N l-Methionine- O 299154-250MG 99 atom % C H3 C OH 13 13 D3 CS methyl- C,d3, OH 299154-1G Sarcosine-d O 493120-1G 13 3 99 atom % C; NH2 N (methyl-d3), D3C OH 99 atom % D 99 atom % D d-Methionine- - 589780 l-Selenomethionine- O 634093 13 methyl- C, 13 Se methyl- C , H 13C OH 99 atom % 13C 1 3 99 atom % 13C NH2 l-Methionine- O 661562 l-Serine-1-13C, O 490156-250MG D3CS methyl-d3, OH 13 13C 99 atom % C HO OH 98 atom % D NH2 NH2 3-Methyl-d -l-histidine, O 662135 3 13 O l-Serine-2,3- C2, 605174 98 atom % D N OH 13 13 H NH2 99 atom % C C N HO 13C OH

CD3 Stable Isotope-Labeled Metabolites Amino Acid NH2 Phenylacetic acid-1-13C, O 291951-250MG Sodium l-lactate- O 616702-1G 99 atom % 13C 13C OH D3C 3,3,3-d3 solution, ONa 98 atom % D OH Sodium O 490709-250MG 13 13 Phenylacetic C OH 293857-1G pyruvate-1- C, ONa 13C H C 13 acid-1,2-13C , 99 atom % 13C 3 C 2 O 99 atom % 13C O

D Sodium O 490725-500MG Phenylacetic-d7 acid, 493236 D D pyruvate-2-13C, 13C ONa 98 atom % D O H C D 99 atom % 13C 3 D OH O D D 13 O Sodium pyruvate- C3, 490717-500MG 13 l-Phenylalanine-1- C, O 661600 13 99 atom % C 13 13 13 13C H3 C C 99 atom % C OH 13C ONa NH2 O O l-Phenylalanine-3,3-d2, D D 615889-100MG D D D D 98 atom % D OH Spermidine-butane- H 709891-5MG H2N N • 3HCl NH H NH2 d8 trihydrochloride, 2 709891-10MG 98 atom % D, 95% (CP) D D D D D O l-Phenyl-d5-alanine, H 661619 D Spermine-butane-d D D D D H 705330-5MG 98 atom % D OH 8 N NH2 • 4HCl H2N N NH2 tetrahydrochloride, 705330-10MG D D H D D D D D 97 atom % D, 95% (CP) O D D 13 O Succinic acid-2,2,3,3-d4, 293075-1G l-Phenyl-1- C-alanine, 605042 OH 98 atom % D HO 293075-5G 99 atom % 13C D D O 13C OH 13 O NH2 Succinic acid-1,2- C2, 491977 13 13C 99 atom % C OH HO 13C l-Phenylalanine-2-13C, O 490113-250MG 13 O 99 atom % C 13C OH NH 2 13 O Succinic acid-1,4- C2, 485349-500MG 13 13 13 O C OH l-Phenylalanine-3- C, 490121-100MG 99 atom % C 13C 13 HO 13 C 99 atom % C OH O

H2N H 13 O Succinic acid-2,3- C2, 488364-100MG HO 13C 13 O 13 l-Phenyl- C6-alanine, 660884 99 atom % C 13C 13 OH 13 C O 99 atom % C 13C 13C OH NH 13C 13C 2 Succinic acid-13C , O 491985-100MG 13 4 C 13 13 13 99 atom % C C C OH HO 13C 13 l-Phenylalanine-15N, O 660892 C 15 98 atom % N OH O 15 NH2 Taurine-15N, O 491330 H 15N OH D 15 2 l-Phenyl-d5-alanine- 490148-1G 98 atom % N S D D 2,3,3-d3, 98 atom % D H2N D O OH D 13 OH O D D D O l-Threonine-1- C, 605034 99 atom % 13C, 13C H3C OH

97% (CP) NH2

18 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Name Cat. No. Name Cat. No.

L-Threonine- HO D O 701432 l-Tyrosine-phenyl- D 489816-1G HO D C OH 2,3,4,4,4-d5, 3 3,5-d2, 98 atom % D H2N H D NH2 OH 98 atom % D, D 97% (CP) O

3,3 ,5-Triiodo- O 709611-1MG D O ′ l-Tyrosine-phenyl-d4, 661503 HO I 13C D thyronine-tyrosine 13 13 709611-5MG 98 atom % D OH Amino Acid Metabolites Stable Isotope-Labeled 13 C C OH ring- C6 (T3), 709611-10MG NH2 13 13 • HCl HO D 13 C C NH2 99 atom % C, I O 13C D 95% (CP) I HO l-Tyrosine-3,3-d2, H2N H 489840 D l-Tryptophan- O 609064 98 atom % D OH 15 amino- N, OH D O 15 15NH 99 atom % N N 2 H l-Tyrosine-2-13C, O 605107-100MG 13 99 atom % C 13C OH 605107-500MG l-Tyrosine-phenyl-4-13C, O 605093 13 NH 99 atom % C OH HO 2 13 C NH2 HO Urea-13C, research O 299359-1G grade, 99 atom % 13C 13C 299359-5G 13 O l-Tyrosine-phenyl- C6, 489794-100MG H2N NH2 13 99 atom % C 13C 15 O 13C 13C OH Urea- N2, 316830-250MG 98 atom % 15N 316830-1G 13 13 15 15 C C NH2 H2 N NH2 HO 13C

d-Valine-d , D3C D O 637467 13 O 8 l-Tyrosine-phenyl- C6, 660752 98 atom % D D3C OH 13 13 99 atom % C C D NH2 13C 13C OH 13 13 13 l-Valine-1- C, NH2 660906 C C NH2 13C 13 H3C O HO 99 atom % C 13C CH3 OH

