The metabolism of pyruvate provides one source of acetyl-CoA which enters the citric acid (TCA, tricarboxylic acid) cycle to generate energy and the reducing equivalent NADH. These reducing equivalents are re-oxidized back to NAD+ in the electron transport chain (ETC), coupling this process with the export of protons across the inner mitochondrial membrane. The chemiosmotic gradient created is used to drive ATP synthesis.
View original pathway at:Reactome.
Harris RA, Bowker-Kinley MM, Wu P, Jeng J, Popov KM.; ''Dihydrolipoamide dehydrogenase-binding protein of the human pyruvate dehydrogenase complex. DNA-derived amino acid sequence, expression, and reconstitution of the pyruvate dehydrogenase complex.''; PubMedEurope PMCScholia
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Huang B, Gudi R, Wu P, Harris RA, Hamilton J, Popov KM.; ''Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation.''; PubMedEurope PMCScholia
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Yu Y, Deck JA, Hunsaker LA, Deck LM, Royer RE, Goldberg E, Vander Jagt DL.; ''Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4.''; PubMedEurope PMCScholia
Rzem R, Van Schaftingen E, Veiga-da-Cunha M.; ''The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase.''; PubMedEurope PMCScholia
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Holmes RS, Goldberg E.; ''Computational analyses of mammalian lactate dehydrogenases: human, mouse, opossum and platypus LDHs.''; PubMedEurope PMCScholia
Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM.; ''Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex.''; PubMedEurope PMCScholia
Brautigam CA, Chuang JL, Tomchick DR, Machius M, Chuang DT.; ''Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations.''; PubMedEurope PMCScholia
Zhou ZH, McCarthy DB, O'Connor CM, Reed LJ, Stoops JK.; ''The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes.''; PubMedEurope PMCScholia
White SA, Peake SJ, McSweeney S, Leonard G, Cotton NP, Jackson JB.; ''The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria.''; PubMedEurope PMCScholia
Ridderström M, Cameron AD, Jones TA, Mannervik B.; ''Involvement of an active-site Zn2+ ligand in the catalytic mechanism of human glyoxalase I.''; PubMedEurope PMCScholia
Chen X, Gu X, Shan Y, Tang W, Yuan J, Zhong Z, Wang Y, Huang W, Wan B, Yu L.; ''Identification of a novel human lactate dehydrogenase gene LDHAL6A, which activates transcriptional activities of AP1(PMA).''; PubMedEurope PMCScholia
Ceccarelli C, Grodsky NB, Ariyaratne N, Colman RF, Bahnson BJ.; ''Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism.''; PubMedEurope PMCScholia
McCartney RG, Rice JE, Sanderson SJ, Bunik V, Lindsay H, Lindsay JG.; ''Subunit interactions in the mammalian alpha-ketoglutarate dehydrogenase complex. Evidence for direct association of the alpha-ketoglutarate dehydrogenase and dihydrolipoamide dehydrogenase components.''; PubMedEurope PMCScholia
Pircher H, von Grafenstein S, Diener T, Metzger C, Albertini E, Taferner A, Unterluggauer H, Kramer C, Liedl KR, Jansen-Dürr P.; ''Identification of FAH domain-containing protein 1 (FAHD1) as oxaloacetate decarboxylase.''; PubMedEurope PMCScholia
Baldwin GS, Seet KL, Callaghan J, Toncich G, Toh BH, Moritz RL, Rubira MR, Simpson R.; ''Purification and partial amino acid sequence of human aconitase.''; PubMedEurope PMCScholia
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Topçu M, Jobard F, Halliez S, Coskun T, Yalçinkayal C, Gerceker FO, Wanders RJ, Prud'homme JF, Lathrop M, Ozguc M, Fischer J.; ''L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1.''; PubMedEurope PMCScholia
Head RA, Brown RM, Zolkipli Z, Shahdadpuri R, King MD, Clayton PT, Brown GK.; ''Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency.''; PubMedEurope PMCScholia
