Citric acid cycle and respiratory electron transport (Homo sapiens)

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5, 8, 32, 38, 47...2124, 34, 4246, 526, 11, 31, 35, 39...9, 16, 26, 502, 5410, 17, 33, 511, 3, 4311, 19, 31, 3940234024, 34, 4246, 524, 72328, 29, 37, 414, 75, 15, 32, 38, 47...487, 13, 4512, 18, 22, 30, 36...2153, 5514, 20, 25mitochondrial intermembrane spacemitochondrial matrixcytosolSLC16A1 phosphorylatedpyruvatedehydrogenasecomplexMALNADHLipo-DLST SUCLG1 LACT2OGNADPHIDH2 Mn2+ SDHC H+atRA GTPMPC1:MPC2NAD+2HGIDH3G RXRA:PPARD:atRASDHB SUCLA2 FAD PDHA1 malate dehydrogenase2 dimerNADHFH Mn2+ NNT PiIDH3 complexFAD Citrate SynthaseHoloenzymeOGDH FAD CoA-SHFAD fumarate hydratasetetramerHBUTSUCLG1 ADPCoA-SHMg2+NADH2HGRXRA TDP CO2PDP complexPDHB H+TDP alpha-ketoglutaratedehydrogenasecomplexDLD PYRPPARD 2xLipo-DLAT TDP SUCCSAADPNAD+MDH2 Co2+PYRDLD ADHFE1(1-?)PDHX lactatedehydrogenasecomplexBSG NADHNAD+ATPH+Mn2+FADGDPMPC1 Ac-CoAPDK isoformsNAD+NNT dimerNAD+Succinatedehydrogenasecomplex (oxidised)SLC16A8 NAD+NADHH+H+PDHB H+FUMASLC16A3 PDHA1 IDH2 dimerADPCoA-SHSUCCAZn2+2xLipo-DLAT SDHA PiCO2SDHD FADH2CO2ACO2NADHOAIDH3A ATPCITL2HGDHNADHMPC2 ISCITCS PDHX H+Succinyl-CoAsynthetaseheterodimer(ADP-forming)Respiratory electrontransport, ATPsynthesis bychemiosmoticcoupling, and heatproduction byuncouplingproteins.LACTCoA-SHH+LIPAM H2OSUCC-CoAH+Succinyl-CoAsynthetaseheterodimer(GDP-forming)NADP+BSG:MCTsD2HGDHIDH3B pyruvatedehydrogenasecomplexDLD SUCLG2 H2OH2O333311119, 3911333327, 31, 39, 5827, 31, 39, 5827, 5827, 5811


