Lysine catabolism (Homo sapiens)

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6, 121, 2, 126, 1814-1784, 197, 101193, 56, 1811, 131, 2, 128mitochondrial intermembrane spacemitochondrial matrixperoxisomal matrixGCDH tetramerSACNH2OPPCAAADAT dimerNAD+P2CSLC25A21L-GluNAD+FADH2HYKKPXLP-AADAT NADHH2OH+ALDH7A1 GTPCoA-SHNADP+GCDH PXLP-K278-PHYKPLtetramerH+NH3CRYM2OGH2Ocrotonyl-CoANADHPIPOXDLD 2OGFADTDP NADPHGL-CoAaKADA5PHLlipo-aKGDHLIPAM 2OGNADHPXLP-K278-PHYKPL Lipo-K110-DLST NAD+FAD AASS tetramerH+AASS 2AMA2AMASL-LysaKADAH2OOGDH P6CGDPNADPHPiFAD H2O2O2CO2ALDH7A1 tetramerNADP+L-GluH+5HLYS167101, 214, 171961, 2


Description

In humans, most catabolism of L-lysine normally proceeds via a sequence of seven reactions which feeds into the pathway for fatty acid catabolism. In the first two reactions, catalyzed by a single enzyme complex, lysine is combined with alpha-ketoglutarate to form saccharopine, which in turn is cleaved and oxidized to yield glutamate and alpha-ketoadipic semialdehyde. The latter molecule is further oxidized to alpha-ketoadipate. Alpha-ketoadipate is oxidatively decarboxylated by the alpha-ketoglutarate dehydrogenase complex (the same enzyme complex responsible for the conversion of alpha-ketoglutarate to succinyl-CoA in the citric acid cycle), yielding glutaryl-CoA. Glutaryl-CoA is converted to crotonyl-CoA, crotonyl-CoA is converted to beta-hydroxybutyryl-CoA, and beta-hydroxybutyryl-CoA is converted to acetoacetyl-CoA. The products of lysine catabolism are thus exclusively ketogenic; i.e., under starvation conditions they can be used for the synthesis of ketone bodies, beta-hydroxybutyrate and acetoacetate, but not for the net synthesis of glucose (Cox 2001; Goodman and Freeman 2001). View original pathway at Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 71064
Reactome-version 
Reactome version: 73
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Bibliography

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  1. Goh DL, Patel A, Thomas GH, Salomons GS, Schor DS, Jakobs C, Geraghty MT.; ''Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT).''; PubMed Europe PMC Scholia
  2. Dodt G, Kim DG, Reimann SA, Reuber BE, McCabe K, Gould SJ, Mihalik SJ.; ''L-Pipecolic acid oxidase, a human enzyme essential for the degradation of L-pipecolic acid, is most similar to the monomeric sarcosine oxidases.''; PubMed Europe PMC Scholia
  3. Zhou ZH, McCarthy DB, O'Connor CM, Reed LJ, Stoops JK.; ''The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes.''; PubMed Europe PMC Scholia
  4. Han Q, Robinson H, Li J.; ''Crystal structure of human kynurenine aminotransferase II.''; PubMed Europe PMC Scholia
  5. Hallen A, Jamie JF, Cooper AJ.; ''Lysine metabolism in mammalian brain: an update on the importance of recent discoveries.''; PubMed Europe PMC Scholia
  6. Fiermonte G, Dolce V, Palmieri L, Ventura M, Runswick MJ, Palmieri F, Walker JE.; ''Identification of the human mitochondrial oxodicarboxylate carrier. Bacterial expression, reconstitution, functional characterization, tissue distribution, and chromosomal location.''; PubMed Europe PMC Scholia
  7. Sacksteder KA, Biery BJ, Morrell JC, Goodman BK, Geisbrecht BV, Cox RP, Gould SJ, Geraghty MT.; ''Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia.''; PubMed Europe PMC Scholia