Brown RM, Head RA, Boubriak II, Leonard JV, Thomas NH, Brown GK.; ''Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency.''; PubMedEurope PMCScholia
Luo C, Wang X, Long J, Liu J.; ''An NADH-tetrazolium-coupled sensitive assay for malate dehydrogenase in mitochondria and crude tissue homogenates.''; PubMedEurope PMCScholia
Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM.; ''Diversity of the pyruvate dehydrogenase kinase gene family in humans.''; PubMedEurope PMCScholia
Klyuyeva A, Tuganova A, Popov KM.; ''Amino acid residues responsible for the recognition of dichloroacetate by pyruvate dehydrogenase kinase 2.''; PubMedEurope PMCScholia
Lawson JE, Park SH, Mattison AR, Yan J, Reed LJ.; ''Cloning, expression, and properties of the regulatory subunit of bovine pyruvate dehydrogenase phosphatase.''; PubMedEurope PMCScholia
Ridderström M, Saccucci F, Hellman U, Bergman T, Principato G, Mannervik B.; ''Molecular cloning, heterologous expression, and characterization of human glyoxalase II.''; PubMedEurope PMCScholia
Wilson MC, Meredith D, Fox JE, Manoharan C, Davies AJ, Halestrap AP.; ''Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4: the ancillary protein for the insensitive MCT2 is EMBIGIN (gp70).''; PubMedEurope PMCScholia
Hsieh JY, Li SY, Chen MC, Yang PC, Chen HY, Chan NL, Liu JH, Hung HC.; ''Structural characteristics of the nonallosteric human cytosolic malic enzyme.''; PubMedEurope PMCScholia
LeVan KM, Goldberg E.; ''Properties of human testis-specific lactate dehydrogenase expressed from Escherichia coli.''; PubMedEurope PMCScholia
Polekhina G, Board PG, Blackburn AC, Parker MW.; ''Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity.''; PubMedEurope PMCScholia
Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL.; ''Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase.''; PubMedEurope PMCScholia
Lambeth DO, Tews KN, Adkins S, Frohlich D, Milavetz BI.; ''Expression of two succinyl-CoA synthetases with different nucleotide specificities in mammalian tissues.''; PubMedEurope PMCScholia
Hartong DT, Dange M, McGee TL, Berson EL, Dryja TP, Colman RF.; ''Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle.''; PubMedEurope PMCScholia
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Maj MC, MacKay N, Levandovskiy V, Addis J, Baumgartner ER, Baumgartner MR, Robinson BH, Cameron JM.; ''Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation.''; PubMedEurope PMCScholia
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KORNBERG A, PRICER WE.; ''Di- and triphosphopyridine nucleotide isocitric dehydrogenases in yeast.''; PubMedEurope PMCScholia
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Huizing M, Ruitenbeek W, Thinnes FP, DePinto V, Wendel U, Trijbels FJ, Smit LM, ter Laak HJ, van den Heuvel LP.; ''Deficiency of the voltage-dependent anion channel: a novel cause of mitochondriopathy.''; PubMedEurope PMCScholia
Wanders RJ, Mooyer P.; ''D-2-hydroxyglutaric acidaemia: identification of a new enzyme, D-2-hydroxyglutarate dehydrogenase, localized in mitochondria.''; PubMedEurope PMCScholia
Lissens W, De Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM, Ito M, Naito E, Kuroda Y, Kerr DS, Wexler ID, Patel MS, Robinson BH, Seyda A.; ''Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency.''; PubMedEurope PMCScholia
Struys EA, Verhoeven NM, Ten Brink HJ, Wickenhagen WV, Gibson KM, Jakobs C.; ''Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias.''; PubMedEurope PMCScholia
Tao X, Yang Z, Tong L.; ''Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism.''; PubMedEurope PMCScholia
Sakai I, Sharief FS, Pan YC, Li SS.; ''The cDNA and protein sequences of human lactate dehydrogenase B.''; PubMedEurope PMCScholia
