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GGCX
Identifiers
Aliases	GGCX, VKCFD1, gamma-glutamyl carboxylase, Gamma-glutamyl carboxylase; GGCX
External IDs	OMIM: 137167; MGI: 1927655; HomoloGene: 639; GeneCards: GGCX; OMA:GGCX - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2p11.2 Start 85,544,720 bp End 85,561,532 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell tendon of biceps brachii liver right lobe of liver endothelial cell stromal cell of endometrium internal globus pallidus saphenous vein body of pancreas parotid gland n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function gamma-glutamyl carboxylase activity lyase activity Cellular component integral component of membrane endoplasmic reticulum membrane membrane endoplasmic reticulum Biological process peptidyl-glutamic acid carboxylation blood coagulation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2677 56316 Ensembl ENSG00000115486 ENSMUSG00000053460 UniProt P38435 Q9QYC7 RefSeq (mRNA) NM_000821 NM_001142269 NM_001311312 NM_019802 RefSeq (protein) NP_000812 NP_001135741 NP_001298241 NP_062776 Location (UCSC) Chr 2: 85.54 – 85.56 Mb n/a PubMed search
Wikidata
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Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the GGCX gene, located on chromosome 2 at 2p12.

Function

Gamma-glutamyl carboxylase is an enzyme that catalyzes the posttranslational modification of vitamin K-dependent proteins. Many of these vitamin K-dependent proteins are involved in coagulation so the function of the encoded enzyme is essential for hemostasis. Most gla domain-containing proteins depend on this carboxylation reaction for posttranslational modification. In humans, the gamma-glutamyl carboxylase enzyme is most highly expressed in the liver.

Catalytic reaction

Gamma-glutamyl carboxylase oxidizes vitamin K hydroquinone to Vitamin K-2,3-epoxide, while simultaneously adding CO₂ to protein-bound glutamic acid (abbreviation = Glu) to form gamma-carboxyglutamic acid (also called gamma-carboxyglutamate, abbreviation = Gla). Presence of two carboxylate groups causes chelation of Ca, resulting in change in tertiary structure of protein and its activation. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions.

No experimental structure is known for GGCX, limiting understanding of its reaction mechanism. Based on the fact that the two reactions are coupled, a computational study is able to propose how the reactants interact with each other to form the products. Lys228 has been shown to be the residue responsible for starting the reaction. How the enzyme holds the reactants in place to have them interact with each other remains poorly shown. 491-507 and 395-401 are probably responsible for propeptide and glutamate binding respectively.

Clinical significance

Mutations in this gene are associated with vitamin K-dependent coagulation defect and PXE-like disorder with multiple coagulation factor deficiency.