Description

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. Source:Reactome.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
123311view07:12, 15 July 2022EgonwTyped a datanode (and added missing label)
116655view11:45, 9 May 2021EweitzModified title
101141view21:32, 31 October 2018ReactomeTeamreactome version 65
100669view20:06, 31 October 2018ReactomeTeamreactome version 64
100219view16:51, 31 October 2018ReactomeTeamreactome version 63
99770view15:17, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99328view12:47, 31 October 2018ReactomeTeamreactome version 62
93815view13:38, 16 August 2017ReactomeTeamreactome version 61
93361view11:21, 9 August 2017ReactomeTeamreactome version 61
87138view18:51, 18 July 2016EgonwOntology Term : 'classic metabolic pathway' added !
87136view18:51, 18 July 2016EgonwOntology Term : 'citric acid cycle pathway' added !
86443view09:18, 11 July 2016ReactomeTeamreactome version 56
83385view11:04, 18 November 2015ReactomeTeamVersion54
81567view13:06, 21 August 2015ReactomeTeamVersion53
77032view08:33, 17 July 2014ReactomeTeamFixed remaining interactions
76737view12:10, 16 July 2014ReactomeTeamFixed remaining interactions
76062view10:12, 11 June 2014ReactomeTeamRe-fixing comment source
75772view11:28, 10 June 2014ReactomeTeamReactome 48 Update
75122view14:07, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74769view08:51, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2HGMetaboliteCHEBI:32796 (ChEBI)
2HGMetaboliteCHEBI:32797 (ChEBI)
2OGMetaboliteCHEBI:30915 (ChEBI)
2xLipo-DLAT ProteinP10515 (Uniprot-TrEMBL)
ACO2ProteinQ99798 (Uniprot-TrEMBL)
ADHFE1(1-?)ProteinQ8IWW8 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
BSG ProteinP35613 (Uniprot-TrEMBL)
BSG:MCTsComplexR-HSA-204396 (Reactome)
CITMetaboliteCHEBI:30769 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
CS ProteinO75390 (Uniprot-TrEMBL)
Citrate Synthase HoloenzymeComplexR-HSA-70973 (Reactome)
Co2+MetaboliteCHEBI:27638 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
D2HGDHProteinQ8N465 (Uniprot-TrEMBL)
DLD ProteinP09622 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FADMetaboliteCHEBI:16238 (ChEBI)
FADH2MetaboliteCHEBI:17877 (ChEBI)
FH ProteinP07954 (Uniprot-TrEMBL)
FUMAMetaboliteCHEBI:18012 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HBUTMetaboliteCHEBI:16724 (ChEBI)
IDH2 ProteinP48735 (Uniprot-TrEMBL)
IDH2 dimerComplexR-HSA-450982 (Reactome)
IDH3 complexComplexR-HSA-70965 (Reactome)
IDH3A ProteinP50213 (Uniprot-TrEMBL)
IDH3B ProteinO43837 (Uniprot-TrEMBL)
IDH3G ProteinP51553 (Uniprot-TrEMBL)
ISCITMetaboliteCHEBI:151 (ChEBI)
L2HGDHProteinQ9H9P8 (Uniprot-TrEMBL)
LACTMetaboliteCHEBI:422 (ChEBI)
LIPAM MetaboliteCHEBI:17460 (ChEBI)
Lipo-DLST ProteinP36957 (Uniprot-TrEMBL)
MALMetaboliteCHEBI:30797 (ChEBI)
MDH2 ProteinP40926 (Uniprot-TrEMBL)
MPC1 ProteinQ9Y5U8 (Uniprot-TrEMBL)
MPC1:MPC2ComplexR-HSA-2512902 (Reactome)
MPC2 ProteinO95563 (Uniprot-TrEMBL)
Mg2+MetaboliteCHEBI:18420 (ChEBI)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
Mn2+MetaboliteCHEBI:29035 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NNT ProteinQ13423 (Uniprot-TrEMBL)
NNT dimerComplexR-HSA-451008 (Reactome)
OAMetaboliteCHEBI:30744 (ChEBI)
OGDH ProteinQ02218 (Uniprot-TrEMBL)
PDHA1 ProteinP08559 (Uniprot-TrEMBL)
PDHB ProteinP11177 (Uniprot-TrEMBL)
PDHX ProteinO00330 (Uniprot-TrEMBL)
PDK isoformsR-HSA-203947 (Reactome)
PDP complexR-HSA-204219 (Reactome)
PPARD ProteinQ03181 (Uniprot-TrEMBL)
PYRMetaboliteCHEBI:32816 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
RXRA ProteinP19793 (Uniprot-TrEMBL)
RXRA:PPARD:atRAComplexR-HSA-5634107 (Reactome)
Respiratory electron

transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling

proteins.		PathwayR-HSA-163200 (Reactome) 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.
SDHA ProteinP31040 (Uniprot-TrEMBL)
SDHB ProteinP21912 (Uniprot-TrEMBL)
SDHC ProteinQ99643 (Uniprot-TrEMBL)
SDHD ProteinO14521 (Uniprot-TrEMBL)
SLC16A1 ProteinP53985 (Uniprot-TrEMBL)
SLC16A3 ProteinO15427 (Uniprot-TrEMBL)
SLC16A8 ProteinO95907 (Uniprot-TrEMBL)
SUCC-CoAMetaboliteCHEBI:15380 (ChEBI)
SUCCAMetaboliteCHEBI:15741 (ChEBI)
SUCCSAMetaboliteCHEBI:16265 (ChEBI)
SUCLA2 ProteinQ9P2R7 (Uniprot-TrEMBL)
SUCLG1 ProteinP53597 (Uniprot-TrEMBL)
SUCLG2 ProteinQ96I99 (Uniprot-TrEMBL)
Succinate