Loeber G, Maurer-Fogy I, Schwendenwein R.; ''Purification, cDNA cloning and heterologous expression of the human mitochondrial NADP(+)-dependent malic enzyme.''; PubMedEurope PMCScholia
Vassylyev DG, Symersky J.; ''Crystal structure of pyruvate dehydrogenase phosphatase 1 and its functional implications.''; PubMedEurope PMCScholia
Li W, James MO, McKenzie SC, Calcutt NA, Liu C, Stacpoole PW.; ''Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1.''; PubMedEurope PMCScholia
Dange M, Colman RF.; ''Each conserved active site tyr in the three subunits of human isocitrate dehydrogenase has a different function.''; PubMedEurope PMCScholia
Rzem R, Veiga-da-Cunha M, Noël G, Goffette S, Nassogne MC, Tabarki B, Schöller C, Marquardt T, Vikkula M, Van Schaftingen E.; ''A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria.''; PubMedEurope PMCScholia
Manjasetty BA, Niesen FH, Delbrück H, Götz F, Sievert V, Büssow K, Behlke J, Heinemann U.; ''X-ray structure of fumarylacetoacetate hydrolase family member Homo sapiens FLJ36880.''; PubMedEurope PMCScholia
Goldenthal MJ, Marin-Garcia J, Ananthakrishnan R.; ''Cloning and molecular analysis of the human citrate synthase gene.''; PubMedEurope PMCScholia
Li J, Kato M, Chuang DT.; ''Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate.''; PubMedEurope PMCScholia
Oxidation of fatty acids and pyruvate in the mitochondrial matrix yield large amounts of NADH. The respiratory electron transport chain couples the re-oxidation of this NADH to NAD+ to the export of protons from the mitochonrial matrix, generating a chemiosmotic gradient across the inner mitochondrial membrane. This gradient is used to drive the synthesis of ATP; it can also be bypassed by uncoupling proteins to generate heat, a reaction in brown fat that may be important in regulation of body temperature in newborn children.
The mitochondrial pyruvate dehydrogenase (PDH) complex (lipo-PDH) irreversibly decarboxylates pyruvate to acetyl CoA, thereby serving to oxidatively remove lactate, which is in equilibrium with pyruvate, and to link glycolysis in the cytosol to the tricarboxylic acid cycle in the mitochondria matrix. Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the PDH complex, inactivating it. Pyruvate negatively regulates this reaction, and NADH and acetyl CoA positively regulate it (Bao et al. 2004). Four PDK isoforms have been identified and shown to catalyze the phosphorylation of E1 alpha in vitro (Gudi et al. 1995, Kolobova et al. 2001, Rowles et al. 1996). They differ in their expression patterns and quantitative responses to regulatory small molecules. All four isoforms catalyze the phosphorylation of serine residues 293 ("site 1") and 300 ("site 2"); PDK1 can also catalyse the phosphorylation of serine 232 ("site 3"). Phosphorylation of a single site in a single E1 alpha subunit is sufficient for enzyme inactivation (Bowker-Kinley et al. 1998, Gudi et al. 1995, Kolobova et al. 2001, Korotchkina and Patel, 2001).
Pyruvate dehydrogenase phosphatase (PDP) in the mitochondrial matrix catalyzes the hydrolytic removal of phosphate groups from phosphoserine residues in the E1 alpha subunit of the pyruvate dehydrogenase complex. The active form of PDP is a heterodimer of a catalytic subunit and a regulatory one. Two isoforms of the catalytic subunit have been identified and biochemically characterized (Huang et al. 1998) and mutations in PDP1 have been associated with PDP deficiency in vivo (Maj et al. 2005). The properties of the human regulatory subunit have been deduced from those of its bovine homologue (Lawson et al. 1997). The activity of PDP1 is greatly enhanced through Ca2+ -dependent binding of the catalytic subunit (PDP1c) to the L2 (inner lipoyl) domain of dihydrolipoyl acetyltransferase (E2), which is also integrated in the pyruvate dehydrogenase complex. PDP activity requires Mg2+ (Huang et al. 1998).
