The Enzyme Database

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Accepted name: peptidyl-glutamate 4-carboxylase
Reaction: peptidyl-4-carboxyglutamate + 2,3-epoxyphylloquinone + H2O = peptidyl-glutamate + CO2 + O2 + phylloquinol
For diagram of the vitamin K cycle, click here
Other name(s): vitamin K-dependent carboxylase; γ-glutamyl carboxylase; peptidyl-glutamate 4-carboxylase (2-methyl-3-phytyl-1,4-naphthoquinone-epoxidizing)
Systematic name: peptidyl-glutamate 4-carboxylase (2-methyl-3-phytyl-1,4-naphthoquinol-epoxidizing)
Comments: The enzyme can use various vitamin-K derivatives, including menaquinol, but does not contain iron. The mechanism appears to involve the generation of a strong base by oxygenation of vitamin K. It catalyses the post-translational carboxylation of glutamate residues of several proteins of the blood-clotting system. 9–12 glutamate residues are converted to 4-carboxyglutamate (Gla) in a specific domain of the target protein. The 4-pro-S hydrogen of the glutamate residue is removed [5] and there is an inversion of stereochemistry at this position [6].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
1.  Dowd, P., Hershline, R., Ham, S.W. and Naganathan, S. Vitamin K and energy transduction: a base strength amplification mechanism. Science 269 (1995) 1684–1691. [PMID: 7569894]
2.  Furie, B., Bouchard, B.A. and Furie, B.C. Vitamin K-dependent biosynthesis of γ-carboxyglutamic acid. Blood 93 (1999) 1798–1808. [PMID: 10068650]
3.  Rishavy, M.A., Hallgren, K.W., Yakubenko, A.V., