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.
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.''; PubMedEurope PMCScholia
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Takada Y, Kaneko N, Esumi H, Purdue PE, Danpure CJ.; ''Human peroxisomal L-alanine: glyoxylate aminotransferase. Evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon.''; PubMedEurope PMCScholia
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Harris RA, Bowker-Kinley MM, Wu P, Jeng J, Popov KM.; ''Dihydrolipoamide dehydrogenase-binding protein of the human pyruvate dehydrogenase complex. DNA-derived amino acid sequence, expression, and reconstitution of the pyruvate dehydrogenase complex.''; PubMedEurope PMCScholia
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Danpure CJ, Jennings PR.; ''Further studies on the activity and subcellular distribution of alanine:glyoxylate aminotransferase in the livers of patients with primary hyperoxaluria type 1.''; PubMedEurope PMCScholia
Fujiwara K, Okamura-Ikeda K, Hayasaka K, Motokawa Y.; ''The primary structure of human H-protein of the glycine cleavage system deduced by cDNA cloning.''; PubMedEurope PMCScholia
Rodionov RN, Murry DJ, Vaulman SF, Stevens JW, Lentz SR.; ''Human alanine-glyoxylate aminotransferase 2 lowers asymmetric dimethylarginine and protects from inhibition of nitric oxide production.''; PubMedEurope PMCScholia
MAITRA U, DEKKER EE.; ''PURIFICATION AND PROPERTIES OF RAT LIVER 2-KETO-4-HYDROXYGLUTARATE ALDOLASE.''; PubMedEurope PMCScholia
Wanders RJ, Waterham HR, Ferdinandusse S.; ''Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum.''; PubMedEurope PMCScholia
Coulter-Mackie MB, Lian Q, Wong SG.; ''Overexpression of human alanine:glyoxylate aminotransferase in Escherichia coli: renaturation from guanidine-HCl and affinity for pyridoxal phosphate co-factor.''; PubMedEurope PMCScholia
MAITRA U, DEEKKER E.; ''PURIFICATION OF RAT-LIVER GAMMA-HYDROXYGLUTAMATE TRANSAMINASE AND ITS PROBABLE IDENTITY WITH GLUTAMATE-ASPARTATE TRANSAMINASE.''; PubMedEurope PMCScholia
Pakhomova S, Luka Z, Grohmann S, Wagner C, Newcomer ME.; ''Glycine N-methyltransferases: a comparison of the crystal structures and kinetic properties of recombinant human, mouse and rat enzymes.''; PubMedEurope PMCScholia
ADAMS E, GOLDSTONE A.; ''Hydroxyproline metabolism. IV. Enzymatic synthesis of gamma-hydroxyglutamate from Delta 1-pyrroline-3-hydroxy-5-carboxylate.''; PubMedEurope PMCScholia
Valle D, Goodman SI, Harris SC, Phang JM.; ''Genetic evidence for a common enzyme catalyzing the second step in the degradation of proline and hydroxyproline.''; PubMedEurope PMCScholia
Rokka A, Antonenkov VD, Soininen R, Immonen HL, Pirilä PL, Bergmann U, Sormunen RT, Weckström M, Benz R, Hiltunen JK.; ''Pxmp2 is a channel-forming protein in Mammalian peroxisomal membrane.''; PubMedEurope PMCScholia
Purdue PE, Takada Y, Danpure CJ.; ''Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.''; PubMedEurope PMCScholia
Danpure CJ.; ''Primary hyperoxaluria: from gene defects to designer drugs?''; PubMedEurope PMCScholia
Amery L, Brees C, Baes M, Setoyama C, Miura R, Mannaerts GP, Van Veldhoven PP.; ''C-terminal tripeptide Ser-Asn-Leu (SNL) of human D-aspartate oxidase is a functional peroxisome-targeting signal.''; PubMedEurope PMCScholia
Tort F, Ferrer-Cortès X, Thió M, Navarro-Sastre A, Matalonga L, Quintana E, Bujan N, Arias A, García-Villoria J, Acquaviva C, Vianey-Saban C, Artuch R, García-Cazorla À, Briones P, Ribes A.; ''Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes.''; PubMedEurope PMCScholia
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Jones JM, Morrell JC, Gould SJ.; ''Identification and characterization of HAOX1, HAOX2, and HAOX3, three human peroxisomal 2-hydroxy acid oxidases.''; PubMedEurope PMCScholia
Adams E, Frank L.; ''Metabolism of proline and the hydroxyprolines.''; PubMedEurope PMCScholia
Vignaud C, Pietrancosta N, Williams EL, Rumsby G, Lederer F.; ''Purification and characterization of recombinant human liver glycolate oxidase.''; PubMedEurope PMCScholia
Brown RM, Head RA, Brown GK.; ''Pyruvate dehydrogenase E3 binding protein deficiency.''; PubMedEurope PMCScholia
Murray MS, Holmes RP, Lowther WT.; ''Active site and loop 4 movements within human glycolate oxidase: implications for substrate specificity and drug design.''; PubMedEurope PMCScholia
Molla G, Sacchi S, Bernasconi M, Pilone MS, Fukui K, Polegioni L.; ''Characterization of human D-amino acid oxidase.''; PubMedEurope PMCScholia
Forte-McRobbie CM, Pietruszko R.; ''Purification and characterization of human liver "high Km" aldehyde dehydrogenase and its identification as glutamic gamma-semialdehyde dehydrogenase.''; PubMedEurope PMCScholia