Pyruvate (PYR) and a proton (H+) are cotransported from the mitochondrial intermembrane space to the mitochondrial matrix, mediated by a complex of mitochondrial pyruvate carriers 1 and 2 (MCP1 and MCP2) located in the inner mitochondrial membrane (McCommis & Finck 2015). The proton gradient across the inner mitochondrial membrane must be maintained for ATP production to occur. Transport of PYR across this membrane would collapse this gradient therefore PYR is cotransported with H+. Studies of pyruvate uptake in rat indicate that it is specific, saturable, and competitively inhibitable, indicating a specific role for a membrane transport protein (Papa et al. 1971, Halestrap & Denton 1974), and the stoichiometry of the human reaction is inferred from this work. MCP1 and MCP2 have been identified as essential components of the transporter based on the observation that expression of both proteins (but not either one alone) restored mitochondrial pyruvate uptake in mutant budding yeast. The proteins form a multimeric complex; its stoichiometry is unknown (Bricker et al. 2012).
NNT (nicotinamide nucleotide transhydrogenase) associated with the inner mitochondrial membrane catalyzes the reaction of mitochondrial NADPH and NAD+ to form NADP+ and NADH. The reaction is coupled to the translocation of a proton across the inner mitochondrial membrane into the mitochondrial matrix (White et al, 2000). The active form of NNT is inferred to be a homodimer based on the known structure of its bovine homolog (Yamaguchi and Hatefi 1991).
Mitochondrial aconitase reversibly converts isocitrate to citrate via a cis-aconitate intermediate. Mitochondrial aconitase activity has been demonstrated in diverse human tissue extracts (Slaughter et al. 1975) and a protein homologous to the well-characterized porcine enzyme has been purified from human tissues (Baldwin et al. 1991).
Mitochondrial isocitrate dehydrogenase IDH2 catalyzes the irreversible reaction of isocitrate and NADP+ to form alpha ketoglutarate, CO2, and NADPH + H+ (Hartong et al. 2008). The structure of the active human enzyme has not been determined experimentally, but is inferred to be a homodimer with one Mn++ bound to each subunit based on detailed studies of the homologous pig enzyme (Ceccarelli et al. 2002). NADP-specific IDH2 was the first isocitrate dehydrogenase isoenzyme to be characterized in biochemical studies of the mammalian TCA cycle (Ochoa 1948). Later work with yeast revealed the existence of both NADP-specific (IDH2-homologous) and NAD-specific (IDH3-homologous) enzymes and demonstrated the ADP-dependence of the latter (Kornberg and Pricer 1951), consistent with the now widely accepted view that IDH3 mediates the conversion of isocitrate to alpha-ketoglutarate in the TCA cycle. The physiological function of IDH2 is thus unclear. The recent observation that individuals homozygous for IDH3 mutations that sharply reduce its activity do not show symptoms of deficient energy metabolism in most tissues raises the possibility that the IDH2 reaction may play an accessory role in the TCA cycle (Hartong et al. 2008).
Mitochondrial fumarate hydratase catalyzes the reversible reaction of malate to form fumarate and water (Bourgeron et al. 1994). Unpublished crystallographic data indicate that the protein is a tetramer (PDB 3E04).
Lactoylglutathione lyase (GLO1) catalyses the transformation of methylglyoxal (MGXL) and glutathione (GSH) to (R)-S-lactoylglutathione ((R)-S-LGSH), an intermediate in pyruvate metabolism. MGXL is a reactive 2-oxoaldehyde byproduct of normal metabolism that is a carcinogen and a mutagen (Ridderstrom et al. 1998). This is the first step in the glyoxalase system, a critical two-step detoxification system for MGXL.
