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Reconstruction of Pathways Associated with Amino Acid Metabolism in Human Mitochondria

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Reconstruction of Pathways Associated with Amino Acid Metabolism in Human Mitochondria Article Reconstruction of Pathways Associated with Amino Acid Metabolism in Human Mitochondria Purnima Guda1, Chittibabu Guda1*, and Shankar Subramaniam2,3 1 Gen*NY*sis Center for Excellence in Cancer Genomics and Department of Epidemiology and Biostatistics, State University of New York at Albany, Rensselaer, NY 12144-3456, USA; 2 San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA 92093-0505, USA; 3 Departments of Bioengineering, Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA. We have used a bioinformatics approach for the identification and reconstruction of metabolic pathways associated with amino acid metabolism in human mitochon- dria. Human mitochondrial proteins determined by experimental and computa- tional methods have been superposed on the reference pathways from the KEGG database to identify mitochondrial pathways. Enzymes at the entry and exit points for each reconstructed pathway were identified, and mitochondrial solute carrier proteins were determined where applicable. Intermediate enzymes in the mito- chondrial pathways were identified based on the annotations available from public databases, evidence in current literature, or our MITOPRED program, which pre- dicts the mitochondrial localization of proteins. Through integration of the data derived from experimental, bibliographical, and computational sources, we recon- structed the amino acid metabolic pathways in human mitochondria, which could help better understand the mitochondrial metabolism and its role in human health. Key words: mitochondria, metabolic pathways, amino acid metabolism, human Introduction Reconstruction of the metabolic maps of fully se- potential value to biomedical research areas such as quenced organisms is becoming a task of ma- drug targeting, reconstruction of disease pathways, jor importance in order to help biologists iden- understanding protein interaction networks, and an- tify and analyze the maps of newly sequenced or- notation of new or alternative pathways. ganisms and newly found pathways (1 ). There A number of methods have been used for path- are several online databases that provide informa- way reconstruction by integrating a combination of tion on metabolic content and pathway diagrams data determined by experimental and computational for a majority of the fully sequenced microbes means (2–4 ). Most of these methods have been de- and eukaryotic species. Databases such as EcoCyc veloped to understand metabolic networks in prokary- (http://ecocyc.org) describe the pathways of a sin- otic systems. However, reconstruction and functional gle organism (Escherichia coli), while others such as characterization of ATP production, heme synthesis, KEGG (Kyoto Encyclopedia of Genes and Genomes; and mixed phospholipid synthesis have been reported http://www.genome.jp/kegg/) and MetaCyc (Ency- in human mitochondria (5 ). Mitochondria are pri- clopedia of Metabolic pathways; http://metacyc.org) marily known as energy centers, while they also play provide pathway information on multiple organisms vital roles in the metabolism of many other biolog- including prokaryotic and eukaryotic species. How- ical macromolecules including amino acids. Amino ever, none of these resources emphasize on the subcel- acid metabolism has been well studied in the context lular localization of metabolic pathways, which is an of cellular metabolism, but specific pathways eluci- important part of pathway analysis given that many dating their subcellular localization to mitochondrial biological pathways are distributed across more than organelles have not been reported before. Out of one subcellular location. Studies of this nature hold 20 amino acids, the metabolic pathways of 17 amino acids utilize mitochondrial enzymes, and dysfunction of these enzymes is the causative factor for over 40 *Corresponding author. known mitochondrial diseases or disorders in human E-mail: [email protected] (partly in Table 1). 