See also

• Carboxyglutamate

References

1. ^ GRCh38: Ensembl release 89: ENSG00000115486 – 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. Wu SM, Cheung WF, Frazier D, Stafford DW (December 1991). "Cloning and expression of the cDNA for human gamma-glutamyl carboxylase". Science. 254 (5038): 1634–6. Bibcode:1991Sci...254.1634W. doi:10.1126/science.1749935. PMID 1749935.
5. ^ "Entrez Gene: GGCX".
6. Brenner B, Tavori S, Zivelin A, Keller CB, Suttie JW, Tatarsky I, Seligsohn U (August 1990). "Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants". Br. J. Haematol. 75 (4): 537–42. doi:10.1111/j.1365-2141.1990.tb07795.x. PMID 2145029. S2CID 24679257.
7. Suttie JW (1985). "Vitamin K-dependent carboxylase". Annu. Rev. Biochem. 54 (1): 459–77. doi:10.1146/annurev.bi.54.070185.002331. PMID 3896125.
8. Presnell SR, Stafford DW (2002). "The vitamin K-dependent carboxylase". Thromb. Haemost. 87 (6): 937–46. doi:10.1055/s-0037-1613115. PMID 12083499. S2CID 27634025.
9. Silva PJ, Ramos MJ (2007). "Reaction mechanism of the vitamin K-dependent glutamate carboxylase: a computational study". J Phys Chem B. 111 (44): 12883–7. doi:10.1021/jp0738208. PMID 17935315.
10. Rishavy MA, Hallgren KW, Yakubenko AV, Shtofman RL, Runge KW, Berkner KL (7 November 2006). "Brønsted analysis reveals Lys218 as the carboxylase active site base that deprotonates vitamin K hydroquinone to initiate vitamin K-dependent protein carboxylation". Biochemistry. 45 (44): 13239–48. doi:10.1021/bi0609523. PMID 17073445.
11. Parker CH, Morgan CR, Rand KD, Engen JR, Jorgenson JW, Stafford DW (11 March 2014). "A conformational investigation of propeptide binding to the integral membrane protein γ-glutamyl carboxylase using nanodisc hydrogen exchange mass spectrometry". Biochemistry. 53 (9): 1511–20. doi:10.1021/bi401536m. PMC 3970815. PMID 24512177.
12. Vanakker OM, Martin L, Gheduzzi D, Leroy BP, Loeys BL, Guerci VI, Matthys D, Terry SF, Coucke PJ, Pasquali-Ronchetti I, De Paepe A (March 2007). "Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity". J. Invest. Dermatol. 127 (3): 581–7. doi:10.1038/sj.jid.5700610. PMID 17110937.

Further reading

• Bandyopadhyay PK (2008). "Vitamin K-dependent gamma-glutamylcarboxylation: an ancient posttranslational modification". Vitam. Horm. Vitamins & Hormones. 78: 157–84. doi:10.1016/S0083-6729(07)00008-8. ISBN 9780123741134. PMID 18374194.
• Berkner KL (2008). "Vitamin K-dependent carboxylation". Vitam. Horm. Vitamins & Hormones. 78: 131–56. doi:10.1016/S0083-6729(07)00007-6. ISBN 9780123741134. PMID 18374193.
• Oldenburg J, Marinova M, Müller-Reible C, Watzka M (2008). "The vitamin K cycle". Vitam. Horm. Vitamins & Hormones. 78: 35–62. doi:10.1016/S0083-6729(07)00003-9. ISBN 9780123741134. PMID 18374189.
• Berkner KL (2005). "The vitamin K-dependent carboxylase". Annu. Rev. Nutr. 25 (1): 127–49. doi:10.1146/annurev.nutr.25.050304.092713. PMID 16011462.
• Zhang B, Ginsburg D (September 2004). "Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders". J. Thromb. Haemost. 2 (9): 1564–72. doi:10.1111/j.1538-7836.2004.00857.x. hdl:2027.42/74529. PMID 15333032. S2CID 7437035.
• Wallin R, Hutson SM (July 2004). "Warfarin and the vitamin K-dependent gamma-carboxylation system". Trends Mol Med. 10 (7): 299–302. doi:10.1016/j.molmed.2004.05.003. PMID 15242675.
• Berkner KL (August 2000). "The vitamin K-dependent carboxylase". J. Nutr. 130 (8): 1877–80. doi:10.1093/jn/130.8.1877. PMID 10917896.
• Presnell SR, Stafford DW (June 2002). "The vitamin K-dependent carboxylase". Thromb. Haemost. 87 (6): 937–46. doi:10.1055/s-0037-1613115. PMID 12083499. S2CID 27634025.
• Bender, David A. (2003). Nutritional biochemistry of the vitamins. Cambridge, UK: Cambridge University Press. ISBN 0-521-80388-8.
• Ball, George E. (2004). Vitamins: their role in the human body. Oxford: Blackwell Science. ISBN 0-632-06478-1.
• Combs, Gerald F. (1998). The vitamins: fundamental aspects in nutrition and health. Boston: Academic Press. ISBN 0-12-183492-1.

External links

• glutamyl+carboxylase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

• Biology

• Genes on human chromosome 2
• EC 6.4