In the second step of the glyoxalase system, hydroxyacylglutathione hydrolase (HAGH) catalyses the hydrolysis of (R)-S-lactoylglutathione ((R)-S-LGSH) to glutathione (GSH) and lactic acid (LACT) (Ridderstrom et al. 1996). The HAGH gene can produce two forms of the protein, form 1 is mitochondrial whereas form 2 is cytosolic (Cordell et al. 2004). HAGH is monomeric but requires two Zn2+ ions for activity (Cameron et al. 1999). This reaction completes the detoxification of methylglyoxal, a reactive byproduct of pyruvate metabolism.
LDHAL6B (L-lactate dehydrogenase A-like 6B) catalyzes the reaction of PYR (pyruvate) and NADH + H+ to form LACT (lactate) and NAD+. The LDHAL6B protein is the inferred product of an open reading frame transcribed in the testis (Wang et al. 2005). Its mitochondrial localization is inferred from the presence of a mitochondrial localization sequence at its amino terminus (Holmes and Goldberg 2009). A physiological role for lactate formation from the abundant pyruvate and NADH expected in rapidly respiring mitochondria is not straightforward to imagine, however.
Cytosolic lactate dehydrogenase catalyzes the freely reversible reaction of lactate and NAD+ to form pyruvate and NADH + H+. In liver parenchymal cells, this reaction allows lactate from red blood cells and exercising muscle to be converted to pyruvate which in turn is typically used for gluconeogenesis which also consumes the NADH from the reaction.
Lactate dehydrogenase is active as a tetramer. Two isoforms of lactate dehydrogenase, A and B, are widely expressed in human tissues, and all five tetramers - A4, A3B, A2B2, AB3, and B4 - are found (Read et al. 2001; Sakai et al. 1987; Yu et al. 2001). A third isoform, C, and its tetramer, C4, are found in testis (Millan et al. 1987; LeVan & Goldberg 1991). A fourth isoform, LDHAL6A, is less fully characterized than these others but limited data suggest that it may be testis-specific (Chen et al. 2009).
Mitochondrial isocitrate dehydrogenase IDH3 catalyzes the irreversible reaction of isocitrate and NAD+ to form alpha ketoglutarate, CO2, and NADH + H+. The enzyme is a heteromer containing four polypeptide chains, two IDH3A, one IDH3B, and one IDH3G, and two Mn++ (Dange and Colman 2010). It is activated by ADP (Soundar et al. 2003, 2006; Bzymek and Colman 2007). This is the first of four oxidation reactions in the citric acid cycle, and the first decarboxylation.
Mitochondrial aconitase reversibly converts citrate to isocitrate via a cis-aconitate intermediate. Mitochondrial aconitase activity has been demonstrated in diverse human tissue extracts (Slaughter et al. 1975) and a protein homologous to the well-characterized porcine enzyme has been purified from human tissues (Baldwin et al. 1991).
Mitochondrial citrate synthase dimer catalyzes the irreversible reaction of acetyl-CoA, water, and oxaloacetate to form citrate and coenzyme A. This reaction is the entry point of two-carbon units into the citric acid cycle. The reaction is subject to allosteric regulation. The gene encoding the human enzyme has been cloned (Goldenthal et al. 1998), but the enzyme has not been characterized in detail - its properties are inferred from those of the well-studied homologous pig enzyme (e.g., Morgunov and Srere 1998).
Mitochondrial malate dehydrogenase catalyzes the reversible reaction of malate and NAD+ to form oxaloacetate and NADH + H+ (Luo et al. 2006). This reaction is highly endergonic but is pulled in the direction annotated here when the TCA cycle is operating. Unpublished crystallographic data indicate that the protein is a dimer (PDB 3E04).
Mitochondrial fumarate hydratase catalyzes the reversible reaction of fumarate and water to form malate, the seventh step of the TCA cycle (Bourgeron et al. 1994). Unpublished crystallographic data indicate that the protein is a tetramer (PDB 3E04).
The succinate dehydrogenase complex, associated with the inner mitochondrial membrane, catalyzes the dehydrogenation of succinate to fumarate, reducing the FAD cofactor bound to the enzyme. This redox potential is then used in the electron transfer chain to drive a proton motive force to generate ATP.