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Our Innovation, Your Research — Shaping the Future of Life Science 19 Metabolite Libraries

Choose your own components, and build a custom library online using the Sigma-Aldrich® Metabolomics Resources. Many Metabolite Standards are available in specialized 10 mg sizes packaged in autosampler vials. Libraries Currently Available—Choose from: Amino Acids and Metabolic Intermediates Carbohydrates and Metabolic Intermediates

Metabolite Libraries Lipids and Metabolic Intermediates Currently in development: Nucleotide Library Vitamin/Cofactor Library Hundreds of other metabolites are available in standard packaging and can be found in the Sigma Life Science Catalog or online (sigma-aldrich.com/metabolites). Custom Packaging Our DiscoveryCPR program can custom package metabolites in the sizes and containers you specify. See page 26 for more details.

Online Metabolomics Resource

Use the IUBMB–Sigma-Aldrich Interactive Chart to find the Metabolite Standards you need. http://www.sigma-aldrich.com/ProductLookup.html? ProdNo=C7352&Brand=SIGMA The Metabolic Pathways Map contains over 500 hyperlinks to Sigma product listings. Just click on the metabolite name or the enzyme’s E.C. number to access product information.

You can access the chart at sigma-aldrich.com/metpath

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20 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Amino Acid Metabolite Library

Metabolite Cat. No. Packaging Metabolite Cat. No. Packaging

Acetyl-l-carnitine hydrochloride A6706 10 mg Autosampler vial d l -Homocystine H0501 10 mg Autosampler vial

O-Acetyl-l-serine hydrochloride A6262 10 mg Autosampler vial Homogentisic acid H0751 10 mg Autosampler vial Metabolite Libraries Metabolite Adenosine 5'-phosphosulfate sodium salt A5508 5 mg l-Homoserine H6515 10 mg Autosampler vial

S-(5'-Adenosyl)-l-homocysteine A9384 10 mg Autosampler vial cis-4-Hydroxy-d-proline H5877 10 mg Autosampler vial l-Alanine A7469 10 mg Autosampler vial trans-4-Hydroxy-l-proline H5534 10 mg Autosampler vial β-Alanine A9920 10 mg Autosampler vial Hypotaurine H1384 10 mg Autosampler vial

γ-Aminobutyric acid A5835 10 mg Autosampler vial l-Isoleucine I7403 10 mg Autosampler vial 5-Aminolevulinic acid hydrochloride A7793 10 mg Autosampler vial α-Keto-γ-(methylthio)butyric acid sodium salt K6000 10 mg Autosampler vial

Anthranilic acid A89855 10 mg l-Leucine L8912 10 mg Autosampler vial l-Arginine A8094 10 mg Autosampler vial Lithium carbamoylphosphate dibasic C5625 10 mg Autosampler vial

Argininosuccinic acid disodium salt A5707 10 mg Autosampler vial l-Lysine L5501 10 mg Autosampler vial l-Asparagine A0884 10 mg Autosampler vial l-Methionine M5308 10 mg Autosampler vial l-Aspartic acid A8949 10 mg Autosampler vial l-Methionine sulfoxide M1126 10 mg Autosampler vial

Betaine aldehyde chloride B3650 10 mg Autosampler vial l-Ornithine monohydrochloride O2375 10 mg Autosampler vial

Betaine hydrochloride B7045 10 mg Autosampler vial l-Phenylalanine P5482 10 mg Autosampler vial l-Carnitine hydrochloride C0283 10 mg Autosampler vial chloride calcium salt P0378 10 mg Autosampler vial tetrahydrate l-Carnosine C9625 10 mg Autosampler vial Phosphocreatine disodium salt P7936 10 mg Autosampler vial Choline chloride C7017 10 mg Autosampler vial hydrate enzymatic Chorismic acid from Enterobacter aerogenes C1761 10 mg Autosampler vial O-Phospho-l-serine P0878 10 mg Autosampler vial l-Citrulline C7629 10 mg Autosampler vial Prephenic acid barium salt P2384 10 mg Autosampler vial Creatine C0780 10 mg Autosampler vial l-Proline P0380 10 mg Autosampler vial Creatinine C4255 10 mg Autosampler vial Sarcosine S7672 10 mg Autosampler vial l-Cystathionine C7505 10 mg Autosampler vial l-Serine S4500 10 mg Autosampler vial Cysteamine M9768 10 mg Autosampler vial Shikimic acid S5375 10 mg Autosampler vial l-Cysteine C7352 10 mg Autosampler vial Sodium 2-oxobutyrate K0875 10 mg Autosampler vial Cystine C7602 10 mg Autosampler vial Sodium phenylpyruvate P8001 10 mg Autosampler vial N,N-Dimethylglycine D1156 10 mg Autosampler vial O-Succinyl-l-homoserine S7129 25 mg N-Formyl-l-methionine F3377 10 mg Autosampler vial Taurine T0625 10 mg Autosampler vial l-Glutamic acid G8415 10 mg Autosampler vial l-Threonine T8441 10 mg Autosampler vial l-Glutamine G8540 10 mg Autosampler vial N,N,N-Trimethyllysine T1660 25 mg l-Glutathione, reduced G4251 10 mg Autosampler vial Tryptamine T2891 10 mg Autosampler vial Glycine G7126 10 mg Autosampler vial l-Tryptophan T8941 10 mg Autosampler vial Histamine dihydrochloride H7250 10 mg Autosampler vial Tyramine hydrochloride T2879 10 mg Autosampler vial l-Histidine H6034 10 mg Autosampler vial l-Tyrosine T8566 10 mg Autosampler vial l-Histidinol dihydrochloride H6647 10 mg Autosampler vial l-Valine V0513 10 mg Autosampler vial d l -Homocysteine H4628 10 mg Autosampler vial Sigma is Cell Culture

