Glyoxylate metabolism and glycine degradation (Homo sapiens)

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1213, 16, 3220, 2422, 33145, 23, 25, 3726, 10, 11, 28, 3021, 27, 35194, 7, 8, 17, 1831, 3815, 363, 95, 23, 25, 37cytosolmitochondrial matrixperoxisomal matrixBCKDHA D-Aspoctanoyl group GlycolateGlylipo-K44-DBT glyoxylateNH3DDO HAO1 PDHX PDHA1 NADP+Lipo-K110-DLST AdoMetOACO2FAD TDP NAD+NADHGlyDLD DHTKD1 THFPXLP PDHB H2OGLDC dimer:2xPXLPGNMT tetramerDBT GCSH BCKDHB 5dAdeGNMT AGXT2 tetramerH2OLIAS AGXT dimerLIPT1H2O2PYRDDO:FADLIPAM DLD DAO OGDH 5,10-methylene-THFDHLL AMTHAO1 tetramerH2OPDHX H2O24Fe-4S cluster LIAS:2(4Fe-4S)lipo-K-DHTKD1 GLDC FAD NDUFAB1H+lipoylated DHsGCSH:SAMDLLAdoHcyGCSH:DHLLFAD PXLP-AGXT DLST GCSH LIPAM octanoyl:NDUFAB1NADPHL-AlaTDP O2SOGDH lipoyl-K107-GCSHoctanoyl-K107-GCSHFMN glyoxylateOXL-AlaNDUFAB1 AdoMetDLD PDHB LIPT2SAMDLL GlyPDHA1 NH4+BCKDHB O2FAD SARCGRHPRFAD DHsDAO dimerPYRGCSHDLAT lipo-K132,K259-DLAT DLD dimer:2xFADPXLP-AGXT2 O2BCKDHA H+L-Met9, 34111269, 342620117261, 291, 2910, 301711


Description

Glyoxylate is generated in the course of glycine and hydroxyproline catabolism and can be converted to oxalate. In humans, this process takes place in the liver. Defects in two enzymes of glyoxylate metabolism, alanine:glyoxylate aminotransferase (AGXT) and glycerate dehydrogenase/glyoxylate reductase (GRHPR), are associated with pathogenic overproduction of oxalate (Danpure 2005). The reactions that interconvert glycine, glycolate, and glyoxylate and convert glyoxylate to oxalate have been characterized in molecular detail in humans. A reaction sequence for the conversion of hydroxyproline to glyoxylate has been inferred from studies of partially purified extracts of rat and bovine liver but the enzymes involved in the corresponding human reactions have not been identified. View original pathway at:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114656view16:12, 25 January 2021ReactomeTeamReactome version 75
113104view11:16, 2 November 2020ReactomeTeamReactome version 74
112338view15:26, 9 October 2020ReactomeTeamReactome version 73
101238view11:13, 1 November 2018ReactomeTeamreactome version 66
100777view20:40, 31 October 2018ReactomeTeamreactome version 65
100320view19:17, 31 October 2018ReactomeTeamreactome version 64
99865view16:00, 31 October 2018ReactomeTeamreactome version 63
99422view14:36, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99105view12:39, 31 October 2018ReactomeTeamreactome version 62
93997view13:50, 16 August 2017ReactomeTeamreactome version 61
93606view11:28, 9 August 2017ReactomeTeamreactome version 61
87455view14:02, 22 July 2016MkutmonOntology Term : 'glyoxylate and dicarboxylate metabolic pathway' added !