Mitochondrial succinate CoA ligase (ADP-forming) catalyzes the reversible conversion of succinyl CoA to succinate plus Coenzyme A, coupled to the conversion of ADP and orthophosphate to ATP. The enzyme is a heterodimer containing SUCLG1 and SUCLA2 monomers.
The enzyme catalyzing the reaction in vertebrates is a heterodimer that occurs in two isoforms. The enzymes have been purified from pigeon and rat tissue and characterized in detail. Both isoforms, an alpha:betaA heterodimer and an alpha:betaG heterodimer, catalyze the reversible conversion of succinyl CoA to succinate plus Coenzyme A. The alpha:betaA heterodimer couples this conversion to the synthesis of ATP from ADP and orthophosphate, while the alpha:betaG heterodimer couples it to the synthesis of GTP from GDP and orthophosphate (Johnson et al. 1998a,b; Lambeth et al. 2004). Consistent with these results in model systems, patients homozygous for a mutant allele of the gene encoding the ADP enzyme beta subunit, SUCLA2, are deficient in succinyl CoA ligase activity (Elpeleg et al. 2005).
Both isoforms are found in vivo, and appear to be expressed at different levels in various tissues. Their relative contributions to the flux of carbon atoms through the TCA cycle are unknown. Genetic and biochemical data suggest that the alpha:betaA isoform may be required to catalyze the reverse reaction, conversion of succinate, Coenzyme A, and ATP to succinyl CoA, ADP, and orthophosphate for heme biosynthesis (Furuyama and Sassa 2000).
The mitochondrial pyruvate dehydrogenase complex catalyzes the reaction of pyruvate, CoASH, and NAD+ to form acetylCoA, CO2, and NADH. The enzyme complex contains multiple copies of three different proteins, E1 alpha, E1 beta, E2, and E3, each with distinct catalytic activities (Reed and Hackert 1990; Zhou et al 2001). The reaction starts with the oxidative decarboxylation of pyruvate catalyzed by E1 alpha and beta (pyruvate dehydrogenase). Lipoamide cofactor associated with E1 is reduced at the same time. Next, the acetyl group derived from pyruvate is transferred to coenzyme A in two steps catalyzed by E2 (dihydrolipolyl transacetylase). Finally, the oxidized form of lipoamide is regenerated and electrons are transferred to NAD+ in two steps catalyzed by E3 (dihydrolipoyl dehydrogenase). The biochemical details of this reaction have been worked out with pyruvate dehydrogenase complex and subunits purified from bovine tissue and other non-human sources. Direct evidence for the roles of the corresponding human proteins comes from studies of patients expressing mutant forms of E1 alpha (Lissens et al. 2000), E1 beta (Brown et al. 2004), E2 (Head et al. 2005), and E3 (Brautigam et al. 2005).
The mitochondrial alpha-ketoglutarate dehydrogenase complex catalyzes the reaction of alpha-ketoglutarate, CoASH, and NAD+ to form succinyl-CoA, CO2, and NADH. The enzyme complex contains multiple copies of three different proteins, E1 (OGDH), E2 (DLST), and E3 (DLD), each with distinct catalytic activities (Reed and Hackert 1990; Zhou et al 2001). The reaction starts with the oxidative decarboxylation of alpha ketoglutarate catalyzed by E1alpha and beta (alpha ketoglutarate dehydrogenase). Lipoamide cofactor associated with E1 is reduced at the same time. Next, the succinyl group derived from alpha ketoglutarate is transferred to coenzyme A in two steps catalyzed E2 (dihydrolipolyl transacetylase). Finally, the oxidized form of lipoamide is regenerated and electrons are transferred to NAD+ in two steps catalyzed by E3 (dihydrolipoyl dehydrogenase). The biochemical details of this reaction have been worked out with alpha ketoglutarate dehydrogenase complex and subunits purified from bovine tissue (McCartney et al. 1998). While all of the human proteins are known as predicted protein products of cloned genes, direct experimental evidence for their functions is available only for E3 (DLD) (Brautigam et al. 2005).
