Threonine catabolism (Homo sapiens)

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9, 124, 610, 122, 3, 7, 81, 5, 11, 12mitochondrial matrixmitochondrial intermembrane spacecytosolPXLP CoA-SHTDH L-ThrGCAT SDS dimers:PXLPNAD+GlyATPAc-CoAH+PXLP PPiSDS NH3H2OSDSL HRSP122AA2OBUTANADHL-Thr2A-3OBUGCAT:PXLP dimer:TDHtetramer


Description

The degradation of L-threonine to glycine in both prokaryotes and eukaryotes takes place through a two-step biochemical pathway in mitochondria (Dale 1978). In the first step, L-threonine is oxidised to 2-amino-3-oxobutanoate. This reaction is catalysed by mitochondrial L-threonine 3-dehydrogenase tetramer (TDH tetramer). In the second step, mitochondrial 2-amino-3-ketobutyrate coenzyme A ligase (GCAT, aka KBL) catalyses the reaction between 2-amino-3-oxobutanoate and coenzyme A to form glycine and acetyl-CoA. GCAT resides on the mitochondrial inner membrane in dimeric form and requires pyridoxal 5-phosphate (PXLP) as cofactor. GCAT is thought to exist on the mitochondrial inner membrane in complex with TDH. With these two enzymes located together, it stops the rapid and spontaneous decarboxylation of 2A-3OBU to aminoacetone and carbon dioxide and instead, results in glycine formation (Tressel et al. 1986). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8849175
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Jassal, Bijay

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Ontology Terms

 

