If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
Synonyms: glycine cleavage system, glycine decarboxylase complex, gcv system, glycine cleavage complex
|Superclasses:||Degradation/Utilization/Assimilation → Amino Acids Degradation → Glycine Degradation|
Pathway Summary from MetaCyc:
2-oxo acid dehydrogenase complexes convert 2-oxo acids to the corresponding acyl-CoA derivatives and produce NADH and CO2 in an irreversible reaction. Five members of this family are known at present, including the pyruvate dehydrogenase complex (PDHC), the 2-oxoglutarate dehydrogenase complex (OGDHC), the branched-chain α-keto acid dehydrogenase complex (BCDHC), the glycine cleavage complex (GDHC - this pathway), and the acetoin dehydrogenase complex (ADHC). They all function at strategic points in (usually aerobic) catabolic pathways and are subject to stringent control [deKok98].
With the exception of GDHC, the 2-oxo acid dehydrogenase complexes share a common structure. They consist of three main components, namely a 2-oxo acid dehydrogenase (E1), a dihydrolipoamide acyltransferase (E2), and dihydrolipoamide dehydrogenase (E3). In Gram-positive bacteria and mitochondria, the E1 component is a heterodimer composed of two subunits, while in Gram-negative bacteria it is made of a single type of subunit.
In all cases described so far, many copies of each subunit assemble to form the full complex. For example, the Escherichia coli K-12 pyruvate dehydrogenase comprises 24, 24, and 12 units of the E1, E2, and E3 components, respectively. The core of the complex is made of either 24 (Gram-negative bacteria) or 60 (mitochondria) E2 units, which contain the lipoyl active site in the form of lipoyllysine, as well as binding sites for the other two subunits. E1, which contains a thiamin diphosphate cofactor, catalyzes the binding of the 2-oxo acid to the lipoyl group of E2, which then transfers an acyl group (the nature of the acyl group depends on the particular enzyme) to coenzyme A, forming an acyl-CoA. During this transfer, the lipoyl group is reduced to dihydrolipoyl. E3 then transfers the protons to NAD, forming NADH and restoring the dihydrolipoyllysine group back to lipoyllysine.
Cryoelectron microscopy of PDHC from Geobacillus stearothermophilus [Milne02] and ox kidney [Zhou01] has revealed that the E2 inner core is surrounded by an outer shell of E1 and E3 components, with the lipoyl domains confined to the annular space between them where they must make successive journeys between the three types of active sites (E1-E3), which are physically far apart [Fries03].
About This Pathway
In eukaryotes the mitochondrial glycine cleavage complex (glycine decarboxylase complex) is a loosely-associated multienzyme complex that catalyzes the oxidative cleavage of glycine to carbon dioxide, ammonia, and a methylene group, in a multistep reaction (in [Nakai05]). The methylene group, carried by 5,10-methylenetetrahydropteroyl mono-L-glutamate, enters cellular one-carbon metabolism. In mammals, it is the primary pathway for glycine catabolism [Hampson83].
The glycine cleavage complex is composed of four different proteins: the P-protein (EC 22.214.171.124, glycine dehydrogenase (aminomethyl-transferring)); the T-protein (EC 126.96.36.199, aminomethyltransferase); the L-protein (EC 188.8.131.52, dihydrolipoyl dehydrogenase); and the H-protein (lipoyl-carrier protein, a non-enzyme that contains a lipoyl group that interacts successively with the three other components of the complex during the enzymatic reactions. The L-protein (also known as the E3 component) also participates in the pyruvate decarboxylation to acetyl CoA, the 2-oxoglutarate decarboxylation to succinyl-CoA, and the 2-oxoisovalerate decarboxylation to isobutanoyl-CoA multienzyme systems.
In plants, this complex is known as the glycine decarboxylase complex and functions in photorespiration. Its components from the mitochondria of Pisum sativum (pea) leaf have been extensively studied [Walker86] and reviewed in [Douce01]. In vertebrates, the components of the glycine cleavage complex from Gallus gallus (chicken) have been well studied [Kume91, OkamuraIkeda92, Yamamoto91].
The glycine cleavage complex is also present in bacteria as shown here for the Escherichia coli glycine cleavage system [Ghrist01]. In addition, components of the glycine cleavage complex have been characterized in archaea including the T-protein from Pyrococcus horikoshii [Lokanath04] and the L-protein from halophilic archaebacteria [Danson84, Jolley96] (although the role of the L-protein in glycine metabolism in halophiles is unclear [Jolley96]). In yeast, studies have been done on the regulation of genes encoding components of the glycine cleavage complex [Piper02].
In humans, non-ketotic hyperglycinemia results from deficiency-causing mutations in the genes encoding P-protein, or T-protein. This autosomal recessively inherited disorder results in accumulation of large amounts of glycine in body fluids such as plasma and cerebrospinal fluid, causing severe neurological symptoms [Kure06] and in [OkamuraIkeda05]. Mutations in gene DLD that encodes L-protein can result in lipoamide dehydrogenase deficiency, a disease with multiple physiological symptoms and significant morbidity [Shaag99].
Crystal structures of the components of the glycine cleavage complex have been determined from plant, animal, and bacterial sources. References include: P-protein [Nakai05], T-protein [Lokanath04, OkamuraIkeda05], L-protein [Faure00], and H-protein [Faure00].
The reactions of the glycine cleavage complex are reversible, and also provide a route for glycine biosynthesis (see MetaCyc pathway glycine biosynthesis II).