The 3rd edition of the Sigma Cell Culture Manual is a hybrid reference and product guide designed to be a foundation for your discovery efforts. ■ Extensive cell culture technical information and formulas ■ Our most popular cell culture products and equipment ■ Invaluable tool to help advance your research goals Order your copy of the 2008–2009 Cell Culture Manual by visiting sigma.com/ccmanual

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Our Innovation, Your Research — Shaping the Future of Life Science 21 Lipid Metabolite Library

Metabolite Cat. No. Packaging Metabolite Cat. No. Packaging Acetoacetyl coenzyme A sodium salt hydrate A1625-10MG 10 mg Isovaleryl coenzyme A lithium salt I9381-10MG 10 mg Acetone 154598-IL 1 L Lanosterol from sheep wool L5768-5MG 5 mg

O-Acetyl-l-carnitine hydrochloride A6706-10MG 10 mg Autosampler vial Lauroyl coenzyme A lithium salt L2659-5MG 5 mg

Acetyl coenzyme A sodium salt A2056-10MG 10 mg Leukotriene B4 L0517-50UG 50 μg Acetyl coenzyme A trilithium salt A2181-10MG 10 mg Linoleic acid L1376-10MG 10 mg Autosampler vial Acetylcholine chloride A6625-10MG 10 mg Autosampler vial γ-Linolenic acid L2378-10MG 10 mg Autosampler vial Arachidonic acid from porcine liver A9673-10MG 10 mg Linoleoyl coenzyme A lithium salt L9754-10MG 10 mg Arachidonoyl coenzyme A lithium salt A5837-10MG 10 mg Lithium acetoacetate A8509-10MG 10 mg Autosampler vial

Benzoyl coenzyme A lithium salt B1638-5MG 5 mg l-α- from L1381-5MG 5 mg bovine brain

Metabolite Libraries 2-Butenoyl Coenzyme A lithium salt C6146-10MG 10 mg Malonyl coenzyme A lithium salt M4263-10MG 10 mg Autosampler vial Butyryl coenzyme A dilithium salt hydrate B1508-10MG 10 mg β-Methylcrotonyl coenzyme A lithium salt M3013-10MG 10 mg solution bovine heart C1649-10MG 10 mg Methylmalonyl coenzyme A tetralithium M1762-5MG 5 mg Choline chloride C7017-10MG 10 mg Autosampler vial salt hexahydrate Coenzyme A hydrate from yeast C4282-10MG 10 mg (±)-Mevalonolactone M4667-1G 1 G Coenzyme A sodium salt hydrate C3144-10MG 10 mg myo- I5125-10MG 10 mg Autosampler vial from yeast Myristoyl coenzyme A lithium salt M4414-5MG 5 mg Coenzyme A trilithium salt from yeast C3019-10MG 10 mg Octanoyl coenzyme A lithium salt O6877-10MG 10 mg 5'-diphosphocholine sodium C0256-10MG 10 mg monohydrate salt dihydrate Oleoyl coenzyme A lithium salt O1012-10MG 10 mg Cytidine 5'-diphosphoethanolamine C0456-10MG 10 mg sodium salt Oxalic acid dihydrate O0376-10MG 10 mg Autosampler vial Decanoyl coenzyme A monohydrate D5269-5MG 5 mg Palmitoleoyl coenzyme A lithium salt P6775-10MG 10 mg 3'-Dephosphocoenzyme A D3385-5MG 5 mg Palmitoyl coenzyme A lithium salt P9716-10MG 10 mg Desmosterol D6513-10MG 10 mg 3-sn- sodium salt egg P9511-10MG 10 mg yolk d l -erythro-Dihydrosphingosine D6908-10MG 10 mg l-α- P3841-10MG 25 mg γ,γ-Dimethylallyl pyrophosphate D4287-1VL 1VL (200 μg) ammonium salt l-α-Phosphatidyl-d l - sodium salt P8318-10MG 10 mg Autosampler vial Ethanolamine E9508-10UL 10 μL 3-sn- from P7693-5MG 5 mg bovine brain Farnesyl pyrophosphate ammonium salt F6892-1VL 1VL (200 μg) l-α- ammonium salt P2517-10MG 10 mg Geranyl pyrophosphate ammonium salt G6772-1VL 1VL (200 μg) solution Geranylgeranyl pyrophosphate G6025-1VL 1VL (200 μg) 3-sn-Phosphatidyl-l-serine sodium salt P5660-5MG 5 mg ammonium salt bovine brain Glycerol G7757-500ML 500 mL Phosphocholine chloride calcium salt P0378-10MG 10 mg Autosampler vial rac-Glycerol 3-phosphate disodium salt G2138-10MG 10 mg Autosampler vial tetrahydrate hexahydrate O-Phosphorylethanolamine P0503-10MG 10 mg Autosampler vial Glycolaldehyde dimer G6805-1G 1 g 5-Pregnen-3β-ol-20-one P9129-10MG 10 mg Autosampler vial Glycolic acid G8284-10MG 10 mg Autosampler vial Progesterone P0130-25G 25 G Glyoxylic acid solution G1134-20UL 20 μL n-Propionyl coenzyme A lithium salt P5397-10MG 10 mg n-Heptadecanoyl coenzyme A lithium salt H1385-5MG 5 mg Prostaglandin E2 P5640-10MG 10 mg Hexanoyl coenzyme A trilithium salt trihydrate H2012-10MG 10 mg Psychosine from bovine brain P9256-10MG 10 mg d l -3-Hydroxy-3-methylglutaryl coenzyme A H6132-10MG 10 mg from bovine brain S7004-10MG 10 mg sodium salt Squalene S3626-10ML 10 mg γ-Hydroxybutyric acid sodium salt H3635-10MG 10 G Stearoyl coenzyme A lithium sal S0802-10MG 10 mg d l -β-Hydroxybutyryl coenzyme A H0261-10MG 10 mg lithium salt Succinyl coenzyme A sodium salt S1129-5MG 5 mg