86713view09:24, 11 July 2016ReactomeTeamreactome version 56
83452view12:26, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
4Fe-4S cluster MetaboliteCHEBI:49883 (ChEBI)
5,10-methylene-THFMetaboliteCHEBI:12071 (ChEBI)
5dAdeMetaboliteCHEBI:17319 (ChEBI)
AGXT dimerComplexR-HSA-389671 (Reactome)
AGXT2 tetramerComplexR-HSA-904854 (Reactome)
AMTProteinP48728 (Uniprot-TrEMBL)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BCKDHA ProteinP12694 (Uniprot-TrEMBL)
BCKDHB ProteinP21953 (Uniprot-TrEMBL)
CO2MetaboliteCHEBI:16526 (ChEBI)
D-AspMetaboliteCHEBI:17364 (ChEBI)
DAO ProteinP14920 (Uniprot-TrEMBL)
DAO dimerComplexR-HSA-389849 (Reactome)
DBT ProteinP11182 (Uniprot-TrEMBL)
DDO ProteinQ99489 (Uniprot-TrEMBL)
DDO:FADComplexR-HSA-6810064 (Reactome)
DHLL MetaboliteCHEBI:50746 (ChEBI)
DHTKD1 ProteinQ96HY7 (Uniprot-TrEMBL)
DHsComplexR-HSA-6792579 (Reactome)
DLAT ProteinP10515 (Uniprot-TrEMBL)
DLD ProteinP09622 (Uniprot-TrEMBL)
DLD dimer:2xFADComplexR-HSA-5694020 (Reactome)
DLST ProteinP36957 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FMN MetaboliteCHEBI:17621 (ChEBI)
GCSH ProteinP23434 (Uniprot-TrEMBL)
GCSH:DHLLComplexR-HSA-5693982 (Reactome)
GCSH:SAMDLLComplexR-HSA-5693969 (Reactome)
GCSHProteinP23434 (Uniprot-TrEMBL)
GLDC ProteinP23378 (Uniprot-TrEMBL)
GLDC dimer:2xPXLPComplexR-HSA-5693954 (Reactome)
GNMT ProteinQ14749 (Uniprot-TrEMBL)
GNMT tetramerComplexR-HSA-6798322 (Reactome)
GRHPRProteinQ9UBQ7 (Uniprot-TrEMBL)
GlyMetaboliteCHEBI:15428 (ChEBI)
GlycolateMetaboliteCHEBI:17497 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HAO1 ProteinQ9UJM8 (Uniprot-TrEMBL)
HAO1 tetramerComplexR-HSA-389845 (Reactome)
L-AlaMetaboliteCHEBI:16977 (ChEBI)
L-MetMetaboliteCHEBI:16643 (ChEBI)
LIAS ProteinO43766 (Uniprot-TrEMBL)
LIAS:2(4Fe-4S)ComplexR-HSA-6793623 (Reactome)
LIPAM MetaboliteCHEBI:17460 (ChEBI)
LIPT1ProteinQ9Y234 (Uniprot-TrEMBL)
LIPT2ProteinA6NK58 (Uniprot-TrEMBL)
Lipo-K110-DLST ProteinP36957 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NDUFAB1 ProteinO14561 (Uniprot-TrEMBL)
NDUFAB1ProteinO14561 (Uniprot-TrEMBL)
NH3MetaboliteCHEBI:16134 (ChEBI)
NH4+MetaboliteCHEBI:28938 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
OAMetaboliteCHEBI:30744 (ChEBI)
OGDH ProteinQ02218 (Uniprot-TrEMBL)
OXMetaboliteCHEBI:16995 (ChEBI)
PDHA1 ProteinP08559 (Uniprot-TrEMBL)
PDHB ProteinP11177 (Uniprot-TrEMBL)
PDHX ProteinO00330 (Uniprot-TrEMBL)
PXLP MetaboliteCHEBI:18405 (ChEBI)
PXLP-AGXT ProteinP21549 (Uniprot-TrEMBL)
PXLP-AGXT2 ProteinQ9BYV1 (Uniprot-TrEMBL)
PYRMetaboliteCHEBI:32816 (ChEBI)
SAMDLL MetaboliteCHEBI:14949 (ChEBI)
SARCMetaboliteCHEBI:15611 (ChEBI)
SMetaboliteCHEBI:26833 (ChEBI)
TDP MetaboliteCHEBI:18290 (ChEBI)
THFMetaboliteCHEBI:15635 (ChEBI)
glyoxylateMetaboliteCHEBI:16891 (ChEBI)
lipo-K-DHTKD1 ProteinQ96HY7 (Uniprot-TrEMBL)
lipo-K132,K259-DLAT ProteinP10515 (Uniprot-TrEMBL)
lipo-K44-DBT ProteinP11182 (Uniprot-TrEMBL)
lipoyl-K107-GCSHProteinP23434 (Uniprot-TrEMBL)
lipoylated DHsComplexR-HSA-6792580 (Reactome)