Mitochondrial succinate CoA ligase (ADP-forming) catalyzes the reversible conversion of succinyl CoA to succinate plus Coenzyme A, coupled to the conversion of ADP and orthophosphate to ATP. The enzyme is a heterodimer containing SUCLG1 and SUCLA2 monomers.
The enzyme catalyzing the reaction in vertebrates is a heterodimer that occurs in two isoforms. The enzymes have been purified from pigeon and rat tissue and characterized in detail. Both isoforms, an alpha:betaA heterodimer and an alpha:betaG heterodimer, catalyze the reversible conversion of succinyl CoA to succinate plus Coenzyme A. The alpha:betaA heterodimer couples this conversion to the synthesis of ATP from ADP and orthophosphate, while the alpha:betaG heterodimer couples it to the synthesis of GTP from GDP and orthophosphate (Johnson et al. 1998a,b; Lambeth et al. 2004). Consistent with these results in model systems, patients homozygous for a mutant allele of the gene encoding the ADP enzyme beta subunit, SUCLA2, are deficient in succinyl CoA ligase activity (Elpeleg et al. 2005).
Both isoforms are found in vivo, and appear to be expressed at different levels in various tissues. Their relative contributions to the flux of carbon atoms through the TCA cycle are unknown. Genetic and biochemical data suggest that the alpha:betaA isoform may be required to catalyze the reverse reaction, conversion of succinate, Coenzyme A, and ATP to succinyl CoA, ADP, and orthophosphate for heme biosynthesis (Furuyama and Sassa 2000).
Mitochondrial malate dehydrogenase catalyzes the reversible reaction of oxaloacetate and NADH + H+ to form malate and NAD+ (Luo et al. 2006). Unpublished crystallographic data indicate that the protein is a dimer (PDB 3E04).
Cytosolic lactate dehydrogenase (LDH) catalyzes the freely reversible reaction of pyruvate (PYR) and NADH + H+ to form lactate (LACT) and NAD+. In liver parenchymal cells, this reaction allows lactate from red blood cells and exercising muscle to be converted to pyruvate which in turn is typically used for gluconeogenesis which also consumes the NADH from the reaction.
Lactate dehydrogenase is active as a tetramer. Two isoforms of lactate dehydrogenase, A and B, are widely expressed in human tissues, and all five tetramers - A4, A3B, A2B2, AB3, and B4 - are found (Read et al. 2001; Sakai et al. 1987; Yu et al. 2001). A third isoform, C, and its tetramer, C4, are found in testis (Millan et al. 1987; LeVan & Goldberg 1991). A fourth isoform, LDHAL6A, is less fully characterized than these others but limited data suggest that it may be testis-specific (Chen et al. 2009).
ADHFE1 catalyzes the reversible reaction of (R)-2-hydroxyglutarate and succinate semialdehyde to form 2-oxoglutarate and 4-hydroxybutyrate (Struys et al. 2005). The localization of human ADHFE1 to the mitochondrial matrix is inferred from the location determined experimentally for its rat homolog (Kaufman et al. 1988).
D2HDGH associated with the mitochondrial inner membrane catalyzes the FAD-dependent reaction of (R)-2-hydroxyglutarate to form 2-oxoglutarate (Achouri et al. 2004). D2HDGH mutations are associated with high levels of (R)-2-hydroxyglutarate in vivo and variable neurological symptoms (Struys et al. 2005; Wanders and Mooyer 1995)).
ADHFE1 catalyzes the reversible reaction of 2-oxoglutarate and 4-hydroxybutyrate to form (R)-2-hydroxyglutarate and succinate semialdehyde (Struys et al. 2005). The localization of human ADHFE1 to the mitochondrial matrix is inferred from the location determined experimentally for its rat homolog (Kaufman et al. 1988).