Isobutyryl coenzyme A lithium salt I0383-10MG 10 mg Thromboxane B2 T0516-1MG 1 mg Isopentenyl pyrophosphate ammonium I0503-1VL 1VL (200 μg) salt solution

22 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo Carbohydrate Metabolite Library

Metabolite Cat. No. Packaging Metabolite Cat. No. Packaging

N-Acetyl-d-galactosamine A2795 10 mg Autosampler vial d-Glucuronic acid G5269 10 mg Autosampler vial

N-Acetyl-d-glucosamine A8625 10 mg Autosampler vial Guanosine 5'-diphosphoglucose sodium salt G7502 10 mg Autosampler vial Metabolite Libraries Metabolite N-Acetyl-d-lactosamine A7791 10 mg Autosampler vial myo-Inositol I5125 10 mg Autosampler vial

N-Acetyl-d-mannosamine A8176 10 mg Autosampler vial Isomaltose I7253 100 mg

N-Acetylneuraminic acid A2388 10 mg d-Lactose monohydrate L8783 10 mg Autosampler vial

Adenosine-5'-diphosphoglucose A0627 10 mg Autosampler vial d-(–)-Lyxose 220477 1 G disodium salt d-(+)-Maltose monohydrate M9171 10 mg Autosampler vial Adonitol A5502 10 mg Autosampler vial d-Mannitol M4125 10 mg Autosampler vial d-Allose A6390 10 mg Autosampler vial d-Mannosamine hydrochloride M4670 10 mg Autosampler vial l-(+)-Arabinose A3256 10 mg Autosampler vial d-(+)-Mannose M4319 5 G l-(–)-Arabitol A3506 10 mg Autosampler vial d-Mannose 6-phosphate disodium salt hydrate M6876 10 mg Autosampler vial l-Ascorbic acid A5960 10 mg Autosampler vial Melibiose M5500 10 mg Autosampler vial d-(+)-Cellobiose C7252 10 mg Autosampler vial Palatinose P2007 10 mg Autosampler vial 2-Deoxy-d-glucose D8375 10 mg Autosampler vial Phospho(enol)pyruvic acid P7127 100 mg 6-Deoxy-d-glucose D9761 10 mg Autosampler vial monopotassium salt

2-Deoxy-d-ribose D5899 10 mg Autosampler vial 6-Phosphogluconic acid trisodium salt P6888 10 mg Autosampler vial

2-Deoxyribose 5-phosphate sodium salt D3126 25 mg d-(–)-3-Phosphoglyceric acid disodium salt P8877 10 mg Autosampler vial

Dihydroxyacetone phosphate dilithium salt D7137 10 mg Autosampler vial d-Psicose P8043 10 mg Autosampler vial

2,3-Diphospho-d-glyceric acid D5764 25 mg d-(+)-Raffinose pentahydrate R0514 10 mg Autosampler vial pentasodium salt l-Rhamnose monohydrate R3875 10 mg Autosampler vial Dulcitol D0256 10 mg Autosampler vial d-(–)-Ribose R7500 10 mg Autosampler vial d-Erythrose 4-phosphate sodium salt E0377 10 mg Autosampler vial d-Ribose 5-phosphate disodium salt hydrate R7750 10 mg Autosampler vial d-(–)-Fructose F0127 10 mg Autosampler vial d-Ribulose 1,5-bisphosphate sodium R0878 10 mg Autosampler vial d-Fructose 1,6-bisphosphate trisodium salt F6803 10 mg Autosampler vial salt hydrate d-Fructose 1-phosphate sodium salt F1127 10 mg Autosampler vial d-Ribulose 5-phosphate sodium salt R9875 5 mg d-Fructose 6-phosphate disodium salt F3627 10 mg Autosampler vial Sodium pyruvate P2256 10 mg Autosampler vial dihydrate d-Sorbitol S1876 10 mg Autosampler vial l-(–)-Fucose F2252 10 mg Autosampler vial Stachyose hydrate from Stachys tuberifera S4001 10 mg Autosampler vial α-d-Galactosamine 1-phosphate G5134 25 mg Sucrose S9378 10 mg Autosampler vial d-(+)-Galactosamine hydrochloride G0500 10 mg Autosampler vial d-(–)-Tagatose T2751 10 mg Autosampler vial d-(+)-Galactose G0750 10 mg Autosampler vial Trehalose 6-phosphate dipotassium salt T4272 10 mg α-d-Galactose 1-phosphate dipotassium G0380 10 mg Autosampler vial d-(+)-Trehalose dihydrate T9531 10 mg Autosampler vial salt pentahydrate Uridine 5'-diphosphogalactose U4500 10 mg d-Gluconic acid sodium salt G9005 10 mg Autosampler vial disodium salt d-Glucosamine 6-phosphate G5509 10 mg Autosampler vial Uridine 5'-diphosphoglucose disodium salt U4625 10 mg Autosampler vial d-(+)-Glucosamine hydrochloride G4875 10 mg Autosampler vial Uridine 5'-diphosphoglucuronic acid U6751 25 mg d-(+)-Glucose G7528 10 mg Autosampler vial trisodium salt