  8. Cheng Z, Sun L, He J, Gong W.; ''Crystal structure of human micro-crystallin complexed with NADPH.''; PubMed Europe PMC Scholia
  9. Veiga-da-Cunha M, Hadi F, Balligand T, Stroobant V, Van Schaftingen E.; ''Molecular identification of hydroxylysine kinase and of ammoniophospholyases acting on 5-phosphohydroxy-L-lysine and phosphoethanolamine.''; PubMed Europe PMC Scholia
  10. 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.''; PubMed Europe PMC Scholia
  11. 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 Scholia
  12. Markovitz PJ, Chuang DT, Cox RP.; ''Familial hyperlysinemias. Purification and characterization of the bifunctional aminoadipic semialdehyde synthase with lysine-ketoglutarate reductase and saccharopine dehydrogenase activities.''; PubMed Europe PMC Scholia
  13. Fu Z, Wang M, Paschke R, Rao KS, Frerman FE, Kim JJ.; ''Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions.''; PubMed Europe PMC Scholia
  14. Hallen A, Cooper AJ, Jamie JF, Karuso P.; ''Insights into Enzyme Catalysis and Thyroid Hormone Regulation of Cerebral Ketimine Reductase/μ-Crystallin Under Physiological Conditions.''; PubMed Europe PMC Scholia
  15. Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT.; ''Mutations in antiquitin in individuals with pyridoxine-dependent seizures.''; PubMed Europe PMC Scholia
  16. Wong JW, Chan CL, Tang WK, Cheng CH, Fong WP.; ''Is antiquitin a mitochondrial Enzyme?''; PubMed Europe PMC Scholia
  17. Rossi F, Garavaglia S, Montalbano V, Walsh MA, Rizzi M.; ''Crystal structure of human kynurenine aminotransferase II, a drug target for the treatment of schizophrenia.''; PubMed Europe PMC Scholia
  18. Reed LJ, Hackert ML.; ''Structure-function relationships in dihydrolipoamide acyltransferases.''; PubMed Europe PMC Scholia
  19. Keyser B, Mühlhausen C, Dickmanns A, Christensen E, Muschol N, Ullrich K, Braulke T.; ''Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH).''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
114953view16:47, 25 January 2021ReactomeTeamReactome version 75
113397view11:47, 2 November 2020ReactomeTeamReactome version 74
112823view18:28, 9 October 2020DeSlOntology Term : 'lysine degradation pathway' added !
112770view16:17, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2AMAMetaboliteCHEBI:17082 (ChEBI)
2AMASMetaboliteCHEBI:17917 (ChEBI)
2OGMetaboliteCHEBI:16810 (ChEBI)
5HLYSMetaboliteCHEBI:60175 (ChEBI)
5PHLMetaboliteCHEBI:16752 (ChEBI)
AADAT dimerComplexR-HSA-508545 (Reactome)
AASS ProteinQ9UDR5 (Uniprot-TrEMBL)
AASS tetramerComplexR-HSA-70925 (Reactome)
ALDH7A1 ProteinP49419 (Uniprot-TrEMBL)
ALDH7A1 tetramerComplexR-HSA-508564 (Reactome)
CO2MetaboliteCHEBI:16526 (ChEBI)
CRYMProteinQ14894 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DLD ProteinP09622 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FADMetaboliteCHEBI:16238 (ChEBI)
FADH2MetaboliteCHEBI:17877 (ChEBI)
GCDH ProteinQ92947 (Uniprot-TrEMBL)
GCDH tetramerComplexR-HSA-71040 (Reactome)
GDPMetaboliteCHEBI:17552 (ChEBI)
GL-CoAMetaboliteCHEBI:15524 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HYKKProteinA2RU49 (Uniprot-TrEMBL)
L-GluMetaboliteCHEBI:29985 (ChEBI)
L-LysMetaboliteCHEBI:32551 (ChEBI)
