Branched-chain amino acid catabolism (Homo sapiens)

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23315, 6, 30, 4328, 36, 441, 32112, 35928, 36, 446, 43914, 1938, 4015, 22213, 4, 20, 24, 41111, 3226, 4617, 2512, 16, 33, 344213, 27, 457, 10, 298, 18, 3937cytosolmitochondrial matrixL-Val ISB-CoAMCCC2 DLD CO22M3OPROAH+H2OFAD aMbHBUT-CoATEABTPPM1K FADL-GluFAD NAD+lipo-BCKDHALDH9A1 KIC tiglyl-CoASUCCAACAT1(35-427) NADHH2ObHIB-CoAO2KIC,KMVA,KIVCO2CoA-SH2MBUT-CoA GluH+ACAD8 BCKDKACAT1 tetramerIVD lipo-K44-DBT bMC-CoAHCO3-CARlipo-K44-DBT PPM1K:Mn2+PiAUH enoyl-CoA hydrataseL-Val FADH2HIBADH tetramerISB-CoA H+Leu, Ile, ValGlyH2OTEABLFe2+ SUCCAFe2+ HSD17B10 2OGPiH2ONADHTMLYSBBOX1 dimerACAD8 tetramerAUH hexamerFADH2KMVA NAD+HIBCHISV-CoACoA-SHL-Leu NAD+KMVA FADNAD+ATPTMLHE dimerO2ADPBCKDHB ALDH9A1 tetramerFAD BCAT2 dimerPXLP-BCAT1 H2OKIV H+carnitine exporterBBOX1 CoA-SHbMC-CoAKIC CO2KIV ALDH6A1BCKDHA ADPHTMLYSCO2p-BCKDHTMLHE 2MACA-CoA2OGNADHL-Leu FAD p-S292-BCKDHB NADH2MBUT-CoAFAD HIBADH TDP BCAAsNADHMn2+ Btn-MCCC1 NAD+BCAT1 dimerTDP BCKDHA ACADSB(52-432) Leu, Ile, ValL-Ile HTMLYSACADSB tetramerPXLP-SHMT1 ISV-CoA L-Ile 2OGbHIBAMACR-CoAAc-CoAATPCARDLD CoA-SH6x(Btn-MCCC1:MCCC2)PROP-CoAIVD tetramerbHMG-CoAHSD17B10 tetramerPXLP-BCAT2 SHMT1 tetramerBCAA-CoAs17, 2515, 22534528, 4424, 413393, 434542203322324, 417, 102093917, 25214213, 47155


Description

The branched-chain amino acids, leucine, isoleucine, and valine, are all essential amino acids (i.e., ones required in the diet). They are major constituents of muscle protein. The breakdown of these amino acids starts with two common steps catalyzed by enzymes that act on all three amino acids: reversible transamination by branched-chain amino acid aminotransferase, and irreversible oxidative decarboxylation by the branched-chain ketoacid dehydrogenase complex. Isovaleryl-CoA is produced from leucine by these two reactions, alpha-methylbutyryl-CoA from isoleucine, and isobutyryl-CoA from valine. These acyl-CoA's undergo dehydrogenation, catalyzed by three different but related enzymes, and the breakdown pathways then diverge. Leucine is ultimately converted to acetyl-CoA and acetoacetate; isoleucine to acetyl-CoA and succinyl-CoA; and valine to succinyl-CoA. Under fasting conditions, substantial amounts of all three amino acids are generated by protein breakdown. In muscle, the final products of leucine, isoleucine, and valine catabolism can be fully oxidized via the citric acid cycle; in liver they can be directed toward the synthesis of ketone bodies (acetoacetate and acetyl-CoA) and glucose (succinyl-CoA) (Chuang & Shih 2001, Sweetman & Williams 2001). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 70895
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Ontology Terms

 

Bibliography

View all...