α-d-Glucose 1-phosphate disodium G7018 10 mg Autosampler vial Xylitol X3375 10 mg Autosampler vial salt hydrate d-(+)-Xylose X1500 10 mg Autosampler vial d-Glucose 6-phosphate disodium salt hydrate G7250 10 mg Autosampler vial d-Xylulose X4625 25 mg

Our Innovation, Your Research — Shaping the Future of Life Science 23 The New ML0100 TCA Cycle Metabolite Library provides all Fa ol tty n 10 components of the Kreb’s Cycle in one convenient format. e Ac Etha rin e e tein ine id S ys hion A C tat nabo Cys TCA Cycle Metabolite Library Cysteine li ALANINE Fa sm All components are directly water soluble at ≥ 50 mg/ml. tty PYRUVATE Valine Acid Cata LACTATE Components bolism Iso leucine Acetyl coenzyme A (Sigma A2056) 10 mg Ketone Bodies Lysine Citric acid (Sial C7129) 10 mg ACETYL-CoA Pyrimidines Leucine Sodium fumarate dibasic (Sigma F1506) 10 mg OH- Meth yl OXALOACETATE Leucine d l -Isocitric acid (Sigma I1252) 10 mg glutaryl-CoA MALATE Aspartate l-(−)-Malic acid (Sigma M1000) 10 mg Tyrosine Oxaloacetic acid (Sigma O4126) 10 mg Carotenoids CITRATE FUMARATE Aspartate Sodium pyruvate (Sial P2256) 10 mg Cholesterol Steroids Succinyl coenzyme A (Sigma S1129) 10 mg 4-NH2-Butanoate

Metabolite Libraries SUCCINATE Sodium succinate (Sial S2378) 10 mg ISOCITRATE Pyrimidines Threonine store at: −20°C Heme SUCCINYL-CoA Odd-C Fatty Acids 4-NH -Butanoate ML0010-1KT 1 kit 2-OXOGLUTARATE 2 Glutamate

M IA ITOCHONDR

©2002 IUBMB

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24 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo New Metabolites from Sigma-Aldrich

We are pleased to provide you with the following unique (R)-(−)-Mevalono­lactone metabolites listed below. Many more unique metabolites will (R)-Mevalo­lactone; (R)-3-Hydroxy-3-methyl-δ-valero­lactone; soon be available for frontier research. Please contact your local d-Mevalonic acid lactone from Metabolites New Sigma-Aldrich [19115‑49‑2] C H O FW 130.14 sales representative if you are looking for new metabolites and if 6 10 3 Classical enantiomerically pure metabolite in biosynthetic pathways leading to you do not find the metabolite you need for your research on our sterols, terpenes, carotenoids, and other natural products. metabolomics website.  ≥90.0% (GC) store at: 2-8°C S-(5'-Adenosyl)-3-thio­pro­pyl­amine 68519-100MG 100 mg S-Adenosyl-3-thiopro­ ­pylamine;­ 5'-[(3-Amino­pro­pyl)thio]-5'-deoxyadeno­ ­sine; 68519-500MG 500 mg deca­rbo­xylate­d S-Adenosyl-l-homo­cys­teine; dcAdoHcy; dc-SAH