LIPAM MetaboliteCHEBI:17460 (ChEBI)
Lipo-K110-DLST ProteinP36957 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
OGDH ProteinQ02218 (Uniprot-TrEMBL)
P2CMetaboliteCHEBI:16187 (ChEBI)
P6CMetaboliteCHEBI:58769 (ChEBI)
PIPOXProteinQ9P0Z9 (Uniprot-TrEMBL)
PPCAMetaboliteCHEBI:30913 (ChEBI)
PXLP-AADAT ProteinQ8N5Z0 (Uniprot-TrEMBL)
PXLP-K278-PHYKPL tetramerComplexR-HSA-5696429 (Reactome)
PXLP-K278-PHYKPL ProteinQ8IUZ5 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SACNMetaboliteCHEBI:16927 (ChEBI)
SLC25A21ProteinQ9BQT8 (Uniprot-TrEMBL)
TDP MetaboliteCHEBI:58937 (ChEBI)
aKADAMetaboliteCHEBI:15753 (ChEBI)
crotonyl-CoAMetaboliteCHEBI:15473 (ChEBI)
lipo-aKGDHComplexR-HSA-69996 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2AMAArrowR-HSA-508561 (Reactome)
2AMAArrowR-HSA-70941 (Reactome)
2AMAR-HSA-70952 (Reactome)
2AMASArrowR-HSA-5696408 (Reactome)
2AMASArrowR-HSA-6783883 (Reactome)
2AMASArrowR-HSA-70940 (Reactome)
2AMASR-HSA-70941 (Reactome)
2OGArrowR-HSA-372480 (Reactome)
2OGArrowR-HSA-508561 (Reactome)
2OGR-HSA-372480 (Reactome)
2OGR-HSA-70938 (Reactome)
2OGR-HSA-70952 (Reactome)
5HLYSR-HSA-6788611 (Reactome)
5PHLArrowR-HSA-6788611 (Reactome)
5PHLR-HSA-5696408 (Reactome)
AADAT dimermim-catalysisR-HSA-508561 (Reactome)
AADAT dimermim-catalysisR-HSA-70952 (Reactome)
AASS tetramermim-catalysisR-HSA-70938 (Reactome)
AASS tetramermim-catalysisR-HSA-70940 (Reactome)
ALDH7A1 tetramermim-catalysisR-HSA-70941 (Reactome)
CO2ArrowR-HSA-71037 (Reactome)
CO2ArrowR-HSA-71046 (Reactome)
CRYMmim-catalysisR-HSA-5693347 (Reactome)
CoA-SHR-HSA-71037 (Reactome)
FADH2ArrowR-HSA-71046 (Reactome)
FADR-HSA-71046 (Reactome)
GCDH tetramermim-catalysisR-HSA-71046 (Reactome)
GDPArrowR-HSA-6788611 (Reactome)
GL-CoAArrowR-HSA-71037 (Reactome)
GL-CoAR-HSA-71046 (Reactome)
GTPR-HSA-6788611 (Reactome)
H+ArrowR-HSA-70940 (Reactome)
H+ArrowR-HSA-70941 (Reactome)
H+R-HSA-5693347 (Reactome)
H+R-HSA-70938 (Reactome)
H2O2ArrowR-HSA-6783880 (Reactome)
H2OArrowR-HSA-70938 (Reactome)
H2OR-HSA-5696408 (Reactome)
H2OR-HSA-70940 (Reactome)
H2OR-HSA-70941 (Reactome)
HYKKmim-catalysisR-HSA-6788611 (Reactome)
L-GluArrowR-HSA-70940 (Reactome)
L-GluArrowR-HSA-70952 (Reactome)
L-GluR-HSA-508561 (Reactome)
L-LysR-HSA-70938 (Reactome)
NAD+R-HSA-70940 (Reactome)
NAD+R-HSA-70941 (Reactome)
NAD+R-HSA-71037 (Reactome)
NADHArrowR-HSA-70940 (Reactome)
NADHArrowR-HSA-70941 (Reactome)
NADHArrowR-HSA-71037 (Reactome)
NADP+ArrowR-HSA-5693347 (Reactome)
NADP+ArrowR-HSA-70938 (Reactome)
NADPHR-HSA-5693347 (Reactome)
NADPHR-HSA-70938 (Reactome)
NH3ArrowR-HSA-5696408 (Reactome)
O2R-HSA-6783880 (Reactome)
P2CR-HSA-5693347 (Reactome)
P6CArrowR-HSA-6783880 (Reactome)
P6CR-HSA-6783883 (Reactome)
PIPOXmim-catalysisR-HSA-6783880 (Reactome)
PPCAArrowR-HSA-5693347 (Reactome)
PPCAR-HSA-6783880 (Reactome)
PXLP-K278-PHYKPL tetramermim-catalysisR-HSA-5696408 (Reactome)
PiArrowR-HSA-5696408 (Reactome)
R-HSA-372480 (Reactome) SLC25A21, the mitochondrial 2-oxodicarboxylate carrier, mediates the exchange of 2-oxoadipate and 2-oxoglutarate across the inner mitochondrial membrane. While the exchange is reversible, under physiological conditions it proceeds in the direction of 2-oxoadipate import into the mitochondrial matrix and 2-oxoglutarate export (Fiermonte et al. 2001).