  1. Stadler SC, Polanetz R, Meier S, Mayerhofer PU, Herrmann JM, Anslinger K, Roscher AA, Röschinger W, Holzinger A.; ''Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-CoA carboxylase.''; PubMed Europe PMC
  2. Holzinger A, Röschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch HG, Muntau AC, Roscher AA.; ''Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency.''; PubMed Europe PMC
  3. Finocchiaro G, Ito M, Tanaka K.; ''Purification and properties of short chain acyl-CoA, medium chain acyl-CoA, and isovaleryl-CoA dehydrogenases from human liver.''; PubMed Europe PMC
  4. Kurimoto K, Fukai S, Nureki O, Muto Y, Yokoyama S.; ''Crystal structure of human AUH protein, a single-stranded RNA binding homolog of enoyl-CoA hydratase.''; PubMed Europe PMC
  5. Bremer J.; ''Carnitine--metabolism and functions.''; PubMed Europe PMC
  6. Wynn RM, Kato M, Machius M, Chuang JL, Li J, Tomchick DR, Chuang DT.; ''Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation.''; PubMed Europe PMC
  7. Li J, Wynn RM, Machius M, Chuang JL, Karthikeyan S, Tomchick DR, Chuang DT.; ''Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase.''; PubMed Europe PMC
  8. García-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejón E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacín M, Rodríguez-Pombo P, Alcaide P, Navarrete R, Sanz P, Font-Llitjós M, Vilaseca MA, Ormaizabal A, Pristoupilova A, Agulló SB.; ''Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.''; PubMed Europe PMC
  9. Wynn RM, Kochi H, Cox RP, Chuang DT.; ''Differential processing of human and rat E1 alpha precursors of the branched-chain alpha-keto acid dehydrogenase complex caused by an N-terminal proline in the rat sequence.''; PubMed Europe PMC
  10. Chang CF, Chou HT, Chuang JL, Chuang DT, Huang TH.; ''Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase complex.''; PubMed Europe PMC
  11. Haapalainen AM, Meriläinen G, Pirilä PL, Kondo N, Fukao T, Wierenga RK.; ''Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function.''; PubMed Europe PMC
  12. Kurys G, Ambroziak W, Pietruszko R.; ''Human aldehyde dehydrogenase. Purification and characterization of a third isozyme with low Km for gamma-aminobutyraldehyde.''; PubMed Europe PMC
  13. Lindstedt S, Nordin I.; ''Multiple forms of gamma-butyrobetaine hydroxylase (EC 1.14.11.1).''; PubMed Europe PMC
  14. Goto M, Miyahara I, Hirotsu K, Conway M, Yennawar N, Islam MM, Hutson SM.; ''Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin.''; PubMed Europe PMC
  15. Vaz FM, Fouchier SW, Ofman R, Sommer M, Wanders RJ.; ''Molecular and biochemical characterization of rat gamma-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehydrogenase 9 in carnitine biosynthesis.''; PubMed Europe PMC
  16. Tiffany KA, Roberts DL, Wang M, Paschke R, Mohsen AW, Vockley J, Kim JJ.; ''Structure of human isovaleryl-CoA dehydrogenase at 2.6 A resolution: structural basis for substrate specificity,.''; PubMed Europe PMC
  17. Roe CR, Cederbaum SD, Roe DS, Mardach R, Galindo A, Sweetman L.; ''Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism.''; PubMed Europe PMC
  18. Sandor A, Kispal G, Melegh B, Alkonyi I.; ''Release of carnitine from the perfused rat liver.''; PubMed Europe PMC
  19. IJlst L, Loupatty FJ, Ruiter JP, Duran M, Lehnert W, Wanders RJ.; ''3-Methylglutaconic aciduria type I is caused by mutations in AUH.''; PubMed Europe PMC
  20. Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D.; ''The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.''; PubMed Europe PMC
  21. Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, Gleeson JG.; ''Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.''; PubMed Europe PMC
  22. Hulse JD, Ellis SR, Henderson LM.; ''Carnitine biosynthesis. beta-Hydroxylation of trimethyllysine by an alpha-ketoglutarate-dependent mitochondrial dioxygenase.''; PubMed Europe PMC
  23. Ofman R, Ruiter JP, Feenstra M, Duran M, Poll-The BT, Zschocke J, Ensenauer R, Lehnert W, Sass JO, Sperl W, Wanders RJ.; ''2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene.''; PubMed Europe PMC
  24. Kissinger CR, Rejto PA, Pelletier LA, Thomson JA, Showalter RE, Abreo MA, Agree CS, Margosiak S, Meng JJ, Aust RM, Vanderpool D, Li B, Tempczyk-Russell A, Villafranca JE.; ''Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics.''; PubMed Europe PMC