octanoyl group MetaboliteCHEBI:25650 (ChEBI)
octanoyl-K107-GCSHProteinP23434 (Uniprot-TrEMBL)
octanoyl:NDUFAB1ComplexR-HSA-6793596 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
5,10-methylene-THFArrowR-HSA-5693977 (Reactome)
5dAdeArrowR-HSA-6793591 (Reactome)
AGXT dimermim-catalysisR-HSA-389684 (Reactome)
AGXT2 tetramermim-catalysisR-HSA-904864 (Reactome)
AMTmim-catalysisR-HSA-5693977 (Reactome)
AdoHcyArrowR-HSA-6798317 (Reactome)
AdoMetR-HSA-6793591 (Reactome)
AdoMetR-HSA-6798317 (Reactome)
CO2ArrowR-HSA-5693967 (Reactome)
D-AspR-HSA-6810076 (Reactome)
DAO dimermim-catalysisR-HSA-389821 (Reactome)
DDO:FADmim-catalysisR-HSA-6810076 (Reactome)
DHsR-HSA-6792572 (Reactome)
DLD dimer:2xFADmim-catalysisR-HSA-5694018 (Reactome)
GCSH:DHLLArrowR-HSA-5693977 (Reactome)
GCSH:DHLLR-HSA-5694018 (Reactome)
GCSH:SAMDLLArrowR-HSA-5693967 (Reactome)
GCSH:SAMDLLR-HSA-5693977 (Reactome)
GCSHArrowR-HSA-6792572 (Reactome)
GCSHR-HSA-6793590 (Reactome)
GLDC dimer:2xPXLPmim-catalysisR-HSA-5693967 (Reactome)
GNMT tetramermim-catalysisR-HSA-6798317 (Reactome)
GRHPRmim-catalysisR-HSA-389826 (Reactome)
GlyArrowR-HSA-389684 (Reactome)
GlyArrowR-HSA-904864 (Reactome)
GlyR-HSA-389821 (Reactome)
GlyR-HSA-5693967 (Reactome)
GlyR-HSA-6798317 (Reactome)
GlycolateArrowR-HSA-389826 (Reactome)
GlycolateR-HSA-389842 (Reactome)
H+ArrowR-HSA-5694018 (Reactome)
H+R-HSA-389826 (Reactome)
H2O2ArrowR-HSA-389821 (Reactome)
H2O2ArrowR-HSA-389842 (Reactome)
H2O2ArrowR-HSA-389862 (Reactome)
H2O2ArrowR-HSA-6810076 (Reactome)
H2OR-HSA-389821 (Reactome)
H2OR-HSA-389862 (Reactome)
H2OR-HSA-6810076 (Reactome)
HAO1 tetramermim-catalysisR-HSA-389842 (Reactome)
HAO1 tetramermim-catalysisR-HSA-389862 (Reactome)
L-AlaR-HSA-389684 (Reactome)
L-AlaR-HSA-904864 (Reactome)
L-MetArrowR-HSA-6793591 (Reactome)
LIAS:2(4Fe-4S)mim-catalysisR-HSA-6793591 (Reactome)
LIPT1mim-catalysisR-HSA-6792572 (Reactome)
LIPT2mim-catalysisR-HSA-6793590 (Reactome)
NAD+R-HSA-5694018 (Reactome)
NADHArrowR-HSA-5694018 (Reactome)
NADP+ArrowR-HSA-389826 (Reactome)
NADPHR-HSA-389826 (Reactome)
NDUFAB1ArrowR-HSA-6793590 (Reactome)
NH3ArrowR-HSA-5693977 (Reactome)
NH4+ArrowR-HSA-389821 (Reactome)
NH4+ArrowR-HSA-6810076 (Reactome)
O2R-HSA-389821 (Reactome)
O2R-HSA-389842 (Reactome)
O2R-HSA-389862 (Reactome)
O2R-HSA-6810076 (Reactome)
OAArrowR-HSA-6810076 (Reactome)
OXArrowR-HSA-389862 (Reactome)
PYRArrowR-HSA-389684 (Reactome)
PYRArrowR-HSA-904864 (Reactome)
R-HSA-389684 (Reactome) Alanine-glyoxylate transaminase (AGXT) catalyzes the irreversible reaction of glyoxylate and alanine to form glycine and pyruvate (Danpure and Jennings 1988). The active form of the enzyme is a homodimer (Zhang et al. 2003) with one molecule of pyridoxal phosphate bound to each subunit (Coulter-Mackie et al. 2005). Mutations in this enzyme are associated with primary hyperoxaluria type I. Mutant alleles encode both catalytically inactive proteins and active ones that are mis-localized to mitochondria (Purdue et al. 1990; Takada et al. 1990).