dehydrogenase

complex (oxidised)		ComplexR-HSA-70990 (Reactome)
Succinyl-CoA

synthetase heterodimer

(ADP-forming)		ComplexR-HSA-156625 (Reactome)
Succinyl-CoA

synthetase heterodimer

(GDP-forming)		ComplexR-HSA-156627 (Reactome)
TDP MetaboliteCHEBI:18290 (ChEBI)
Zn2+MetaboliteCHEBI:29105 (ChEBI)
alpha-ketoglutarate

dehydrogenase

complex		ComplexR-HSA-69996 (Reactome)
atRA MetaboliteCHEBI:15367 (ChEBI)
fumarate hydratase tetramerComplexR-HSA-451041 (Reactome)
lactate

dehydrogenase

complex		R-HSA-184549 (Reactome)
malate dehydrogenase 2 dimerComplexR-HSA-198511 (Reactome)
phosphorylated

pyruvate dehydrogenase

complex		ComplexR-HSA-210342 (Reactome)
pyruvate

dehydrogenase

complex		ComplexR-HSA-70070 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2HGArrowR-HSA-880033 (Reactome)
2HGR-HSA-880002 (Reactome)
2HGR-HSA-880007 (Reactome)
2HGR-HSA-880050 (Reactome)
2OGArrowR-HSA-450984 (Reactome)
2OGArrowR-HSA-70967 (Reactome)
2OGArrowR-HSA-880002 (Reactome)
2OGArrowR-HSA-880007 (Reactome)
2OGArrowR-HSA-880050 (Reactome)
2OGR-HSA-71401 (Reactome)
2OGR-HSA-880033 (Reactome)
ACO2mim-catalysisR-HSA-450975 (Reactome)
ACO2mim-catalysisR-HSA-70971 (Reactome)
ADHFE1(1-?)mim-catalysisR-HSA-880002 (Reactome)
ADHFE1(1-?)mim-catalysisR-HSA-880033 (Reactome)
ADPArrowR-HSA-203946 (Reactome)
ADPArrowR-HSA-70967 (Reactome)
ADPR-HSA-70997 (Reactome)
ATPArrowR-HSA-70997 (Reactome)
ATPR-HSA-203946 (Reactome)
Ac-CoAArrowR-HSA-203946 (Reactome)
Ac-CoAArrowR-HSA-71397 (Reactome)
Ac-CoAR-HSA-70975 (Reactome)
BSG:MCTsmim-catalysisR-HSA-373867 (Reactome)
BSG:MCTsmim-catalysisR-HSA-373875 (Reactome)
CITArrowR-HSA-450975 (Reactome)
CITArrowR-HSA-70975 (Reactome)
CITR-HSA-70971 (Reactome)
CO2ArrowR-HSA-450984 (Reactome)
CO2ArrowR-HSA-70967 (Reactome)
CO2ArrowR-HSA-71397 (Reactome)
CO2ArrowR-HSA-71401 (Reactome)
Citrate Synthase Holoenzymemim-catalysisR-HSA-70975 (Reactome)
Co2+ArrowR-HSA-880007 (Reactome)
CoA-SHArrowR-HSA-70975 (Reactome)
CoA-SHArrowR-HSA-70997 (Reactome)
CoA-SHArrowR-HSA-71775 (Reactome)
CoA-SHR-HSA-71397 (Reactome)
CoA-SHR-HSA-71401 (Reactome)
D2HGDHmim-catalysisR-HSA-880007 (Reactome)
FADH2ArrowR-HSA-880007 (Reactome)
FADH2ArrowR-HSA-880050 (Reactome)
FADR-HSA-880007 (Reactome)
FADR-HSA-880050 (Reactome)
FUMAArrowR-HSA-451033 (Reactome)
FUMAArrowR-HSA-70994 (Reactome)
FUMAR-HSA-70982 (Reactome)
GDPR-HSA-71775 (Reactome)
GTPArrowR-HSA-71775 (Reactome)
H+ArrowR-HSA-372342 (Reactome)
H+ArrowR-HSA-373867 (Reactome)
H+ArrowR-HSA-373875 (Reactome)
H+ArrowR-HSA-450971 (Reactome)
H+ArrowR-HSA-450984 (Reactome)
H+ArrowR-HSA-70510 (Reactome)
H+ArrowR-HSA-70967 (Reactome)
H+ArrowR-HSA-70979 (Reactome)
H+R-HSA-372342 (Reactome)
H+R-HSA-373867 (Reactome)
H+R-HSA-373875 (Reactome)
H+R-HSA-450971 (Reactome)
H+R-HSA-71783 (Reactome)
H+R-HSA-71849 (Reactome)
H2OArrowR-HSA-451033 (Reactome)
H2OR-HSA-204169 (Reactome)
H2OR-HSA-70975 (Reactome)
H2OR-HSA-70982 (Reactome)
HBUTArrowR-HSA-880002 (Reactome)
HBUTR-HSA-880033 (Reactome)
IDH2 dimermim-catalysisR-HSA-450984 (Reactome)
IDH3 complexmim-catalysisR-HSA-70967 (Reactome)
ISCITArrowR-HSA-70971 (Reactome)
ISCITR-HSA-450975 (Reactome)
ISCITR-HSA-450984 (Reactome)
ISCITR-HSA-70967 (Reactome)
L2HGDHmim-catalysisR-HSA-880050 (Reactome)
LACTArrowR-HSA-373867 (Reactome)
LACTArrowR-HSA-373875 (Reactome)
