GCSH
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGCSH, GCE, NKH, glycine cleavage system protein H
External IDsOMIM: 238330 MGI: 1915383 HomoloGene: 90880 GeneCards: GCSH
Orthologs
SpeciesHumanMouse
Entrez

2653

68133

Ensembl

ENSG00000140905

ENSMUSG00000034424

UniProt

P23434

Q91WK5

RefSeq (mRNA)

NM_004483

NM_026572

RefSeq (protein)

NP_004474

NP_080848

Location (UCSC)Chr 16: 81.08 – 81.1 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Glycine cleavage system H protein, mitochondrial (abbreviated as GCSH) is a protein that in humans is encoded by the GCSH gene.[4][5][6] Degradation of glycine is brought about by the glycine cleavage system (GCS), which is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein; this protein), T protein (a tetrahydrofolate-requiring aminomethyltransferase enzyme), and L protein (a lipoamide dehydrogenase).[6] The H protein shuttles the methylamine group of glycine from the P protein to the T protein. The protein encoded by GCSH gene is the H protein, which transfers the methylamine group of glycine from the P protein to the T protein.[7] Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[8] Two transcript variants, one protein-coding and the other probably not protein-coding, have been found for this gene. Also, several transcribed and non-transcribed pseudogenes of this gene exist throughout the genome.[9]

Function

The glycine cleavage system (GCS) is the major physiological pathway for glycine degradation in mammals and is confined to mitochondria of the liver, kidney, small intestine, pituitary, thyroid glands, and brain.[10] The P-protein is a pyridoxal phosphate-dependent glycine decarboxylase that transfers the methylamine moiety of glycine to one of the thiol groups in the lipoyl component of H-protein, a hydrogen-carrier protein and the second component of the complex. The T-protein catalyzes the release of ammonia and transfer of the one-carbon fragment from the intermediate lipoyl residue to tetrahydrofolate, while the L-protein, a lipoamide dehydrogenase, catalyzes the oxidation of the dihydrolipoyl residue of H-protein and reduction of NAD.[11]

Structure

Gene

Human GCSH gene has 5 exons spanning 13.5kb and resides on chromosome 16 at q23.2.[7]

Protein

The GCSH is a heat-stable small protein with a covalently attached lipoic acid prosthetic group which interacts with the three enzymes during the catalysis. The chemically determined amino acid sequence revealed that chicken H-protein is composed of 125 amino acids with a lipoic acid prosthetic group at lysine 59 (Lys59).[5] Because of its restricted tissue expression in humans, H-protein purified from chicken liver has been routinely used for the assay.[12] The H-protein comprises a mitochondrial targeting sequence and a mature mitochondrial matrix protein sequence. Its activation in vivo requires the attachment of a lipoic acid prosthetic group at Lys59 of the mature protein.[7] The matrix protein sequence is highly conserved and chicken H-protein has 85.6% amino acid sequence similarity to the human form.[13]

Clinical significance

Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism caused by deficiency in the glycine cleavage system (GCS).[14] Enzymatic analysis has identified three metabolic lesions in NKH, deficiencies of P-, T-, and H-proteins.[9] The first mutation identified in NKH was in the P-protein gene.[15] Subsequently, some patients were found to have mutations in the T-protein gene.[16] The structure, polymorphism, and expression of GCSH could facilitate the molecular analysis of patients with variant forms of NKH that are caused by H-protein deficiency.[7]

Interactions

GCSH has been shown to interact with the other glycine cleavage system protein components: P protein, T protein and L protein.[7][9]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000140905 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ Koyata H, Hiraga K (Feb 1991). "The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias". American Journal of Human Genetics. 48 (2): 351–61. PMC 1683031. PMID 1671321.
  5. 1 2 Fujiwara K, Okamura-Ikeda K, Hayasaka K, Motokawa Y (Apr 1991). "The primary structure of human H-protein of the glycine cleavage system deduced by cDNA cloning". Biochemical and Biophysical Research Communications. 176 (2): 711–6. doi:10.1016/S0006-291X(05)80242-6. PMID 2025283.
  6. 1 2 "Entrez Gene: GCSH glycine cleavage system protein H (aminomethyl carrier)".
  7. 1 2 3 4 5 Kure S, Kojima K, Kudo T, Kanno K, Aoki Y, Suzuki Y, Shinka T, Sakata Y, Narisawa K, Matsubara Y (2001). "Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia". Journal of Human Genetics. 46 (7): 378–84. doi:10.1007/s100380170057. PMID 11450847.
  8. ↑ Kikuchi G (Jun 1973). "The glycine cleavage system: composition, reaction mechanism, and physiological significance". Molecular and Cellular Biochemistry. 1 (2): 169–87. doi:10.1007/bf01659328. PMID 4585091. S2CID 22516474.
  9. 1 2 3 Zay A, Choy FY, Patrick C, Sinclair G (Jun 2011). "Glycine cleavage enzyme complex: molecular cloning and expression of the H-protein cDNA from cultured human skin fibroblasts". Biochemistry and Cell Biology. 89 (3): 299–307. doi:10.1139/o10-156. PMID 21539457.
  10. ↑ Kikuchi G, Motokawa Y, Yoshida T, Hiraga K (2008). "Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia". Proceedings of the Japan Academy, Series B. 84 (7): 246–63. Bibcode:2008PJAB...84..246K. doi:10.2183/pjab.84.246. PMC 3666648. PMID 18941301.
  11. ↑ Hiraga K, Kure S, Yamamoto M, Ishiguro Y, Suzuki T (Mar 1988). "Cloning of cDNA encoding human H-protein, a constituent of the glycine cleavage system". Biochemical and Biophysical Research Communications. 151 (2): 758–62. doi:10.1016/s0006-291x(88)80345-0. PMID 3348809.
  12. ↑ Fujiwara K, Okamura-Ikeda K, Motokawa Y (Jul 1986). "Chicken liver H-protein, a component of the glycine cleavage system. Amino acid sequence and identification of the N epsilon-lipoyllysine residue". The Journal of Biological Chemistry. 261 (19): 8836–41. doi:10.1016/S0021-9258(19)84457-5. PMID 3522581.
  13. ↑ Choy F, Sharp L, Applegarth DA (2000). "Glycine cleavage enzyme complex: rabbit H-protein cDNA sequence analysis and comparison to human, cow, and chicken". Biochemistry and Cell Biology. 78 (6): 725–30. doi:10.1139/bcb-78-6-725. PMID 11206584.
  14. ↑ Tada K, Narisawa K, Yoshida T, Konno T, Yokoyama Y (Jul 1969). "Hyperglycinemia: a defect in glycine cleavage reaction". The Tohoku Journal of Experimental Medicine. 98 (3): 289–96. doi:10.1620/tjem.98.289. PMID 5307488.
  15. ↑ Kure S, Narisawa K, Tada K (Feb 1991). "Structural and expression analyses of normal and mutant mRNA encoding glycine decarboxylase: three-base deletion in mRNA causes nonketotic hyperglycinemia". Biochemical and Biophysical Research Communications. 174 (3): 1176–82. doi:10.1016/0006-291x(91)91545-n. PMID 1996985.
  16. ↑ Kure S, Mandel H, Rolland MO, Sakata Y, Shinka T, Drugan A, Boneh A, Tada K, Matsubara Y, Narisawa K (Apr 1998). "A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia". Human Genetics. 102 (4): 430–4. doi:10.1007/s004390050716. PMID 9600239. S2CID 20224399.

Further reading

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