R-HSA-389821 (Reactome) Peroxisomal D-amino-acid oxidase catalyzes the reaction of glycine, water, and O2 to form glyoxylate, H2O2, and NH4+. The active form of the enzyme is a homodimer and has FAD as a cofactor (Kawazoe et al. 2006; Molla et al. 2006).
R-HSA-389826 (Reactome) Peroxisomal GRHPR catalyzes the reaction of glyoxylate and NADPH + H+ to form glycolate and NADP+. The active form of the enzyme is a monomer (Rumsby and Cregeen 1999); mutations in it are associated with primary hyperoxaluria type II (Cramer et al. 1999).
R-HSA-389842 (Reactome) Peroxisomal hydroxyacid oxidase 1 catalyzes the reaction of glycolate and O2 to form glyoxylate and H2O2. The active form of the enzyme is associated with FMN and is a tetramer (Jones et al. 2000; Murray et al. 2008; Vignaud et al. 2007; Williams et al. 2000).
R-HSA-389862 (Reactome) Peroxisomal hydroxyacid oxidase 1 catalyzes the reaction of glyoxylate to form oxalate. The active form of the enzyme is associated with FMN and is a tetramer (Jones et al. 2000; Murray et al. 2008; Vignaud et al. 2007; Williams et al. 2000).
R-HSA-5693967 (Reactome) The simplest amino acid, glycine, is catabolised by several different pathways. The major pathway is via the glycine cleavage system. In the first reaction, glycine (Gly) is decarboxylated to carbon dioxide (CO2) and aminomethyl group (NH2CH2) by mitochondrial glycine dehydrogenase (decarboxylating) (GLDC, P protein), a dimeric protein using pyridoxal 5-phosphate (PXPL) as cofactor per subunit (Kume et al. 1991). Mitochondrial glycine cleavage system H protein (GCSH) is used as a co-substrate in this reaction. GCSH uses lipoate as a cofactor which accepts the aminomethylgroup from glycine decarboxylation to form a S-aminomethyldihydrolipoylated protein (GCSH:SAMDLL) (Fujiwara et al. 1991, Fujiwara et al. 1991).
R-HSA-5693977 (Reactome) The major degradative pathway for the amino acid glycine is via the glycine cleavage system. In the second reaction in this system, the decarboxylated moiety from glycine decarboxylation attached to H protein (GCSH:SAMDLL) is further degraded by mitochondrial aminomethyltransferase (AMT, GCST, T protein) to ammonia (NH3) and GCSH with reduced lipoate. Tetrahydrofolate (THF) is required for this reaction and accepts the methyl group to form 5,10MTHF (Fujiwara et al. 1984).
R-HSA-5694018 (Reactome) The last step in the glycine cleavage system is the reoxidation of the reduced lipoate (dihydrolipoyl group) attached to the H protein (GCSH:DHLL) catalysed by the L protein (mitochondrial dihydrolipoyl dehydrogenase, DLD) (Harris et al. 1997, Ciszak et al. 2006).
R-HSA-6792572 (Reactome) Lipoate is an essential cofactor for two enzymes from energy metabolism (alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase) and three from amino acid metabolism (branched-chain ketoacid dehydrogenase, 2-oxoadipate dehydrogenase, and the glycine cleavage system). Lipoate synthesis in mitochondria requires three steps. In the third step, mitochondrial lipoyltransferase 1 (LIPT1) catalyses the transfer of a lipoyl group from lipoyl-K107-GCSH to lysine residue(s) of lipoate-dependent enzymes (Fujiwara et al. 1999). Defects in LIPT1 reduce lipoylation of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, causing a cofactor disorder of mitochondrial energy metabolism (Soreze et al. 2013, Tort et al. 2014).