  25. Hector ML, Cochran BC, Logue EA, Fall RR.; ''Subcellular localization of 3-methylcrotonyl-coenzyme A carboxylase in bovine kidney.''; PubMed Europe PMC
  26. Longo N, Frigeni M, Pasquali M.; ''Carnitine transport and fatty acid oxidation.''; PubMed Europe PMC
  27. AEvarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG.; ''Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease.''; PubMed Europe PMC
  28. Bledsoe RK, Dawson PA, Hutson SM.; ''Cloning of the rat and human mitochondrial branched chain aminotransferases (BCATm).''; PubMed Europe PMC
  29. 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.''; PubMed Europe PMC
  30. Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ.; ''Molecular and Biochemical Characterization of Rat epsilon -N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis.''; PubMed Europe PMC
  31. Vaz FM, van Gool S, Ofman R, Ijlst L, Wanders RJ.; ''Carnitine biosynthesis: identification of the cDNA encoding human gamma-butyrobetaine hydroxylase.''; PubMed Europe PMC
  32. Narisawa K, Gibson KM, Sweetman L, Nyhan WL, Duran M, Wadman SK.; ''Deficiency of 3-methylglutaconyl-coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria.''; PubMed Europe PMC
  33. Chambliss KL, Gray RG, Rylance G, Pollitt RJ, Gibson KM.; ''Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency.''; PubMed Europe PMC
  34. Gibson KM, Burlingame TG, Hogema B, Jakobs C, Schutgens RB, Millington D, Roe CR, Roe DS, Sweetman L, Steiner RD, Linck L, Pohowalla P, Sacks M, Kiss D, Rinaldo P, Vockley J.; ''2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism.''; PubMed Europe PMC
  35. Yennawar NH, Conway ME, Yennawar HP, Farber GK, Hutson SM.; ''Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms.''; PubMed Europe PMC
  36. Rhead WJ, Tanaka K.; ''Demonstration of a specific mitochondrial isovaleryl-CoA dehydrogenase deficiency in fibroblasts from patients with isovaleric acidemia.''; PubMed Europe PMC
  37. Nguyen TV, Andresen BS, Corydon TJ, Ghisla S, Abd-El Razik N, Mohsen AW, Cederbaum SD, Roe DS, Roe CR, Lench NJ, Vockley J.; ''Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans.''; PubMed Europe PMC
  38. Wynn RM, Li J, Brautigam CA, Chuang JL, Chuang DT.; ''Structural and biochemical characterization of human mitochondrial branched-chain α-ketoacid dehydrogenase phosphatase.''; PubMed Europe PMC
  39. Kispal G, Melegh B, Alkonyi I, Sandor A.; ''Enhanced uptake of carnitine by perfused rat liver following starvation.''; PubMed Europe PMC
  40. Reed LJ, Hackert ML.; ''Structure-function relationships in dihydrolipoamide acyltransferases.''; PubMed Europe PMC
  41. ROBINSON WG, COON MJ.; ''The purification and properties of beta-hydroxyisobutyric dehydrogenase.''; PubMed Europe PMC
  42. Kedishvili NY, Popov KM, Rougraff PM, Zhao Y, Crabb DW, Harris RA.; ''CoA-dependent methylmalonate-semialdehyde dehydrogenase, a unique member of the aldehyde dehydrogenase superfamily. cDNA cloning, evolutionary relationships, and tissue distribution.''; PubMed Europe PMC
  43. Battaile KP, Nguyen TV, Vockley J, Kim JJ.; ''Structures of isobutyryl-CoA dehydrogenase and enzyme-product complex: comparison with isovaleryl- and short-chain acyl-CoA dehydrogenases.''; PubMed Europe PMC
  44. Andresen BS, Christensen E, Corydon TJ, Bross P, Pilgaard B, Wanders RJ, Ruiter JP, Simonsen H, Winter V, Knudsen I, Schroeder LD, Gregersen N, Skovby F.; ''Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism.''; PubMed Europe PMC
  45. Yennawar N, Dunbar J, Conway M, Hutson S, Farber G.; ''The structure of human mitochondrial branched-chain aminotransferase.''; PubMed Europe PMC
  46. Hawes JW, Jaskiewicz J, Shimomura Y, Huang B, Bunting J, Harper ET, Harris RA.; ''Primary structure and tissue-specific expression of human beta-hydroxyisobutyryl-coenzyme A hydrolase.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101285view11:17, 1 November 2018ReactomeTeamreactome version 66
100822view20:48, 31 October 2018ReactomeTeamreactome version 65
100363view19:23, 31 October 2018ReactomeTeamreactome version 64
99908view16:06, 31 October 2018ReactomeTeamreactome version 63
99464view14:39, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99120view12:40, 31 October 2018ReactomeTeamreactome version 62