[53186‑57‑5] C13H20N6O3S FW 340.40 2-Oxo­adipic acid This decarboxylated S-Adenosyl-L-methionine is an important metabolite in 2-Oxo­hexane­dioic acid; α-Keto­adipic acid polyamine biosynthesis, acting as aminopropyl group donor for propylamine [3184‑35‑8] C6H8O5 FW 160.12 transferases such as spermine synthase and spermidine synthase. Important metabolite between the TCA cycle and lysine biosynthesis.  ≥98.0% (HPLC) Of interest for research on mitochondrial metabolite transporters. store at: 2-8°C  ≥95.0% (HPLC) 43713 ≥97.0% (T) store at: 2-8°C 5-Dehydro­quin­ic acid potassium salt 75447-100MG 100 mg 3-Dehydro­quin­ic acid potassium salt; (1R,3R,4S)-1,3,4-Tri­hydroxy-5-oxo­cyclo­ 75447-500MG 500 mg hexane­carboxy­lic acid potassium salt [494211‑79‑9] C7H9KO6 FW 228.24 d(+)2-Phos­pho­gly­ceric acid sodium salt hydrate Metabolite of the shikimate pathway, which is required for the synthesis of d-Gly­cer­ate 2-phos­phate sodium salt; Sodium D-2-phos­pho­gly­cer­ate hydrate aromatic compounds in microorganisms and plants. [70195‑25‑4] C3H7O7P · H2O FW 252.00 (FA/Anh)  ≥97.0% (TLC) Enantiomerically pure metabolite of glycolysis/gluconeogenesis and also 40216-25MG 25 mg substrate for a number of important enzymes in central metabolism like enolase and phosphoglycerate mutase. 40216-100MG 100 mg  ≥75% (enzymatic, calc. on dry substance) 3-Dehydro­shikimic acid store at: 2-8°C 5-Dehydro­shikimic acid; (4S,5R)-(−)-4,5-Dihydroxy-3-oxo-1-cyclohex­ ­ene-1- 79470-50MG 50 mg carboxy­lic acid 79470-250MG 250 mg [2922‑42‑1] C7H8O5 FW 172.14 79470-1G 1 g Metabolite of the shikimate pathway with a chromophore suitable for continuous spectrophotometric assay. Precursor of aromatic metabolites in microorganisms. l-2-Phos­pho­gly­ceric acid disodium salt hydrate  ≥98.0% (HPLC) Disodium l-2-phos­pho­gly­cer­ate; l-Gly­cer­ate 2-phos­phate disodium salt C H Na O P · xH O FW 230.02 (Anh) 05616-10MG 10 mg 3 5 2 7 2 Opposite enantiomer to the standard configuration found in 05616-100MG 100 mg glycolysis/gluconeogenesis. 05616-500MG 500 mg  ≥80% (CE) 1-Deoxy-d-xylulose-5-phosphate­ sodium salt 19710-50MG 50 mg + C5H11O7P · xNa FW 214.11 (FA) 19710-250MG 250 mg Metabolite of the non-mevalonate pathway, generally found in prokaryotes, as precursor to isoprenoids as well as non-isoprenoids like vitamins. As this pathway is not present in humans, it is of interest for the development of bacterium- specific drugs in the search for treatments of infectious diseases.  ≥99.0% (TLC) 13368

(±)-Mevalonic acid 5-phosphate­ trilithium salt hydrate rac-5-Phos­pho­mevalonate trilithium salt

C6H10Li3O7P · xH2O FW 245.94 (Anh) Metabolite of the mevalonate pathway, which plays a key role in the biosynthesis of sterols, dolichol, heme and ubiquinone. Of interest for research in the disease areas oncology, autoimmune diseases, artherosclerosis and Alzheimer disease, as well as for inherited deficiencies of mevalonate kinase.  95% (TLC) store at: 2-8°C 79849-10MG 10 mg 79849-50MG 50 mg

Our Innovation, Your Research — Shaping the Future of Life Science 25 Drug Discovery DiscoveryCPR: Discover with Custom Packaged Pharmacologically Active Compounds and Metabolites The New Standard in Reagent Management Flexibility

When projects require a custom array of reagents, DiscoveryCPR Drug Discovery can meet the challenge. Our packaging groups will custom pack DiscoveryCPR reagents to your specifications. If you have questions about our unique service or wish to request a quotation on a custom reagent To register for an set, please contact us at: [email protected] online ordering account or Features of this service: to submit inquiries: discoverycpr.com ■ No minimum order required ■ Widest selection of reagents available ­— over 25,000 and growing Compounds for ■ Complete reagents sets ­— order products from any vendor High Throughput Screening ■ Order reagents in any amount, from micromoles to grams Sigma-Aldrich® is pleased to announce the availability of the ■ Specify vial type, labeling/bar-coding, and packaging MyriaScreen Diversity Collection of drug-like screening compounds. The collection, produced in collaboration with TimTec Inc., is the Efficiency result of careful evaluation, filtering, and refinement of selections from each of our screening compound collections. The MyriaScreen ■ 24-48 hour turnaround time for most compounds Diversity Collection is comprised of 10,000 high-purity screening ■ Guaranteed delivery in both the U.S. and Europe compounds handpicked to maximize chemical diversity while ■ Ready-to-use ­— save time, reduce waste, enhance productivity maintaining drug-likeness.

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26 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo LOPAC®1280: Library of Pharmacologically Active Compounds

New Insights With Predictable Activities and Proven Scaffolds Drug Discovery

Sigma-Aldrich® invites you to use this interactive tool to easily browse through LOPAC1280, a collection of 1,280 pharmacologically Reveal! active compounds. The power and convenience of the known To browse the compounds on actives in Sigma®’s Library of Pharmacologically Active Compounds the LOPAC1280 Navigator or request a is assured. This annotated collection of small molecule modulators complete list of components, and approved drugs impacts most cellular processes and covers all please visit sigma.com/lopac major drug target classes. Consider the bioactives you want in your library and reveal why researchers worldwide trust the ones in ours: Relevant Compounds and ■ 1,280 pharmacologically active compounds – All major target Pharmacological Activities classes are represented, including GPCRs and kinases, making ■ Antiproliferatives ■ Cell cycle regulators LOPAC the most flexible assay validation library available. ■ Enzyme inhibitors ■ Apoptosis inducers ■ Marketed drugs and pharmaceutically relevant structures – Predictable activities and proven scaffolds directed against a wide ■ ■ GPCR ligands range of drug targets. LOPAC1280 compounds are also indexed in the NCBI’s ■ Annotated structure/activity database – Convenient PubChem database. management of individual samples, subsets, or the entire collection. ■ Guaranteed Sigma quality and easy re-supply – Highly pure compounds, each available as an individual catalog item. ■ Pre-solubilized and normalized compounds – Ready-to-use DMSO stocks require less time-consuming sample preparation.

