Gamma-glutamyl carboxylase

Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the GGCX gene, located on chromosome 2 at 2p12.[4]

GGCX
Identifiers
AliasesGGCX, VKCFD1, gamma-glutamyl carboxylase, Gamma-glutamyl carboxylase; GGCX
External IDsOMIM: 137167; MGI: 1927655; HomoloGene: 639; GeneCards: GGCX; OMA:GGCX - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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.[5] Most gla domain-containing proteins depend on this carboxylation reaction for posttranslational modification.[6] In humans, the gamma-glutamyl carboxylase enzyme is most highly expressed in the liver.

Catalytic reaction

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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 Ca2 , 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.[7][8]

 
a [protein]-α-L-glutamate (Glu) phylloquinol (KH
2
) CO
2
oxygen → a [protein] 4-carboxy-L-glutamate (Gla) vitamin K 2,3-epoxide (KO) H
H
2
O

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.[9] Lys228 has been shown to be the residue responsible for starting the reaction.[10] 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.[11]

Clinical significance

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Mutations in this gene are associated with vitamin K-dependent coagulation defect and PXE-like disorder with multiple coagulation factor deficiency.[5][12]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000115486Ensembl, 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 1749935.1634-6&rft.date=1991-12&rft_id=info:pmid/1749935&rft_id=info:doi/10.1126/science.1749935&rft_id=info:bibcode/1991Sci...254.1634W&rft.aulast=Wu&rft.aufirst=SM&rft.au=Cheung, WF&rft.au=Frazier, D&rft.au=Stafford, DW&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  5. ^ a b "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 24679257.537-42&rft.date=1990-08&rft_id=https://api.semanticscholar.org/CorpusID:24679257#id-name=S2CID&rft_id=info:pmid/2145029&rft_id=info:doi/10.1111/j.1365-2141.1990.tb07795.x&rft.aulast=Brenner&rft.aufirst=B&rft.au=Tavori, S&rft.au=Zivelin, A&rft.au=Keller, CB&rft.au=Suttie, JW&rft.au=Tatarsky, I&rft.au=Seligsohn, U&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  7. ^ Suttie JW (1985). "Vitamin K-dependent carboxylase". Annu. Rev. Biochem. 54 (1): 459–77. doi:10.1146/annurev.bi.54.070185.002331. PMID 3896125.459-77&rft.date=1985&rft_id=info:doi/10.1146/annurev.bi.54.070185.002331&rft_id=info:pmid/3896125&rft.au=Suttie JW&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  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 27634025.937-46&rft.date=2002&rft_id=https://api.semanticscholar.org/CorpusID:27634025#id-name=S2CID&rft_id=info:pmid/12083499&rft_id=info:doi/10.1055/s-0037-1613115&rft.aulast=Presnell&rft.aufirst=SR&rft.au=Stafford, DW&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  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 17935315.12883-7&rft.date=2007&rft_id=info:doi/10.1021/jp0738208&rft_id=info:pmid/17935315&rft.aulast=Silva&rft.aufirst=PJ&rft.au=Ramos, MJ&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  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 17073445.13239-48&rft.date=2006-11-07&rft_id=info:doi/10.1021/bi0609523&rft_id=info:pmid/17073445&rft.aulast=Rishavy&rft.aufirst=MA&rft.au=Hallgren, KW&rft.au=Yakubenko, AV&rft.au=Shtofman, RL&rft.au=Runge, KW&rft.au=Berkner, KL&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  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 24512177.1511-20&rft.date=2014-03-11&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970815#id-name=PMC&rft_id=info:pmid/24512177&rft_id=info:doi/10.1021/bi401536m&rft.aulast=Parker&rft.aufirst=CH&rft.au=Morgan, CR&rft.au=Rand, KD&rft.au=Engen, JR&rft.au=Jorgenson, JW&rft.au=Stafford, DW&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970815&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  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 17110937.581-7&rft.date=2007-03&rft_id=info:doi/10.1038/sj.jid.5700610&rft_id=info:pmid/17110937&rft.aulast=Vanakker&rft.aufirst=OM&rft.au=Martin, L&rft.au=Gheduzzi, D&rft.au=Leroy, BP&rft.au=Loeys, BL&rft.au=Guerci, VI&rft.au=Matthys, D&rft.au=Terry, SF&rft.au=Coucke, PJ&rft.au=Pasquali-Ronchetti, I&rft.au=De Paepe, A&rft_id=https://doi.org/10.1038%2Fsj.jid.5700610&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">

Further reading

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  • 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 18374194.157-84&rft.date=2008&rft_id=info:pmid/18374194&rft_id=info:doi/10.1016/S0083-6729(07)50008-8&rft.isbn=9780123741134&rft.au=Bandyopadhyay PK&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  • 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 18374193.131-56&rft.date=2008&rft_id=info:pmid/18374193&rft_id=info:doi/10.1016/S0083-6729(07)50007-6&rft.isbn=9780123741134&rft.au=Berkner KL&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  • 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 18374189.35-62&rft.date=2008&rft_id=info:pmid/18374189&rft_id=info:doi/10.1016/S0083-6729(07)50003-9&rft.isbn=9780123741134&rft.aulast=Oldenburg&rft.aufirst=J&rft.au=Marinova, M&rft.au=Müller-Reible, C&rft.au=Watzka, M&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  • Berkner KL (2005). "The vitamin K-dependent carboxylase". Annu. Rev. Nutr. 25 (1): 127–49. doi:10.1146/annurev.nutr.25.050304.092713. PMID 16011462.127-49&rft.date=2005&rft_id=info:doi/10.1146/annurev.nutr.25.050304.092713&rft_id=info:pmid/16011462&rft.au=Berkner KL&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  • 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 7437035.1564-72&rft.date=2004-09&rft_id=info:hdl/2027.42/74529&rft_id=https://api.semanticscholar.org/CorpusID:7437035#id-name=S2CID&rft_id=info:pmid/15333032&rft_id=info:doi/10.1111/j.1538-7836.2004.00857.x&rft.aulast=Zhang&rft.aufirst=B&rft.au=Ginsburg, D&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  • 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 15242675.299-302&rft.date=2004-07&rft_id=info:doi/10.1016/j.molmed.2004.05.003&rft_id=info:pmid/15242675&rft.aulast=Wallin&rft.aufirst=R&rft.au=Hutson, SM&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  • Berkner KL (August 2000). "The vitamin K-dependent carboxylase". J. Nutr. 130 (8): 1877–80. doi:10.1093/jn/130.8.1877. PMID 10917896.1877-80&rft.date=2000-08&rft_id=info:doi/10.1093/jn/130.8.1877&rft_id=info:pmid/10917896&rft.au=Berkner KL&rft_id=https://doi.org/10.1093%2Fjn%2F130.8.1877&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  • 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 27634025.937-46&rft.date=2002-06&rft_id=https://api.semanticscholar.org/CorpusID:27634025#id-name=S2CID&rft_id=info:pmid/12083499&rft_id=info:doi/10.1055/s-0037-1613115&rft.aulast=Presnell&rft.aufirst=SR&rft.au=Stafford, DW&rfr_id=info:sid/en.wikipedia.org:Gamma-glutamyl carboxylase" class="Z3988">
  • 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.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.