93924view13:45, 16 August 2017ReactomeTeamreactome version 61
93505view11:25, 9 August 2017ReactomeTeamreactome version 61
87096view14:29, 18 July 2016MkutmonOntology Term : 'amino acid metabolic pathway' added !
86600view09:21, 11 July 2016ReactomeTeamreactome version 56
83446view12:25, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2M3OPROAMetaboliteCHEBI:16256 (ChEBI)
2MACA-CoAMetaboliteCHEBI:15476 (ChEBI)
2MBUT-CoA MetaboliteCHEBI:15477 (ChEBI)
2MBUT-CoAMetaboliteCHEBI:15477 (ChEBI)
2OGMetaboliteCHEBI:30915 (ChEBI)
6x(Btn-MCCC1:MCCC2)ComplexR-HSA-70770 (Reactome)
ACAD8 ProteinQ9UKU7 (Uniprot-TrEMBL)
ACAD8 tetramerComplexR-HSA-70856 (Reactome)
ACADSB tetramerComplexR-HSA-70797 (Reactome)
ACADSB(52-432) ProteinP45954 (Uniprot-TrEMBL)
ACAT1 tetramerComplexR-HSA-70839 (Reactome)
ACAT1(35-427) ProteinP24752 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ALDH6A1ProteinQ02252 (Uniprot-TrEMBL)
ALDH9A1 ProteinP49189 (Uniprot-TrEMBL)
ALDH9A1 tetramerComplexR-HSA-71258 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
AUH ProteinQ13825 (Uniprot-TrEMBL)
AUH hexamerComplexR-HSA-508309 (Reactome)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
BBOX1 ProteinO75936 (Uniprot-TrEMBL)
BBOX1 dimerComplexR-HSA-71107 (Reactome)
BCAA-CoAsComplexR-ALL-508261 (Reactome)
BCAAsComplexR-ALL-508181 (Reactome)
BCAT1 dimerComplexR-HSA-70699 (Reactome)
BCAT2 dimerComplexR-HSA-70704 (Reactome)
BCKDHA ProteinP12694 (Uniprot-TrEMBL)
BCKDHB ProteinP21953 (Uniprot-TrEMBL)
BCKDKProteinO14874 (Uniprot-TrEMBL)
Btn-MCCC1 ProteinQ96RQ3 (Uniprot-TrEMBL)
CARMetaboliteCHEBI:17126 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DLD ProteinP09622 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FADMetaboliteCHEBI:16238 (ChEBI)
FADH2MetaboliteCHEBI:17877 (ChEBI)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
GluMetaboliteCHEBI:29985 (ChEBI)
GlyMetaboliteCHEBI:57305 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCO3-MetaboliteCHEBI:17544 (ChEBI)
HIBADH ProteinP31937 (Uniprot-TrEMBL)
HIBADH tetramerComplexR-HSA-70883 (Reactome)
HIBCHProteinQ6NVY1 (Uniprot-TrEMBL)
HSD17B10 ProteinQ99714 (Uniprot-TrEMBL)
HSD17B10 tetramerComplexR-HSA-508381 (Reactome)
HTMLYSMetaboliteCHEBI:15786 (ChEBI)
ISB-CoA MetaboliteCHEBI:15479 (ChEBI)
ISB-CoAMetaboliteCHEBI:15479 (ChEBI)
ISV-CoA MetaboliteCHEBI:15487 (ChEBI)
ISV-CoAMetaboliteCHEBI:15487 (ChEBI)
IVD ProteinP26440 (Uniprot-TrEMBL)
IVD tetramerComplexR-HSA-70730 (Reactome)
KIC MetaboliteCHEBI:17865 (ChEBI)
KIC,KMVA,KIVComplexR-ALL-508187 (Reactome)
KIV MetaboliteCHEBI:16530 (ChEBI)
KMVA MetaboliteCHEBI:28654 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
L-Ile MetaboliteCHEBI:58045 (ChEBI)
L-Leu MetaboliteCHEBI:57427 (ChEBI)
L-Val MetaboliteCHEBI:57762 (ChEBI)
Leu, Ile, ValComplexR-ALL-508182 (Reactome)
Leu, Ile, ValComplexR-ALL-508190 (Reactome)
MACR-CoAMetaboliteCHEBI:27754 (ChEBI)
MCCC2 ProteinQ9HCC0 (Uniprot-TrEMBL)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PPM1K ProteinQ8N3J5 (Uniprot-TrEMBL)
PPM1K:Mn2+ComplexR-HSA-5693133 (Reactome)
PROP-CoAMetaboliteCHEBI:15539 (ChEBI)
PXLP-BCAT1 ProteinP54687 (Uniprot-TrEMBL)
PXLP-BCAT2 ProteinO15382 (Uniprot-TrEMBL)
PXLP-SHMT1 ProteinP34896 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SHMT1 tetramerComplexR-HSA-71243 (Reactome)
SUCCAMetaboliteCHEBI:15741 (ChEBI)
TDP MetaboliteCHEBI:18290 (ChEBI)
TEABLMetaboliteCHEBI:18020 (ChEBI)
TEABTMetaboliteCHEBI:16244 (ChEBI)
TMLHE ProteinQ9NVH6 (Uniprot-TrEMBL)
TMLHE dimerComplexR-HSA-71098 (Reactome)
TMLYSMetaboliteCHEBI:17311 (ChEBI)
aMbHBUT-CoAMetaboliteCHEBI:15449 (ChEBI)
bHIB-CoAMetaboliteCHEBI:28259 (ChEBI)
bHIBAMetaboliteCHEBI:11805 (ChEBI)
bHMG-CoAMetaboliteCHEBI:15467 (ChEBI)
bMC-CoAMetaboliteCHEBI:15486 (ChEBI)
bMC-CoAMetaboliteCHEBI:15488 (ChEBI)
carnitine exporterR-HSA-165022 (Reactome)
enoyl-CoA hydrataseR-HSA-70827 (Reactome)
lipo-BCKDHComplexR-HSA-70019 (Reactome)
lipo-K44-DBT ProteinP11182 (Uniprot-TrEMBL)
p-BCKDHComplexR-HSA-5693120 (Reactome)
p-S292-BCKDHB ProteinP21953 (Uniprot-TrEMBL)
tiglyl-CoAMetaboliteCHEBI:15478 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2M3OPROAArrowR-HSA-70885 (Reactome)
2M3OPROAR-HSA-508473 (Reactome)
2M3OPROAR-HSA-70893 (Reactome)
2MACA-CoAArrowR-HSA-70837 (Reactome)
2MACA-CoAR-HSA-508369 (Reactome)