LACTArrowR-HSA-71849 (Reactome)
LACTR-HSA-373867 (Reactome)
LACTR-HSA-373875 (Reactome)
LACTR-HSA-70510 (Reactome)
MALArrowR-HSA-70982 (Reactome)
MALArrowR-HSA-71783 (Reactome)
MALR-HSA-451033 (Reactome)
MALR-HSA-70979 (Reactome)
MPC1:MPC2mim-catalysisR-HSA-372342 (Reactome)
Mg2+ArrowR-HSA-204169 (Reactome)
Mn2+ArrowR-HSA-880007 (Reactome)
NAD+ArrowR-HSA-71783 (Reactome)
NAD+ArrowR-HSA-71849 (Reactome)
NAD+R-HSA-450971 (Reactome)
NAD+R-HSA-70510 (Reactome)
NAD+R-HSA-70967 (Reactome)
NAD+R-HSA-70979 (Reactome)
NAD+R-HSA-71397 (Reactome)
NAD+R-HSA-71401 (Reactome)
NADHArrowR-HSA-203946 (Reactome)
NADHArrowR-HSA-450971 (Reactome)
NADHArrowR-HSA-70510 (Reactome)
NADHArrowR-HSA-70967 (Reactome)
NADHArrowR-HSA-70979 (Reactome)
NADHArrowR-HSA-71397 (Reactome)
NADHArrowR-HSA-71401 (Reactome)
NADHR-HSA-71783 (Reactome)
NADHR-HSA-71849 (Reactome)
NADP+ArrowR-HSA-450971 (Reactome)
NADP+R-HSA-450984 (Reactome)
NADPHArrowR-HSA-450984 (Reactome)
NADPHR-HSA-450971 (Reactome)
NNT dimermim-catalysisR-HSA-450971 (Reactome)
OAArrowR-HSA-70979 (Reactome)
OAR-HSA-70975 (Reactome)
OAR-HSA-71783 (Reactome)
PDK isoformsmim-catalysisR-HSA-203946 (Reactome)
PDP complexmim-catalysisR-HSA-204169 (Reactome)
PYRArrowR-HSA-372342 (Reactome)
PYRArrowR-HSA-70510 (Reactome)
PYRR-HSA-372342 (Reactome)
PYRR-HSA-71397 (Reactome)
PYRR-HSA-71849 (Reactome)
PYRTBarR-HSA-203946 (Reactome)
PiArrowR-HSA-204169 (Reactome)
PiR-HSA-70997 (Reactome)
PiR-HSA-71775 (Reactome)
R-HSA-203946 (Reactome) Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the pyruvate dehydrogenase 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 also catalyzes 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).
In the nucleus, cellular retinoic acid-binding protein 1 or 2 (CRABP1 or 2), bound to all-trans-retinoic acid (atRA), directly binds to the heterodimeric complex of retinoic acid receptor alpha RXRA) and peroxisome proliferator-activated receptor delta (PPARD). When bound to PPARD, atRA can significantly increase the expression of proteins involved in energy metabolism such as PDK via its induction of PPARD (Wolf 2010).
R-HSA-204169 (Reactome) 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).
R-HSA-372342 (Reactome) Pyruvate (PYR) and a proton are transported from the cytosol into the mitochondrial matrix, mediated by a complex of MCP1 and MCP2 in the inner mitochondrial membrane. 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 and 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).
R-HSA-373867 (Reactome) The membrane-associated MCT:basigin complex mediates the reversible uptake of extracellular lactate and H+ (Wilson et al. 2005).
R-HSA-373875 (Reactome) The membrane-associated MCT:basigin complex mediates the reversible export of cytosolic lactate and H+ (Wilson et al. 2005).
R-HSA-450971 (Reactome) 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).
R-HSA-450975 (Reactome) 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).
R-HSA-450984 (Reactome) 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).
R-HSA-451033 (Reactome) 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).
R-HSA-70510 (Reactome) 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. A third isoform, C, and its tetramer, C4, are found in testis.

