Gamma-glutamyl carboxylase explained

Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the GGCX gene, located on chromosome 2 at 2p12.^[1]

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.^[2] Most gla domain-containing proteins depend on this carboxylation reaction for posttranslational modification.^[3] 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.^{[4] [5]}

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.^[6] Lys228 has been shown to be the residue responsible for starting the reaction.^[7] 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.^[8]

Clinical significance

Mutations in this gene are associated with vitamin K-dependent coagulation defect and PXE-like disorder with multiple coagulation factor deficiency.^{[2] [9]}

See also

• Carboxyglutamate

Further reading

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

Notes and References

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