2MACA-CoAR-HSA-70844 (Reactome)
2MBUT-CoAR-HSA-70800 (Reactome)
2OGArrowR-HSA-508179 (Reactome)
2OGArrowR-HSA-508189 (Reactome)
2OGR-HSA-70723 (Reactome)
2OGR-HSA-70724 (Reactome)
2OGR-HSA-71241 (Reactome)
2OGR-HSA-71261 (Reactome)
6x(Btn-MCCC1:MCCC2)mim-catalysisR-HSA-508308 (Reactome)
6x(Btn-MCCC1:MCCC2)mim-catalysisR-HSA-70773 (Reactome)
ACAD8 tetramermim-catalysisR-HSA-70859 (Reactome)
ACADSB tetramermim-catalysisR-HSA-70800 (Reactome)
ACAT1 tetramermim-catalysisR-HSA-70844 (Reactome)
ADPArrowR-HSA-5693148 (Reactome)
ADPArrowR-HSA-70773 (Reactome)
ADPR-HSA-508308 (Reactome)
ALDH6A1mim-catalysisR-HSA-70893 (Reactome)
ALDH9A1 tetramermim-catalysisR-HSA-71260 (Reactome)
ATPArrowR-HSA-508308 (Reactome)
ATPR-HSA-5693148 (Reactome)
ATPR-HSA-70773 (Reactome)
AUH hexamermim-catalysisR-HSA-70785 (Reactome)
Ac-CoAArrowR-HSA-70844 (Reactome)
BBOX1 dimermim-catalysisR-HSA-71261 (Reactome)
BCAA-CoAsArrowR-HSA-70713 (Reactome)
BCAAsArrowR-HSA-70724 (Reactome)
BCAAsR-HSA-508179 (Reactome)
BCAAsR-HSA-70713 (Reactome)
BCAT1 dimermim-catalysisR-HSA-508189 (Reactome)
BCAT1 dimermim-catalysisR-HSA-70723 (Reactome)
BCAT2 dimermim-catalysisR-HSA-508179 (Reactome)
BCAT2 dimermim-catalysisR-HSA-70724 (Reactome)
BCKDKmim-catalysisR-HSA-5693148 (Reactome)
CARArrowR-HSA-164967 (Reactome)
CARArrowR-HSA-71261 (Reactome)
CARR-HSA-164967 (Reactome)
CO2ArrowR-HSA-70713 (Reactome)
CO2ArrowR-HSA-70893 (Reactome)
CO2ArrowR-HSA-71241 (Reactome)
CO2ArrowR-HSA-71261 (Reactome)
CoA-SHArrowR-HSA-70881 (Reactome)
CoA-SHR-HSA-70713 (Reactome)
CoA-SHR-HSA-70844 (Reactome)
CoA-SHR-HSA-70893 (Reactome)
FADH2ArrowR-HSA-70745 (Reactome)
FADH2ArrowR-HSA-70800 (Reactome)
FADH2ArrowR-HSA-70859 (Reactome)
FADR-HSA-70745 (Reactome)
FADR-HSA-70800 (Reactome)
FADR-HSA-70859 (Reactome)
GluArrowR-HSA-70724 (Reactome)
GluR-HSA-508179 (Reactome)
GlyArrowR-HSA-71249 (Reactome)
H+ArrowR-HSA-70837 (Reactome)
H+ArrowR-HSA-70885 (Reactome)
H+ArrowR-HSA-70893 (Reactome)
H+ArrowR-HSA-71260 (Reactome)
H+R-HSA-508369 (Reactome)
H+R-HSA-508473 (Reactome)
H2OR-HSA-508308 (Reactome)
H2OR-HSA-5693153 (Reactome)
H2OR-HSA-70785 (Reactome)
H2OR-HSA-70830 (Reactome)
H2OR-HSA-70870 (Reactome)
H2OR-HSA-70881 (Reactome)
H2OR-HSA-71260 (Reactome)
HCO3-ArrowR-HSA-508308 (Reactome)
HCO3-R-HSA-70773 (Reactome)
HIBADH tetramermim-catalysisR-HSA-508473 (Reactome)
HIBADH tetramermim-catalysisR-HSA-70885 (Reactome)
HIBCHmim-catalysisR-HSA-70881 (Reactome)
HSD17B10 tetramermim-catalysisR-HSA-508369 (Reactome)
HSD17B10 tetramermim-catalysisR-HSA-70837 (Reactome)
HTMLYSArrowR-HSA-71241 (Reactome)
HTMLYSArrowR-HSA-8949413 (Reactome)
HTMLYSR-HSA-71249 (Reactome)
HTMLYSR-HSA-8949413 (Reactome)
ISB-CoAR-HSA-70859 (Reactome)
ISV-CoAR-HSA-70745 (Reactome)
IVD tetramermim-catalysisR-HSA-70745 (Reactome)
KIC,KMVA,KIVArrowR-HSA-70723 (Reactome)
KIC,KMVA,KIVR-HSA-508189 (Reactome)
L-GluArrowR-HSA-70723 (Reactome)
L-GluR-HSA-508189 (Reactome)
Leu, Ile, ValArrowR-HSA-508179 (Reactome)
Leu, Ile, ValArrowR-HSA-508189 (Reactome)
Leu, Ile, ValR-HSA-70723 (Reactome)
Leu, Ile, ValR-HSA-70724 (Reactome)
MACR-CoAArrowR-HSA-70859 (Reactome)
MACR-CoAR-HSA-70870 (Reactome)
NAD+ArrowR-HSA-508369 (Reactome)
NAD+ArrowR-HSA-508473 (Reactome)
NAD+R-HSA-70713 (Reactome)
NAD+R-HSA-70837 (Reactome)
NAD+R-HSA-70885 (Reactome)
NAD+R-HSA-70893 (Reactome)
NAD+R-HSA-71260 (Reactome)
NADHArrowR-HSA-70713 (Reactome)
NADHArrowR-HSA-70837 (Reactome)
NADHArrowR-HSA-70885 (Reactome)
NADHArrowR-HSA-70893 (Reactome)
NADHArrowR-HSA-71260 (Reactome)
NADHR-HSA-508369 (Reactome)
NADHR-HSA-508473 (Reactome)
O2R-HSA-71241 (Reactome)
O2R-HSA-71261 (Reactome)
PPM1K:Mn2+mim-catalysisR-HSA-5693153 (Reactome)
PROP-CoAArrowR-HSA-70844 (Reactome)
PROP-CoAArrowR-HSA-70893 (Reactome)
PiArrowR-HSA-5693153 (Reactome)
PiArrowR-HSA-70773 (Reactome)
PiR-HSA-508308 (Reactome)
R-HSA-164967 (Reactome) Studies of carnitine (CAR) export from intact rat liver indicate that this process is mediated by a specific, saturable transporter molecule (Sandor et al. 1985). The transporter itself has not been identified, but its properties are distinct from those of OCTN2, the major transport protein responsible for carnitine uptake (Kispal et al. 1987). The existence of a human transport reaction (again without an identified transporter) is inferred from the rat one.