R-HSA-70967 (Reactome) 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.
R-HSA-70971 (Reactome) 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).
R-HSA-70975 (Reactome) 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).
R-HSA-70979 (Reactome) 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).
R-HSA-70982 (Reactome) 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).
R-HSA-70994 (Reactome) 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.
R-HSA-70997 (Reactome) 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).

R-HSA-71397 (Reactome) 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).
R-HSA-71401 (Reactome) 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).
R-HSA-71775 (Reactome) 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).

R-HSA-71783 (Reactome) 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).
R-HSA-71849 (Reactome) Cytosolic lactate dehydrogenase catalyzes the reversible reaction of pyruvate and NADH + H+ to form lactate and NAD+. In the body under anaerobic conditions such as are found in red blood cells or rapidly exercising skeletal muscle, this reaction regenerates NAD+, allowing the continuation of glycolysis.

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. A third isoform, C, and its tetramer, C4, are found in testis.

R-HSA-880002 (Reactome) 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).
R-HSA-880007 (Reactome) 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)).
R-HSA-880033 (Reactome) 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).
R-HSA-880050 (Reactome) 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).
RXRA:PPARD:atRAArrowR-HSA-203946 (Reactome)
SUCC-CoAArrowR-HSA-71401 (Reactome)
SUCC-CoAR-HSA-70997 (Reactome)
SUCC-CoAR-HSA-71775 (Reactome)
SUCCAArrowR-HSA-70997 (Reactome)
SUCCAArrowR-HSA-71775 (Reactome)
SUCCAR-HSA-70994 (Reactome)
SUCCSAArrowR-HSA-880033 (Reactome)
SUCCSAR-HSA-880002 (Reactome)
Succinate

dehydrogenase

complex (oxidised)		mim-catalysisR-HSA-70994 (Reactome)
Succinyl-CoA

synthetase heterodimer

(ADP-forming)		mim-catalysisR-HSA-70997 (Reactome)
Succinyl-CoA

synthetase heterodimer

(GDP-forming)		mim-catalysisR-HSA-71775 (Reactome)
Zn2+ArrowR-HSA-880007 (Reactome)
alpha-ketoglutarate

dehydrogenase

complex		mim-catalysisR-HSA-71401 (Reactome)
fumarate hydratase tetramermim-catalysisR-HSA-451033 (Reactome)
fumarate hydratase tetramermim-catalysisR-HSA-70982 (Reactome)
lactate

dehydrogenase

complex		mim-catalysisR-HSA-70510 (Reactome)
lactate

dehydrogenase

complex		mim-catalysisR-HSA-71849 (Reactome)
malate dehydrogenase 2 dimermim-catalysisR-HSA-70979 (Reactome)
malate dehydrogenase 2 dimermim-catalysisR-HSA-71783 (Reactome)
phosphorylated

pyruvate dehydrogenase

complex		ArrowR-HSA-203946 (Reactome)
phosphorylated

pyruvate dehydrogenase

complex		R-HSA-204169 (Reactome)
pyruvate

dehydrogenase

complex		ArrowR-HSA-204169 (Reactome)
pyruvate

dehydrogenase

complex		R-HSA-203946 (Reactome)
pyruvate

dehydrogenase

complex		mim-catalysisR-HSA-71397 (Reactome)
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