166 Geno. Prot. Bioinfo. Vol. 5 No. 3–4 2007 Guda et al. Table 1 Diseases associated with the enzymes involved in the metabolism of amino acids in human mitochondria Pathway EC number Disease or disorder OMIM ID Arginine degradation 2.1.1.2 Guanidinoacetate methyltransferase deficiency 601240 Arginine degradation 3.5.3.1 Argininemia 207800 Arginine metabolism 2.1.3.3 Ornithine transcarbamylase deficiency 311250 Arginine synthesis 2.6.1.13 Ornithinemia with gyrate atrophy of choroid and retina 258870 Asparatate/asparagine metabolism 6.4.1.1 Pyruvate carboxylase deficiency 266150 Glutamate metabolism 1.4.1.3 Hyperinsulinism-hyperammonemia syndrome (HHS) 606762 Glutamate/glutamine synthesis 1.5.1.12 Hyperprolinemia II 239510 Glutamine degradation 1.2.1.24 4-hydroxybutyricaciduria 271980 Glutamine degradation 2.6.1.19 GABA-transaminase deficiency 137150 Glutamine degradation 4.1.1.15 Pyridoxine-dependent infantile convulsions 266100 Glycine degradation 1.1.1.79 Hyperoxularia primary type II (HP 2) 260000 Glycine degradation 1.4.4.2 Nonketotic hyperglycinemia (NKH) 605899 Glycine degradation 2.1.2.10 NKH 605899 Isoleucine degradation 6.4.1.3 Beta-methylcrotonylglycinuria type II 210210 Leucine degradation 1.3.99.10 Isovalericacidemia 243500 Leucine degradation 2.8.3.5 Infantile ketoacidosis 245050 Lysine degradation 1.1.1.35 Hydroxyl-CoA dehydrogenase deficiency 300438 Lysine degradation 1.5.1.8 Hyperlysinemia 238700 Lysine degradation 2.3.1.61 Maple syrup urine disease type II 248610 Lysine degradation 2.3.1.9 Alpha-methylacetoaceticaciduria 203750 Lysine degradation 4.2.1.17 Trifunctional protein deficiency, type 2 607037 Lysine degradation 4.2.1.17 3-methylglutaconicaciduria 250950 Methionine degradation 1.2.4.4 Maple syrup urine disease 248600 Methionine degradation 5.4.99.2 Methylmalonicaciduria I (B12-unresponsive) 251000 Methionine degradation 6.4.1.3 Propionicacidemia 606054 Phenylalanine metabolism 1.14.16.1 Phenylketonuria 261600 Proline metabolism 1.5.1.12 Hyperprolinemia II 239510 Serine degradation 2.6.1.44 Oxalosis I (glycolicaciduria) 259900 & 2.6.1.51 Serine metabolism 2.1.2.10 NKH 605899 Serine metabolism 1.1.1.79 Hyperoxaluria primary type II 260000 Threonine degradation 1.4.3.4 Brunner syndrome 309850 Tyrosine metabolism 1.11.1.8 Defect in thyroid hormonogenesis II 274500 Valine degradation 1.1.1.31 3-hydroxyisobutyricaciduria 236795 Valine degradation 1.3.99.2 Short-chain acyl-CoA dehydrogenase deficiency 201470 Valine degradation 1.3.99.2 Medium-chain acyl-CoA dehydrogenase deficiency 201450 Valine degradation 5.4.99.2 Methylmalonicaciduria I (B12-unresponsive) 251000 Val/Leu/Ile degradation 1.2.1.3 Sjoegren-Larsson syndrome (SLS) 270200 Val, Leu, Ile degradation 1.2.4.4 Maple syrup urine disease 248600 The main goal of this study is to identify and an- data from isozyme studies to systematically identify notate complete or partial segments of mitochondrial the reactions, and also employ computational predic- pathways associated with amino acid metabolism in tion methods to identify proteins targeted to mito- human, and reconstruct these pathways by filling chondria. By effectively integrating all these data, in the gaps. We use a sequence-based homology we have reconstructed a majority of the pathways as- approach to identify mitochondrial pathways from sociated with amino acid metabolism in human mito- KEGG, search for literature-based annotations and chondria. Geno. Prot. Bioinfo. Vol. 5 No. 3–4 2007 167 Amino Acid Pathways in Human Mitochondria Results ways while the non-essential ones have both anabolic and catabolic pathways. All the 20 amino acids ex- Identification of amino acid pathways cept histidine, alanine, and cysteine have metabolic associated with human mitochondria pathways associated with mitochondria. Neverthe- less, these three amino acids are eventually converted A non-redundant set of human mitoproteome was into pyruvate in cytosol, which enters into mitochon- compiled from experimental, bibliographical, and dria for consumption by the tricarboxylic acid (TCA) computational sources (see Materials and Methods). cycle. Below, we provide the reconstructed metabolic KEGG database is the most comprehensive resource pathways and pathway maps for those amino acids as- on metabolic pathways, which builds maps based on sociated with mitochondria. Note that some of them the Enzyme Classification (EC) numbers. In human, are grouped together because they are connected in- KEGG mapping is available only for about 3,000 en- terdependently. zymes, since it fails to map the enzymes lacking EC numbers. We have used a homology-based approach to find the amino acid pathways associated with mi- Lysine degradation tochondria by searching the human mitoproteome set against KEGG’s human proteome set. In human, lysine degradation is known to occur both in mitochondria and cytosol, and here we describe Reconstruction of amino acid pathways only the mitochondrial pathway (Figure 1). Lysine is transported into mitochondria by ornithine carrier associated with human mitochondria that has two isoforms in human. Inside mitochondria, Plants and some bacteria are capable of synthesizing lysine together with 2-ketoglutarate is first reduced all the 20 amino acids necessary for the formation to saccharopine by lysine-ketoglutarate reductase (EC of proteins and other vital molecules; however, that 1.5.1.8) and then to α-aminoadipate semialdehyde (α- is not the case in mammals including human. Hu- AAS) by saccharopine dehydrogenase (EC 1.5.1.9). In man can synthesize
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