Superpathways: glycine biosynthesis II
Pathway Evidence Glyph:
Key to pathway glyph edge colors:
An enzyme catalyzing this reaction is present in this organism
An enzyme catalyzing this reaction was identified in this organism by the Pathway Hole Filler
The reaction and any enzyme that catalyzes it (if one has been identified) is unique to this pathway
Created in MetaCyc 08-Jul-1994 by Riley M , Marine Biological Laboratory
Revised in MetaCyc 11-Jan-2007 by Caspi R , SRI International
Revised in MetaCyc 31-Jan-2007 by Fulcher CA , SRI International
Imported from MetaCyc 08-Aug-2014 by Subhraveti P , SRI International
Faure00: Faure M, Bourguignon J, Neuburger M, MacHerel D, Sieker L, Ober R, Kahn R, Cohen-Addad C, Douce R (2000). "Interaction between the lipoamide-containing H-protein and the lipoamide dehydrogenase (L-protein) of the glycine decarboxylase multienzyme system 2. Crystal structures of H- and L-proteins." Eur J Biochem 267(10);2890-8. PMID: 10806386
Fries03: Fries M, Jung HI, Perham RN (2003). "Reaction mechanism of the heterotetrameric (alpha2beta2) E1 component of 2-oxo acid dehydrogenase multienzyme complexes." Biochemistry 42(23);6996-7002. PMID: 12795594
Jolley96: Jolley KA, Rapaport E, Hough DW, Danson MJ, Woods WG, Dyall-Smith ML (1996). "Dihydrolipoamide dehydrogenase from the halophilic archaeon Haloferax volcanii: homologous overexpression of the cloned gene." J Bacteriol 178(11);3044-8. PMID: 8655478
Kume91: Kume A, Koyata H, Sakakibara T, Ishiguro Y, Kure S, Hiraga K (1991). "The glycine cleavage system. Molecular cloning of the chicken and human glycine decarboxylase cDNAs and some characteristics involved in the deduced protein structures." J Biol Chem 266(5);3323-9. PMID: 1993704
Kure06: Kure S, Kato K, Dinopoulos A, Gail C, DeGrauw TJ, Christodoulou J, Bzduch V, Kalmanchey R, Fekete G, Trojovsky A, Plecko B, Breningstall G, Tohyama J, Aoki Y, Matsubara Y (2006). "Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia." Hum Mutat 27(4);343-52. PMID: 16450403
Lokanath04: Lokanath NK, Kuroishi C, Okazaki N, Kunishima N (2004). "Purification, crystallization and preliminary crystallographic analysis of the glycine-cleavage system component T-protein from Pyrococcus horikoshii OT3." Acta Crystallogr D Biol Crystallogr 60(Pt 8);1450-2. PMID: 15272174
Milne02: Milne JL, Shi D, Rosenthal PB, Sunshine JS, Domingo GJ, Wu X, Brooks BR, Perham RN, Henderson R, Subramaniam S (2002). "Molecular architecture and mechanism of an icosahedral pyruvate dehydrogenase complex: a multifunctional catalytic machine." EMBO J 21(21);5587-98. PMID: 12411477
Nakai05: Nakai T, Nakagawa N, Maoka N, Masui R, Kuramitsu S, Kamiya N (2005). "Structure of P-protein of the glycine cleavage system: implications for nonketotic hyperglycinemia." EMBO J 24(8);1523-36. PMID: 15791207
OkamuraIkeda05: Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H (2005). "Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia." J Mol Biol 351(5);1146-59. PMID: 16051266
OkamuraIkeda92: Okamura-Ikeda K, Fujiwara K, Motokawa Y (1992). "Molecular cloning of a cDNA encoding chicken T-protein of the glycine cleavage system and expression of the functional protein in Escherichia coli. Effect of mRNA secondary structure in the translational initiation region on expression." J Biol Chem 267(26);18284-90. PMID: 1526969
Piper02: Piper MD, Hong SP, Eissing T, Sealey P, Dawes IW (2002). "Regulation of the yeast glycine cleavage genes is responsive to the availability of multiple nutrients." FEMS Yeast Res 2(1);59-71. PMID: 12702322
Shaag99: Shaag A, Saada A, Berger I, Mandel H, Joseph A, Feigenbaum A, Elpeleg ON (1999). "Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews." Am J Med Genet 82(2);177-82. PMID: 9934985
Walker86: Walker JL, Oliver DJ (1986). "Glycine decarboxylase multienzyme complex. Purification and partial characterization from pea leaf mitochondria." J Biol Chem 1986;261(5);2214-21. PMID: 3080433
Yamamoto91: Yamamoto M, Koyata H, Matsui C, Hiraga K (1991). "The glycine cleavage system. Occurrence of two types of chicken H-protein mRNAs presumably formed by the alternative use of the polyadenylation consensus sequences in a single exon." J Biol Chem 266(5);3317-22. PMID: 1993703
Zhou01: Zhou ZH, McCarthy DB, O'Connor CM, Reed LJ, Stoops JK (2001). "The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes." Proc Natl Acad Sci U S A 98(26);14802-7. PMID: 11752427
Jabrin03: Jabrin S, Ravanel S, Gambonnet B, Douce R, Rebeille F (2003). "One-carbon metabolism in plants. Regulation of tetrahydrofolate synthesis during germination and seedling development." Plant Physiol 131(3);1431-9. PMID: 12644692
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