Bibliography

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  1. Edgar AJ.; ''Molecular cloning and tissue distribution of mammalian L-threonine 3-dehydrogenases.''; PubMed Europe PMC
  2. Lambrecht JA, Flynn JM, Downs DM.; ''Conserved YjgF protein family deaminates reactive enamine/imine intermediates of pyridoxal 5'-phosphate (PLP)-dependent enzyme reactions.''; PubMed Europe PMC
  3. Niehaus TD, Gerdes S, Hodge-Hanson K, Zhukov A, Cooper AJ, ElBadawi-Sidhu M, Fiehn O, Downs DM, Hanson AD.; ''Genomic and experimental evidence for multiple metabolic functions in the RidA/YjgF/YER057c/UK114 (Rid) protein family.''; PubMed Europe PMC
  4. Sun L, Bartlam M, Liu Y, Pang H, Rao Z.; ''Crystal structure of the pyridoxal-5'-phosphate-dependent serine dehydratase from human liver.''; PubMed Europe PMC
  5. Kao YC, Davis L.; ''Purification and structural characterization of porcine L-threonine dehydrogenase.''; PubMed Europe PMC
  6. Yamada T, Komoto J, Kasuya T, Takata Y, Ogawa H, Mori H, Takusagawa F.; ''A catalytic mechanism that explains a low catalytic activity of serine dehydratase like-1 from human cancer cells: crystal structure and site-directed mutagenesis studies.''; PubMed Europe PMC
  7. Lambrecht JA, Schmitz GE, Downs DM.; ''RidA proteins prevent metabolic damage inflicted by PLP-dependent dehydratases in all domains of life.''; PubMed Europe PMC
  8. Cooper AJ, Krasnikov BF, Niatsetskaya ZV, Pinto JT, Callery PS, Villar MT, Artigues A, Bruschi SA.; ''Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents.''; PubMed Europe PMC
  9. Dale RA.; ''Catabolism of threonine in mammals by coupling of L-threonine 3-dehydrogenase with 2-amino-3-oxobutyrate-CoA ligase.''; PubMed Europe PMC
  10. Edgar AJ, Polak JM.; ''Molecular cloning of the human and murine 2-amino-3-ketobutyrate coenzyme A ligase cDNAs.''; PubMed Europe PMC
  11. Edgar AJ.; ''The human L-threonine 3-dehydrogenase gene is an expressed pseudogene.''; PubMed Europe PMC
  12. Tressel T, Thompson R, Zieske LR, Menendez MI, Davis L.; ''Interaction between L-threonine dehydrogenase and aminoacetone synthetase and mechanism of aminoacetone production.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101631view11:49, 1 November 2018ReactomeTeamreactome version 66
101167view21:36, 31 October 2018ReactomeTeamreactome version 65
100693view20:09, 31 October 2018ReactomeTeamreactome version 64
100243view16:54, 31 October 2018ReactomeTeamreactome version 63
99795view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99345view12:48, 31 October 2018ReactomeTeamreactome version 62
93805view13:37, 16 August 2017ReactomeTeamreactome version 61
93346view11:21, 9 August 2017ReactomeTeamreactome version 61
88405view11:39, 5 August 2016FehrhartOntology Term : 'threonine degradation pathway' added !
86430view09:18, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2A-3OBUMetaboliteCHEBI:16944 (ChEBI)
2AAMetaboliteCHEBI:58020 (ChEBI)
2OBUTAMetaboliteCHEBI:30831 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
GCAT ProteinO75600 (Uniprot-TrEMBL)
GCAT:PXLP dimer:TDH tetramerComplexR-HSA-6798680 (Reactome)
GlyMetaboliteCHEBI:57305 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HRSP12ProteinP52758 (Uniprot-TrEMBL)
L-ThrMetaboliteCHEBI:57926 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
PPiMetaboliteCHEBI:29888 (ChEBI)
PXLP MetaboliteCHEBI:18405 (ChEBI)
SDS ProteinP20132 (Uniprot-TrEMBL)
SDS dimers:PXLPComplexR-HSA-9014724 (Reactome)
SDSL ProteinQ96GA7 (Uniprot-TrEMBL)
TDH ProteinQ8IZJ6 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2A-3OBUArrowR-HSA-6798667 (Reactome)
2A-3OBUR-HSA-6798345 (Reactome)
2AAArrowR-HSA-9014627 (Reactome)
2AAR-HSA-9014641 (Reactome)
2OBUTAArrowR-HSA-9014641 (Reactome)
ATPR-HSA-6798345 (Reactome)
Ac-CoAArrowR-HSA-6798345 (Reactome)
CoA-SHR-HSA-6798345 (Reactome)
GCAT:PXLP dimer:TDH tetramermim-catalysisR-HSA-6798345 (Reactome)
GCAT:PXLP dimer:TDH tetramermim-catalysisR-HSA-6798667 (Reactome)
GlyArrowR-HSA-6798345 (Reactome)
H+ArrowR-HSA-6798345 (Reactome)
H2OArrowR-HSA-9014627 (Reactome)
HRSP12mim-catalysisR-HSA-9014641 (Reactome)
L-ThrR-HSA-6798667 (Reactome)
L-ThrR-HSA-9014627 (Reactome)
NAD+R-HSA-6798667 (Reactome)
NADHArrowR-HSA-6798667 (Reactome)
NH3ArrowR-HSA-9014641 (Reactome)
PPiArrowR-HSA-6798345 (Reactome)
R-HSA-6798345 (Reactome) The degradation of L-threonine to glycine in both prokaryotes and eukaryotes takes place through a two-step biochemical pathway. In the second step, mitochondrial 2-amino-3-ketobutyrate coenzyme A ligase (GCAT, aka KBL) catalyses the reaction between 2-amino-3-oxobutanoate (2A-3OBU) and coenzyme A (CoA-SH) to form glycine (Gly) and acetyl-CoA (Ac-CoA) (Edgar & Polak 2000). GCAT resides on the mitochondrial inner membrane and requires pyridoxal 5-phosphate (PXLP) as cofactor. It is strongly expressed in heart, brain, liver and pancreas. Dimeric GCAT:PXLP is thought to exist on the mitochondrial inner membrane in complex with tetrameric L-threonine 3-dehydrogenase (TDH), the first enzyme in this pathway (Tressel et al. 1986). With these two enzymes located together, it stops the rapid and spontaneous decarboxylation of 2A-3OBU to aminoacetone and carbon dioxide and instead, results in glycine formation.
R-HSA-6798667 (Reactome) The degradation of L-threonine to glycine in both prokaryotes and eukaryotes takes place through a two-step biochemical pathway. In the first step, L-threonine (L-Thr) is oxidised to 2-amino-3-oxobutanoate (2A-3OBU) using NAD+ as acceptor. This reaction is catalysed by mitochondrial L-threonine 3-dehydrogenase (TDH) (Edgar 2002). The human activity is inferred from the characterised porcine Tdh (Edgar 2002b, Kao & Davis 1994). TDH is thought to exist as a tetramer on the mitochondrial inner membrane in complex with dimeric 2-amino-3-ketobutyrate coenzyme A ligase (GCAT), the second enzyme in this pathway (Tressel et al. 1986). With these two enzymes located together, it stops the rapid and spontaneous decarboxylation of 2A-3OBU to aminoacetone and carbon dioxide and instead, results in glycine formation.
R-HSA-9014627 (Reactome) Various PXLP-dependent enzymes can catalyse α, β-elimination reactions of amino acid substrates, ultimately yielding α-keto (or 2-oxo-) acid products. However, these enzymes, such as L-serine dehydratase/L-threonine deaminase (SDS aka TDH), only form the enamine intermediate as the remainder of the reaction occurs in solution with the enamine intermediate tautomerising to the imine form, which then spontaneously hydrolyzes to the final α-keto acid product (Downs & Ernst 2015). SDS can dehydrate L-threonine (L-Thr) to form the intermediate enamine 2-aminoacrylate (2AA), which can damage the pyridoxal 5'-phosphate cofactor (PXLP) of various enzymes, causing inactivation and significant cellular damage if allowed to accumulate (Lambrecht et al. 2013). SDS exists as a homodimer and requires PXLP for activity (Sun et al. 2005). An isoform of SDS, serine dehydratase-like (SDSL aka SDH2), is found in human cancer cell lines and possesses lower catalytic activity than SDS (Yamada et al. 2008).
R-HSA-9014641 (Reactome) The toxic enamine/imine intermediates generated by pyridoxal 5'-phosphate (PXLP) containing enzymes can cause severe cellular damage if allowed to accumulate (Downs & Ernst 2015). 2-iminobutanoate/2-iminopropanoate deaminase (RIDA aka HRSP12) is a widely conserved protein that prevents 2AA accumulation by facilitating its conversion to the stable metabolite 2-oxobutanoate (2OBUTA aka 2-ketobutyrate) (Cooper et al. 2011, Lambrecht et al. 2012, 2013, Niehaus et al. 2015).
SDS dimers:PXLPmim-catalysisR-HSA-9014627 (Reactome)
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