Rumsby G, Cregeen DP.; ''Identification and expression of a cDNA for human hydroxypyruvate/glyoxylate reductase.''; PubMedEurope PMCScholia
Da Cruz S, Xenarios I, Langridge J, Vilbois F, Parone PA, Martinou JC.; ''Proteomic analysis of the mouse liver mitochondrial inner membrane.''; PubMedEurope PMCScholia
Atlante A, Seccia TM, Marra E, Minervini GM, Vulpis V, Pirrelli A, Passarella S.; ''Carrier-mediated transport controls hydroxyproline catabolism in heart mitochondria from spontaneously hypertensive rat.''; PubMedEurope PMCScholia
Soreze Y, Boutron A, Habarou F, Barnerias C, Nonnenmacher L, Delpech H, Mamoune A, Chrétien D, Hubert L, Bole-Feysot C, Nitschke P, Correia I, Sardet C, Boddaert N, Hamel Y, Delahodde A, Ottolenghi C, de Lonlay P.; ''Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase.''; PubMedEurope PMCScholia
Ciszak EM, Makal A, Hong YS, Vettaikkorumakankauv AK, Korotchkina LG, Patel MS.; ''How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex.''; PubMedEurope PMCScholia
Katane M, Kawata T, Nakayama K, Saitoh Y, Kaneko Y, Matsuda S, Saitoh Y, Miyamoto T, Sekine M, Homma H.; ''Characterization of the enzymatic and structural properties of human D-aspartate oxidase and comparison with those of the rat and mouse enzymes.''; PubMedEurope PMCScholia
Negri A, Ceciliani F, Tedeschi G, Simonic T, Ronchi S.; ''The primary structure of the flavoprotein D-aspartate oxidase from beef kidney.''; PubMedEurope PMCScholia
ADAMS E, GOLDSTONE A.; ''Hydroxyproline metabolism. II. Enzymatic preparation and properties of Delta 1-pyrroline-3-hydroxy-5-carboxylic acid.''; PubMedEurope PMCScholia
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).
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).
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).
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).
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).
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).
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).
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).
Cytosolic hydroxyproline (HPRO) is transported into the mitochonrial matrix in a saturable process distinct from the one responsible for proline uptake. The carrier that mediates this process has not been identified, however (Atlante et al. 1996).
PRODH2 dimer dehydrogenates hydroxyproline (HPRO) to form 1-pyrroline-3-hydroxy-5-carboxylate (Adams & Goldstone 1960). The enzyme is associated with FAD and ubiquinone (not annotated here) is the likely electron acceptor (Summitt et al. 2015). The mitochondrial localization of the reaction is inferred from studies of HPRO catabolism in rat and bovine systems (Adams & Frank 1980), and the localization of PRODH2 to the inner mitochondrial membrane is inferred from that of the homologous mouse protein (Da Cruz et al. 2003).
GOT2 dimer transaminates 4-OH-L-glutamate (4-OH-L-Glu) and oxaloacetate (OA) to form 4-hydroxy-2-oxoglutarate (HOG) and L-Asp. The ability of human GOT2 to catalyze this reaction has been inferred from studies of its rat homologue (Maitra & Dekker 1964).
Mitochondrial delta-1-pyrroline-5-carboxylate dehydrogenase (ALDH4A1) catalyzes the reaction of 4-hydroxy-L-glutamate gamma-semialdehyde and NAD+ to form 4-hydroxyglutamate and NADH + H+. ALDH4A1 also catalyzes the corresponding reaction of proline catabolism, as shown in biochemical and structural studies (Adams & Goldstone 1960; Srivastava et al. 2012), and mutations in ALDH4A1 disrupt both catabolic processes in human patients (Valle et al. 1979).
The spontaneous hydrolysis of 1-pyrroline-3-hydroxy-5-carboxylate to form 4-OH-L-glutamate semialdehyde is inferred from the behavior of the analogous intermediate of proline catabolism (Moxley et al. 2011).
Mitochondrial HOGA1 aldol-cleaves 4-OH-2-oxoglutarate (HOG) to glyoxylate and pyruvate. The biochemical details of the enzyme are inferred from the properties of its well-studied rat homologue (Maitra & Dekker 1964). The mature protein lacks a 25-residue mitochondrial targeting sequence and forms a homotetramer (Riedel et al. 2011).
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).
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).
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).
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).
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).
Peroxisomal membrane protein 2 (PXMP2) homotrimer is inferred from the properties of its mouse homolog to form a channel in the peroxisomal membrane that allows the passage of glycolate and other molecules with molecular masses less than 200 Da between the cytosol and the peroxisomal matrix (Rokka et al. 2009; Wanders et al. 2016).
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.
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