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Our Innovation, Your Research — Shaping the Future of Life Science 27 Metabolite Chromatographic Analysis

Ascentis® Express HILIC from Supelco®

Ascentis Express columns provide a breakthrough in HPLC column performance. The complex nature of metabolomic analysis requires superior separation capabilities. The Ascentis Express columns, based on Fused-Core™ technology offer highly efficient separations without the high backpressure associated with sub-2 µm particles. Due to the high efficiencies at low backpressures, Ascentis Express can benefit both conventional HPLC users as well as UPLC® or other ultra pressure system users.

Ascentis Express Extreme Performance benefits include: Ascentis® Express HILIC HPLC Column 8  Double the efficiencies of conventional 3 µm particles Ascentis Express HPLC columns, through the use of Fused-Core particle technology, can provide you with both the high speed and high efficiencies of  Equal efficiencies of sub-2 µm columns at half of the sub-2 µm particles while maintaining lower backpressures. The combination of backpressure high efficiency and low backpressure benefits UPLC (or other ultra high pressure system) users, as well as conventional HPLC users.  Rugged design capable of high pressure operation Visit the Ascentis Express home page for more information on this new column technology. Metabolite Chromatographic Analysis Metabolite Chromatographic  particle size 2.7 μm, L 10 cm × I.D. 2.1 mm Ascentis Express HILIC 53939-U 1 pkg

β-Alanine  particle size 2.7 μm, L 15 cm × I.D. 4.6 mm Length 15 cm Alanine Diameter 0.46 cm 53981-U 1 pkg Particle Size 2.7 μm Mobile Phase A Water/Acetonitrile (10:90 v/v); Methionine 13mM Ammonium Acetate Tryptophan Mobile Phase B Water; 13mM Ammonium Acetate Gradient 0-0B (1 min); 0-90B (19 min) For more information about Ascentis Express, Tyramine Flow Rate 1 mL/min Tryptamine Temperature 35 °C Detector MS TIC (m/z from 50 to 500) visit sigma-aldrich.com/express

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28 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo CHROMASOLV® Solvents

The CHROMASOLV family of submicron filtered solvents from Sigma-Aldrich® delivers superior purity, stability and lot-to-lot consistency making them ideal for a variety of analytical and preparative separations utilizing LC-MS, HPLC and Spectrophometric analysis. Metabolite ChromatographicMetabolite Analysis CHROMASOLV LC-MS CHROMASOLV Plus These LC-MS solvents are designed specifically with low content Manufactured to go beyond our CHROMASOLV for HPLC to be of alkaline impurities, such as calcium, magnesium, potassium, and your high-purity, multipurpose solvent. Tested to meet the most sodium, which can interfere in the analysis by forming adducts demanding HPLC requirements as well as spectrophotometry, with the analytes. CHROMASOLV LC-MS solvents are also run residual analysis and LC-MS applications. through specific UV-spectroscopic quality control tests and LC-MS suitability evaluation to guarantee usability. CHROMASOLV Plus Solvents Cat. No. Acetone, ≥99.9% 650501

CHROMASOLV LC-MS Solvents Cat. No. Acetonitrile, ≥99.9% 34998 2-Propanol, ≥99.9% 34965 Benzene, ≥99.9% 270709 Acetonitrile, ≥99.9% 34967 1-Butanol, ≥99.7% 34867 Ethyl acetate, ≥99.7% 34972 Butyl acetate, 99.7% 270687 Heptane, ≥99% 34999 tert-Butyl methyl ether, 99.9% 650560 Hexane, ≥97% 34986 Chloroform, ≥99.9%, contains amylenes as stabilizer 650498 Methanol, ≥99.9% 34966 Chloroform, ≥99.9%, contains 0.5-1.0% ethanol as stabilizer 650471 Water 39253 Cyclohexane, ≥99.9% 650455 Dichloromethane, ≥99.9%, contains 50-150 ppm amylene as stabilizer 650463 N,N-Dimethylacetamide, ≥99.9% 270555 N,N-Dimethylformamide, ≥99.9% 270547 CHROMASOLV LC-MS Blends Dimethyl sulfoxide, ≥99.7% 34869 LC-MS allows the detection and quantification of many analytes. 1,4-Dioxane, ≥99.5% 34857 The minimization of artifacts requires very well specified solvents Ethyl acetate, 99.9% 650528 spiked with ultra pure salts and acids. These additives are used Heptane, 99% 650536 to improve the chromatographic peak shape and to optimize Hexane, ≥95% 650552 ionization in the MS interface. Hexane, mixture of isomers, ≥98.5% 650544 Methanol, ≥99.9% 646377 1-Methyl-2-pyrrolidinone, ≥99% 270458 CHROMASOLV LC-MS Solvent Blends Cat. No. 2-Propanol, 99.9% 650447 Acetonitrile with 0.1% acetic acid 34678 Pyridine, ≥99.9% 270407 Acetonitrile with 0.1% ammonium acetate 34669 Tetrahydrofuran, ≥99.9%, inhibitor-free 34865 Acetonitrile with 0.1% formic acid 34668 Toluene, ≥99.9% 650579 Acetonitrile with 0.1% formic acid and 0.01% trifluoroacetic acid 34676 2,2,4-Trimethylpentane, ≥99.5% 650439 Acetonitrile with 0.1% trifluoroacetic acid 34976 Water 34877 Methanol with 0.1% acetic acid 34672 o-Xylene, 98% 295884 Methanol with 0.1% ammonium acetate 34670 Methanol with 0.1% formic acid 34671 Methanol with 0.1% trifluoroacetic acid 34974 Water with 0.1% acetic acid 34675 Water with 0.1% ammonium acetate 34674 Water with 0.1% formic acid 34673 Water with 0.1% formic acid and 0.01% trifluoroacetic acid 34677 Water with 0.1% trifluoroacetic acid 34978 Rinsing agent for LC-MS 34689