R-HSA-508179 (Reactome) Mitochondrial branched-chain-amino-acid aminotransferase (BCAT2) catalyzes the reversible reactions of alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or a-ketoisovalerate with glutamate to form leucine, isoleucine, or valine, respectively, and alpha-ketoglutarate (Bledsoe et al. 1997). The active enzyme is a homodimer (Yennawar et al. 2001, 2002). In the body, this enzyme is widely expressed but is especially abundant in muscle tissue.
R-HSA-508189 (Reactome) Cytosolic branched-chain-amino-acid aminotransferase (BCAT1) catalyzes the reversible reactions of alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or a-ketoisovalerate with glutamate to form leucine, isoleucine, or valine, respectively, and alpha-ketoglutarate (2-oxoglutarate). The active enzyme is a homodimer (Goto et al. 2005).
R-HSA-508308 (Reactome) Methylcrotonyl CoA carboxylase (MCCA) catalyzes the reversible reaction of beta-methylglutaconyl-CoA, ADP, orthophosphate, and H2O to form beta-methylcrotonyl-CoA, ATP, and CO2. Active MCCA is composed of two polypeptides, MCCA1 and MCCA2 (Baumgartner et al. 2001; Holzinger et al. 2001). The enzyme has been purified from fibroblast mitochondria. By analogy to the more thoroughly studied bovine homologue, MCCA is thought to be a hexamer of six MCCA1:MCCA2 dimers, and the MCCA1 polypeptides are thought to have biotin moieties covalently bound to a lysine residue at position 681 in the polypeptide chain. Mitochondrial import of MCCA1 and 2 is associated with removal of aminoterminal mitochondrial targeting sequences but the exact lengths of these sequences have not been determined.
R-HSA-508369 (Reactome) Mitochondrial 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10; HADH2) catalyzes the reversible reaction of alpha-methylacetoacetyl-CoA and NADH + H+ to form alpha-methyl-beta-hydroxybutyryl-CoA and NAD+ (Ofman et al. 2003). Crystallographic data indicate that the enzyme is a homotetramer (Kissinger et al. 2004).
R-HSA-508473 (Reactome) Mitochondrial 3-hydroxyisobutyrate dehydrogenase (HIBADH) catalyzes the reversible reaction of methylmalonyl semialdehyde and NADH + H+ to form beta-hydroxyisobutyrate and NAD+. The biochemical properties of human HIBADH are inferred from those of its better-studied porcine homologue (Robinson and Coon 1957). Unpublished crystallographic studies (PDB 2GF2) have shown the active enzyme to be a tetramer of HIBADH polypeptides whose aminoterminal 40 residues, a mitochondrial targeting sequence, have been removed.
R-HSA-5693148 (Reactome) Mitochondrial 3-methyl-2-oxobutanoate dehydrogenase (lipoamide) kinase (BCKDK) catalyses the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, the key regulatory enzyme of the valine, leucine and isoleucine catabolic pathways (Li et al. 2004, Wynn et al. 2004). BCKDH occupies a strategic point in the branched-chain amino acid (BCAA) catabolic pathway, and careful regulation of its activity is essential for correct BCAA metabolism. The overall activity of the BCKDH complex is controlled by the phosphorylation (inactivation)/dephosphorylation (activation) cycle.
Defects in BCKDK can cause branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD; MIM:614923), a metabolic disorder characterised by autism, epilepsy, intellectual disability, and reduced BCAAs (Novarino et al. 2012, Garcia-Cazorla et al. 2014).
R-HSA-5693153 (Reactome) The branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex occupies a strategic point in the branched-chain amino acid (BCAA) catabolic pathway, and careful regulation of its activity is essential for correct BCAA metabolism. The overall activity of the BCKDH complex is controlled by the phosphorylation (inactivation)/dephosphorylation (activation) cycle. Mitochondrial protein phosphatase 1K (PPM1K) dephosphorylates the E1 beta subunit of BCKDH therby regaining its active state. PPM1K requires Mn2+ as a cofactor for phosphatase activity (Wynn et al. 2012).
R-HSA-70713 (Reactome) The mitochondrial branched-chain alpha-ketoacid dehydrogenase (BKCDH) complex catalyzes the reactions of alpha-ketoisocaproate, alpha-keto beta-methylvalerate, or alpha-ketoisovalerate with CoA and NAD+ to form isovaleryl-CoA, a-methylbutyryl-CoA, or isobuyryl-CoA, respectively, and CO2 and NADH (Chuang and Shih 2001). While bovine and microbial BCKD complexes have been characterized most extensively (Reed and Hackert 1990), structural studies of individual components and subcomplexes of human BKCD have confirmed their structures and roles in the overall oxidative carboxylation process, and have related these features to the disruptive effects of mutations on branched-chain amino acid metabolism in vivo: E1a and E1b components - AEvarsson et al. 2000; E2 - Chang et al. 2002; E3- Brautigam et al. 2005. In addition, structural studies have confirmed the lipoylation of lysine residue 44 in E2 protein (Chang et al. 2002) and the loss of an aminoterminal mitochondrial transport sequence from mature E3 protein (Bruatigam et al. 2005). Loss of mitochondrial transport sequences from proteins E1a, E1b, and E2 has been domstrated by sequence analysis (Wynn et al. 1999).
