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
Orthologs
SpeciesHumanMouse
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 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

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.[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

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
2O

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

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

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. 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

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