Our Innovation, Your Research — Shaping the Future of Life Science 29 CHROMASOLV® HPLC Designed for use with HPLC instrumentation and organic synthesis applications. CHROMASOLV HPLC solvents are glass distilled; submicron filtered and undergoes rigorous specification testing to provide you with lot-to-lot consistency.

CHROMASOLV HPLC Solvents Cat. No. CHROMASOLV HPLC Solvents Cat. No. Acetone, ≥99.9% 270725 Hexane, ≥97% 34859 Acetonitrile, gradient, ≥99.9% 34851 Hexane, mixture of isomers, ≥98.5% 293253 Benzonitrile, 99.9% 270318 Methanol, gradient, ≥99.9% 34885 tert-Butanol, ≥99.5% 308250 Methanol, ≥99.9% 34860 2-Butanone, ≥99.7% 34861 2-Methoxyethanol, ≥99.9% 270482 tert-Butyl methyl ether, ≥99.8% 34875 2-Methoxyethyl acetate, ≥99% 308269 Carbon , ≥99.9% 270660 2-Methylbutane, ≥99.5% 270342 Carbon tetrachloride, ≥99.9% 270652 4-Methyl-2-pentanone, ≥99.5% 293261 Chlorobenzene, 99.9% 270644 2-Methyl-1-propanol, 99.5% 270466 1-Chlorobutane, ≥99.8% 34958 Nitromethane, ≥96% 270423 Chloroform, ≥99.8%, contains amylenes as stabilizer 34854 1-Octanol, ≥99% 293245 Chloroform, ≥99.8%, contains 0.5-1.0% ethanol as stabilizer 366927 Pentane, ≥99% 34956 Cyclohexane, ≥99.7% 34855 2-Pentanone, 99.5% 471194 Cyclopentane, ≥75% cyclopentane basis 270601 3-Pentanone, 96% 270334 Metabolite Chromatographic Analysis Metabolite Chromatographic 1,2-Dichlorobenzene, 99% 270598 1-Propanol, ≥99.9% 34871 Dichloromethane, ≥99.8%, contains amylene as stabilizer 34856 2-Propanol, ≥99.8% 34863 Diethylene glycol diethyl ether, ≥99% 308277 Propylene carbonate, 99.7% 414220 Diethyl ether, ≥99.9%, inhibitor-free 309966 Tetrachloroethylene, ≥99.9% 270393 1,2-Dimethoxyethane, 99.9% 307432 1,1,2-Trichloro-1,2,2-trifluoroethane, ≥99.7% 34874 Ethanol, denatured 270741 2,2,4-Trimethylpentane, ≥99% 34862 Ethyl acetate, ≥99.7% 34858 Toluene, 99.9% 34866 Heptane, ≥96% 592579 Water 270733 Heptane, ≥99% 34873 p-Xylene, ≥99% 317195 Hexane, ≥95% 270504

CHROMASOLV HPLC Blends Convenient and accurate pre-blended solvents for HPLC and LC-MS applications. Eliminates time-consuming mobile phase preparation as well as lost sample information and instrument down-time caused by impure mobile phases. For consistent baselines and minimal background noise, these blends are prepared with ultra pure acids.

CHROMASOLV HPLC Solvent Blends Cat. No. CHROMASOLV HPLC Solvent Blends Cat. No. Acetonitrile with 0.1% acetic acid 590754 Methanol with 0.1% formic acid 632546 Acetonitrile with 0.1% ammonium hydroxide 639133 Water with 0.1% ammonium hydroxide 639141 Acetonitrile with 0.1% formic acid 576956 Water with 0.1% formic acid 576913 Acetonitrile with 0.035% trifluoroacetic acid 565423 Water with 0.05% trifluoroacetic acid 590142 Acetonitrile with 0.05% trifluoroacetic acid 574724 Water with 0.1% trifluoroacetic acid 576905 Acetonitrile with 0.1% trifluoroacetic acid 574732

30 sigma.com/lifescience Order: sigma.com/order Technical service: sigma.com/techinfo ® LC-MS CHROMASOLV Solvents and Blends

Super Quality Solvents for Fast and Accurate Analysis Benefits: l Time savings l Low gradient baseline, even with your own optimized protocols l Very low levels of inorganic and metal ions l No particles and non-volatile compounds

Special Offer: 20% off LC-MS CHROMASOLV® Water (Cat. No.: 39253)

To order or for additional information, please visit: sigma-aldrich.com/lc-ms-solvents Reference promotion code 957 when placing your order. Offer ends December 31, 2009.

CHROMASOLV is a registered trademark of Sigma-Aldrich Biotechnology LP and Sigma-Aldrich Co.

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