R-HSA-6793590 (Reactome) Lipoate is an essential cofactor for five redox reactions; four in oxoacid dehydrogenases (active in energy metabolism and amino acid metabolism) and one in the glycine cleavage system (GCS). Lipoate synthesis in mitochondria requires three steps. In the first step, mitochondrial lipoyltransferase 2 (LIPT2) transfers an octanoyl group bound to an acyl-carrier protein (most likely NDUFAB1, acyl-carrier protein, ACP) to mitochondrial glycine cleavage system H protein (GCSH) at lysine 107. The human protein is thought to function in the same way as yeast LIP2 (Schonauer et al. 2009).
R-HSA-6793591 (Reactome) Lipoate is an essential cofactor for five redox reactions; four in oxoacid dehydrogenases (active in energy metabolism and amino acid metabolism) and one in the glycine cleavage system (GCS). Lipoate synthesis in mitochondria requires three steps. In the second step, mitochondrial lipoyl synthase (LIAS) mediates the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to glycine cleavage system H protein (GCSH), transforming the octanoyl moiety to a lipoyl moiety. LIAS requires two 4Fe-4S clusters as cofactor which act as the sulfur donors in the reaction (Morikawa et al. 2001). Defects in LIAS causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation (Mayr et al. 2011).
R-HSA-6798317 (Reactome) Cytosolic glycine N-methyltransferase (GNMT) catalyses the transfer of a methyl group from S-adenosylmethionine (AdoMet) to glycine (Gly) to form sarcosine (SARC, aka N-methylglycine) with the concomitant production of S-adenosylhomocysteine (AdoHcy) (Pakhomova et al. 2004).
R-HSA-6810076 (Reactome) Peroxisomal DDO (D-aspartate oxidase) catalyzes the oxidation of D-Asp (D-aspartate) to OA (oxaloacetate) with the formation of H2O2. The human enzyme is a monomer with an FAD cofactor (Katane et al. 2010, 2015; Setoyama & Miura 1997), as is its well-characterized bovine homolog (Negri et al. 1992). Its peroxisomal location is inferred from studies in cultured cells of fusion proteins containing the carboxyterminal peptide sequence of DDO (Amery et al. 1998).
R-HSA-904864 (Reactome) Mitochondrial AGXT2 (alanine-glyoxylate transaminase 2) catalyzes the irreversible reaction of glyoxylate and alanine to form glycine and pyruvate (Rodionov et al. 2010). The active form of the enzyme is inferred to be a homotetramer from the properties of the homologous rat protein, which has been purified and characterized in vitro (Tamaki et al.990). Most conversion of glyoxylate to glycine in vivo appears to occur in the peroxisome, catalyzed by AGXT, and the physiological role of the AGXT2 reaction is unclear.
SARCArrowR-HSA-6798317 (Reactome)
SR-HSA-6793591 (Reactome)
THFR-HSA-5693977 (Reactome)
glyoxylateArrowR-HSA-389821 (Reactome)
glyoxylateArrowR-HSA-389842 (Reactome)
glyoxylateR-HSA-389684 (Reactome)
glyoxylateR-HSA-389826 (Reactome)
glyoxylateR-HSA-389862 (Reactome)
glyoxylateR-HSA-904864 (Reactome)
lipoyl-K107-GCSHArrowR-HSA-5694018 (Reactome)
lipoyl-K107-GCSHArrowR-HSA-6793591 (Reactome)
lipoyl-K107-GCSHR-HSA-5693967 (Reactome)
lipoyl-K107-GCSHR-HSA-6792572 (Reactome)
lipoylated DHsArrowR-HSA-6792572 (Reactome)
octanoyl-K107-GCSHArrowR-HSA-6793590 (Reactome)
octanoyl-K107-GCSHR-HSA-6793591 (Reactome)
octanoyl:NDUFAB1R-HSA-6793590 (Reactome)
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