R-HSA-70723 (Reactome) Cytosolic branched-chain-amino-acid aminotransferase (BCAT1) catalyzes the reversible reactions of leucine, isoleucine, or valine with alpha-ketoglutarate (2-oxoglutarate) to form alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or a-ketoisovalerate, respectively, and glutamate. The active enzyme is a homodimer. Hutson and colleagues have argues that cytosolic BCAT1 plays a major role in the generation of glutamate involved in synaptic transmission in neural tissue (Goto et al. 2005).
R-HSA-70724 (Reactome) Mitochondrial branched-chain-amino-acid aminotransferase (BCAT2) catalyzes the reversible reactions of leucine, isoleucine, or valine with alpha-ketoglutarate (2-oxoglutarate) to form alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or a-ketoisovalerate, respectively, and glutamate (Bledsoe et al. 1997). The active enzyme is a homodimer (Yennawar et al. 2001, 2002). In the body, this enzyme is widely expressed but is especially abundant in muscle tissue.
R-HSA-70745 (Reactome) Mitochondrial isovaleryl dehydrogenase (IVD) catalyzes the reaction of isovaleryl-CoA and FAD to form beta-methylcrotonyl-CoA and FADH2 (Finocchiaro et al. 1978; Rhead and Tanaka 1980). Crystallographic studies demonstrated the existene of a tetramer of IVD polypeptides lacking an aminoterminal mitochondrial targeting sequence (Tiffany et al. 1997).
R-HSA-70773 (Reactome) Methylcrotonyl CoA carboxylase (MCCA) catalyzes the reversible reaction of beta-methylcrotonyl-CoA, ATP, and CO2 to form beta-methylglutaconyl-CoA, ADP, orthophosphate, and H2O. Active MCCA is composed of two polypeptides, MCCA1 and MCCA2 (Baumgartner et al. 2001; Holzinger et al. 2001). The enzyme has been purified from fibroblast mitochondria. By analogy to the more thoroughly studied bovine homologue, MCCA is thought to be a hexamer of six MCCA1:MCCA2 dimers, and the MCCA1 polypeptide is thought to have a biotin moiety covalently bound to lysine residue 681. Localization of the complex to the mitochondrial inner membrane is inferred from studies of the bovine homologue (Hector et al. 1980). Mitochondrial import of MCCA1 and 2 is associated with removal of aminoterminal mitochondrial targeting sequences (Stadler et al. 2005).
R-HSA-70785 (Reactome) Mitochondrial ethylglutaconyl-CoA hydratase (AUH) catalyzes the hydrolysis of beta-methylglutaconyl-CoA to yield beta-hydroxy-beta-methylglutaryl-CoA (IJlst et al. 2002; Narisawa et al. 1986). Crystallographic studies have shown the active enzyme to be a hexamer of AUH polypeptides whose aminoterminal 67 residues, a mitochondrial targeting sequence, have been removed ((Kurimoto et al. 2001).
R-HSA-70800 (Reactome) Mitochondrial 2-methyl branched chain acyl-CoA dehydrogenase (ACADSB) catalyzes the reaction of alpha-methylbutyryl-CoA and FAD to form 'tiglyl-CoA and FADH2 (Andresen et al. 2000; Gibson et al. 2000). Unpublished crystallographic data (PDB 2JIF) indicate that the enzyme is a tetramer of ACADSB polypeptides whose aminoterminal 51 residues, a mitochondrial targeting sequence, have been removed.
R-HSA-70830 (Reactome) Mitochondrial tiglyl-CoA is hydrolyzed to form alpha-methyl-beta-hydroxybutyryl-CoA. While crude extracts of human liver cells have been shown to catalyze the reaction, the specific enzyme responsible for it has not been identified (Sweetman and Williams 2001).
R-HSA-70837 (Reactome) Mitochondrial 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10; HADH2) catalyzes the reversible reaction of alpha-methyl-beta-hydroxybutyryl-CoA and NAD+ to form alpha-methylacetoacetyl-CoA and NADH + H+ (Ofman et al. 2003). Crystallographic data indicate that the enzyme is a homotetramer (Kissinger et al. 2004).
R-HSA-70844 (Reactome) Mitochondrial acetyl-CoA acetyltransferase (ACAT1) catalyzes the reaction of alpha-methyl-acetoacetyl-CoA and CoA to form propionyl-CoA and acetyl-CoA. Structural studies have shown the active enzyme to be a tetramer of ACAT1 polypeptides whose aminoterminal 34 residues, a mitochondrial targeting sequence, have been removed (Haapalainen et al. 2007).
R-HSA-70859 (Reactome) Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction of isobutyryl-CoA and FAD to form methacrylyl-CoA and FADH2 (Roe et al. 1999; Nguyen et al. 2002). Crystallographic studies have shown the active enzyme to be a tetramer of ACAD8 polypeptides whose aminoterminal 23 residues, a mitochondrial targeting sequence, have been removed (Bataille et al. 2004).
R-HSA-70870 (Reactome) The reversible reaction of methacrylyl-CoA and water to form beta-hydroxybutyryl-CoA takes place in the mitochondrial matrix. While crude extracts of human fibroblasts and liver cells have been shown to catalyze the reaction, the specific human enzyme responsible for it has not been identified.