L2HDGH associated with the mitochondrial inner membrane catalyzes the FAD-dependent reaction of (S)-2-hydroxyglutarate to form 2-oxoglutarate (Rzem et al. 2006). L2HDGH mutations are associated with high levels of (S)-2-hydroxyglutarate in vivo and variable neurological symptoms (Rzem et al. 2004; Topcu et al. 2004).
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Lactate dehydrogenase is active as a tetramer. Two isoforms of lactate dehydrogenase, A and B, are widely expressed in human tissues, and all five tetramers - A4, A3B, A2B2, AB3, and B4 - are found (Read et al. 2001; Sakai et al. 1987; Yu et al. 2001). A third isoform, C, and its tetramer, C4, are found in testis (Millan et al. 1987; LeVan & Goldberg 1991). A fourth isoform, LDHAL6A, is less fully characterized than these others but limited data suggest that it may be testis-specific (Chen et al. 2009).
The enzyme catalyzing the reaction in vertebrates is a heterodimer that occurs in two isoforms. The enzymes have been purified from pigeon and rat tissue and characterized in detail. Both isoforms, an alpha:betaA heterodimer and an alpha:betaG heterodimer, catalyze the reversible conversion of succinyl CoA to succinate plus Coenzyme A. The alpha:betaA heterodimer couples this conversion to the synthesis of ATP from ADP and orthophosphate, while the alpha:betaG heterodimer couples it to the synthesis of GTP from GDP and orthophosphate (Johnson et al. 1998a,b; Lambeth et al. 2004). Consistent with these results in model systems, patients homozygous for a mutant allele of the gene encoding the ADP enzyme beta subunit, SUCLA2, are deficient in succinyl CoA ligase activity (Elpeleg et al. 2005).
Both isoforms are found in vivo, and appear to be expressed at different levels in various tissues. Their relative contributions to the flux of carbon atoms through the TCA cycle are unknown. Genetic and biochemical data suggest that the alpha:betaA isoform may be required to catalyze the reverse reaction, conversion of succinate, Coenzyme A, and ATP to succinyl CoA, ADP, and orthophosphate for heme biosynthesis (Furuyama and Sassa 2000).
The enzyme catalyzing the reaction in vertebrates is a heterodimer that occurs in two isoforms. The enzymes have been purified from pigeon and rat tissue and characterized in detail. Both isoforms, an alpha:betaA heterodimer and an alpha:betaG heterodimer, catalyze the reversible conversion of succinyl CoA to succinate plus Coenzyme A. The alpha:betaA heterodimer couples this conversion to the synthesis of ATP from ADP and orthophosphate, while the alpha:betaG heterodimer couples it to the synthesis of GTP from GDP and orthophosphate (Johnson et al. 1998a,b; Lambeth et al. 2004). Consistent with these results in model systems, patients homozygous for a mutant allele of the gene encoding the ADP enzyme beta subunit, SUCLA2, are deficient in succinyl CoA ligase activity (Elpeleg et al. 2005).
Both isoforms are found in vivo, and appear to be expressed at different levels in various tissues. Their relative contributions to the flux of carbon atoms through the TCA cycle are unknown. Genetic and biochemical data suggest that the alpha:betaA isoform may be required to catalyze the reverse reaction, conversion of succinate, Coenzyme A, and ATP to succinyl CoA, ADP, and orthophosphate for heme biosynthesis (Furuyama and Sassa 2000).
Lactate dehydrogenase is active as a tetramer. Two isoforms of lactate dehydrogenase, A and B, are widely expressed in human tissues, and all five tetramers - A4, A3B, A2B2, AB3, and B4 - are found (Read et al. 2001; Sakai et al. 1987; Yu et al. 2001). A third isoform, C, and its tetramer, C4, are found in testis (Millan et al. 1987; LeVan & Goldberg 1991). A fourth isoform, LDHAL6A, is less fully characterized than these others but limited data suggest that it may be testis-specific (Chen et al. 2009).