R-HSA-508561 (Reactome) Kynurenine/alpha-aminoadipate aminotransferase (AADAT) catalyzes the reversible reaction of alpha-ketoadipate and glutamate to form alpha-aminoadipate and alpha-ketoglutarate. Crystallographic studies have demonstrated that active AADAT enzyme is a homodimer with a pyridoxal phosphate moiety covalently attached to each monomer (Han et al. 2008; Rossi et al. 2008). The enzyme is inferred to be located within the mitochondrion because of a mitochondrial localization sequence motif at the aminoterminal end of the AADAT polypeptide (Goh et al. 2002).
R-HSA-5693347 (Reactome) The ketimine reductase mu-crystallin protein (CRYM) is a key enzyme in the pipecolate pathway, which is the main lysine degradation pathway in the brain. One substrate from the pipecolate pathway that can be reduced by CRYM is piperideine-2-carboxylate (P2C) to L-pipecolic acid (PPCA) (Hallen et al 2015). CRYM is also a thyroid hormone binding protein, able to bind and transport 3,5,3'-triiodo-L-thyronine (T3) into nuclei and regulate thyroid hormone-related gene expression (Cheng et al. 2007).
R-HSA-5696408 (Reactome) In mitochondria, ethanolamine-phosphate phospho-lyase and 5-phosphohydroxy-L-lysine phospho-lyase (ETNPPL and PHYKPL respectively) are two closely related pyridoxal-phosphate-dependent, homotetrameric ammoniophospholyases that hydrolyse phosphoethanolamine (PETA) and 5-phosphohydroxylysine (5PHL) respectively (Veiga-da-Cunha et al. 2012). PETA is a component and a precursor of phospholipids whereas 5PHL is a breakdown product of collagen. ETNPPL utilises one pyridoxal 5'-phosphate (PXLP) as cofactor per subunit.
R-HSA-6783880 (Reactome) Peroxisomal sarcosine oxidase (PIPOX aka L-pipecolate oxidase) is an important enzyme in the pipecolate pathway of lysine degradation. The saccharopine pathway is the predominant lysine degradative pathway in extracerebral tissues, whereas the pipecolate pathway predominates in adult brain. PIPOX can mediate the oxidation of L-pipecolate (PPCA) to (S)-1-piperideine-6-carboxylate (P6C), an intermediate in equilibrium with alpha-aminoadipate delta-semialdehyde (AAS), which connects the two degradative pathways. Patients lacking PIPOX accumulate PPCA which can lead to psychiatric and neurological disorders (Dodt et al. 2000, Hallen et al. 2013).
R-HSA-6783883 (Reactome) The saccharopine pathway is the predominant lysine degradative pathway in extracerebral tissues, whereas the pipecolate pathway predominates in adult brain. (S)-1-piperideine-6-carboxylate (P6C), an intermediate of the pipecolate pathway, is in equilibrium with alpha-aminoadipate delta-semialdehyde (2AMAS), which connects the two degradative pathways. How peroxisomal P6C transports to mitochondrial 2AMAS is unknown (Hallen et al. 2013).