R-HSA-70881 (Reactome) Mitochondrial 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) catalyzes the hydrolysis of beta-hydroxyisobutyryl-CoA to form beta-hydroxyisobutyrate (3-hydroxy-2-methylpropanoate) and CoA (Hawes et al. 1996).
R-HSA-70885 (Reactome) Mitochondrial 3-hydroxyisobutyrate dehydrogenase (HIBADH) catalyzes the reversible reaction of beta-hydroxyisobutyrate and NAD+ to form methylmalonyl semialdehyde and NADH + H+. The biochemical properties of human HIBADH are inferred from those of its better-studied porcine homologue (Robinson and Coon 1957). Unpublished crystallographic studies (PDB 2GF2) have shown the active enzyme to be a tetramer of HIBADH polypeptides whose aminoterminal 40 residues, a mitochondrial targeting sequence, have been removed.
R-HSA-70893 (Reactome) Mitochondrial methylmalonate semialdehyde dehydrogenase (ALDH6A1) catalyzes the reaction of methylmalonate semialdehyde, NAD+, and CoA to form propionyl-CoA, CO2, and NADH + H+. A human ALDH6A1 gene has been cloned. Its sequence is closely homologous to that of the better-characterized rat enzyme (Kedishvili et al. 1992) and a missense mutation in a normally well-conserved codon has been found in the allele of the gene from a patient with a defect in methylmalonic semialdehyde dehydrogenase activity (Chambliss et al. 2000).
R-HSA-71241 (Reactome) Trimethyllysine dioxygenase (TMLHE) dimer in the mitochondrial matrix catalyzes the reaction of oxygen, 2-oxoglutarate (2OG), and N6,N6,N6-trimethyl-L-lysine (TMLYS) to form CO2, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine (HTMLYS), and succinate (SUCCA) (Vaz et al. 2001).
R-HSA-71249 (Reactome) Cytosolic serine hydroxymethyltransferase tetramer (SHMT1) catalyzes the reaction of 3-Hydroxy-N6,N6,N6-trimethyl-L-lysine (NTMLYS) to form glycine (Gly) and 4-trimethylammoniobutanal (TEABL) in vitro (Hulse et al. 1978). The possibility that an additional enzyme may catalyze this reaction in vivo has not been excluded (Bremer 1983).
R-HSA-71260 (Reactome) Cytosolic 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1) tetramer catalyzes the reaction of NAD+ and 4-trimethylammoniobutanal (TEABL) to form 4-trimethylammoniobutanoate (TEABT) and NADH + H+ (Kurys et al. 1989; Vaz et al. 2000).
R-HSA-71261 (Reactome) Cytosolic gamma-butyrobetaine hydroxylase dimer (BBOX1), a dioxygenase, catalyzes the reaction of oxygen, 4-trimethylammoniobutanoate (TEABT), and 2-oxoglutarate (2OG)to form CO2, succinate (SUCCA), and carnitine (CAR) (Lindstedt and Nordin 1984; Vaz et al. 1998).
R-HSA-8949413 (Reactome) HTMLYS (3-Hydroxy-N6,N6,N6-trimethyl-L-lysine) moves from the mitochondrial matrix to the cytosol (Longo et al. 2016). The molecular mechanism for this translocation is unknown.
SHMT1 tetramermim-catalysisR-HSA-71249 (Reactome)
SUCCAArrowR-HSA-71241 (Reactome)
SUCCAArrowR-HSA-71261 (Reactome)
TEABLArrowR-HSA-71249 (Reactome)
TEABLR-HSA-71260 (Reactome)
TEABTArrowR-HSA-71260 (Reactome)
TEABTR-HSA-71261 (Reactome)
TMLHE dimermim-catalysisR-HSA-71241 (Reactome)
TMLYSR-HSA-71241 (Reactome)
aMbHBUT-CoAArrowR-HSA-508369 (Reactome)
aMbHBUT-CoAArrowR-HSA-70830 (Reactome)
aMbHBUT-CoAR-HSA-70837 (Reactome)
bHIB-CoAArrowR-HSA-70870 (Reactome)
bHIB-CoAR-HSA-70881 (Reactome)
bHIBAArrowR-HSA-508473 (Reactome)
bHIBAArrowR-HSA-70881 (Reactome)
bHIBAR-HSA-70885 (Reactome)
bHMG-CoAArrowR-HSA-70785 (Reactome)
bMC-CoAArrowR-HSA-508308 (Reactome)
bMC-CoAArrowR-HSA-70745 (Reactome)
bMC-CoAArrowR-HSA-70773 (Reactome)
bMC-CoAR-HSA-508308 (Reactome)
bMC-CoAR-HSA-70773 (Reactome)
bMC-CoAR-HSA-70785 (Reactome)
carnitine exportermim-catalysisR-HSA-164967 (Reactome)
enoyl-CoA hydratasemim-catalysisR-HSA-70830 (Reactome)
enoyl-CoA hydratasemim-catalysisR-HSA-70870 (Reactome)
lipo-BCKDHArrowR-HSA-5693153 (Reactome)
lipo-BCKDHR-HSA-5693148 (Reactome)
lipo-BCKDHmim-catalysisR-HSA-70713 (Reactome)
p-BCKDHArrowR-HSA-5693148 (Reactome)
p-BCKDHR-HSA-5693153 (Reactome)
tiglyl-CoAArrowR-HSA-70800 (Reactome)
tiglyl-CoAR-HSA-70830 (Reactome)
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