R-HSA-6788611 (Reactome) Hydroxylysine kinase (HYKK) phosphorylates 5-hydroxylysine (5HLYS), derived from food and collagen breakdown, to 5-phosphonooxy-L-lysine (5PHL) using GTP as the preferential phosphate donor (Veiga-da-Cunha et al. 2012).
R-HSA-70938 (Reactome) The saccharopine dehydrogenase activity of lysine-ketoglutarate reductase / saccharopine dehydrogenase homotetramer in the mitochondrial matrix catalyzes the reaction of lysine, alpha-ketoglutarate, and NADPH + H+ to form saccharopine, NADP+, and H2O (Markovitz et al. 1984; Sacksteder et al. 2001).
R-HSA-70940 (Reactome) The saccharopine dehydrogenase activity of lysine-ketoglutarate reductase / saccharopine dehydrogenase homotetramer in the mitochondrial matrix catalyzes the reaction of saccharopine (N6-(L-1,3-Dicarboxypropyl)-L-lysine), H2O, and NAD+ to form 'L-2-Aminoadipate 6-semialdehyde, glutamate, and NADH + H+ (Markovitz et al. 1984; Sacksteder et al. 2001).
R-HSA-70941 (Reactome) Alpha-aminoadipic semialdehyde dehydrogenase (ALDH7A1) catalyzes the reaction of alpha-aminoadipic semialdehyde and NAD+ to form alpha-aminoadipate and NADH + H+ (Mills et al. 2006). Unpublished crystallographic data (PDB 2J6L) indicate that the enzyme is a homodimer. Recent immunofluorescence studies of both endogenous and GFP-tagged ALDH7A1 proteins in cultured human embryonic kidney cells indicate that the protein is present in both mitochondria and the cytosol (Wong et al. 2010).
R-HSA-70952 (Reactome) Kynurenine/alpha-aminoadipate aminotransferase (AADAT) catalyzes the reversible reaction of alpha-aminoadipate and alpha-ketoglutarate to form alpha-ketoadipate and glutamate. Crystallographic studies have demonstrated that active AADAT enzyme is a homodimer with a pyridoxal phosphate moiety covalently attached to each monomer (Han et al. 2008; Rossi et al. 2008). The enzyme is inferred to be located within the mitochondrion because of a mitochondrial localization sequence motif at the aminoterminal end of the AADAT polypeptide (Goh et al. 2002).
R-HSA-71037 (Reactome) The mitochondrial alpha-ketoglutarate dehydrogenase complex catalyzes the reaction of alpha-ketoadipate, CoASH, and NAD+ to form glutaryl-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-ketoadipate catalyzed by E1alpha and beta (alpha ketoglutarate dehydrogenase). Lipoamide cofactor associated with E1 is reduced at the same time. Next, the glutaryl 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-71046 (Reactome) Mitochondrial glutaryl-CoA dehydrogenase (GCDH) catalyzes the reaction of glutaryl-CoA and FAD to form crotonyl-CoA, FADH2, and CO2. The active enzyme is a tetramer of GCDH polypeptides lacking a 44-residue aminoterminal mitochondrial targeting sequence. Mutations in GCDH cause glutaric aciduria type 1 in vivo (Fu et al. 2004; Keyser et al. 2008).
SACNArrowR-HSA-70938 (Reactome)
SACNR-HSA-70940 (Reactome)
SLC25A21mim-catalysisR-HSA-372480 (Reactome)
aKADAArrowR-HSA-372480 (Reactome)
aKADAArrowR-HSA-70952 (Reactome)
aKADAR-HSA-372480 (Reactome)
aKADAR-HSA-508561 (Reactome)
aKADAR-HSA-71037 (Reactome)
crotonyl-CoAArrowR-HSA-71046 (Reactome)
lipo-aKGDHmim-catalysisR-HSA-71037 (Reactome)
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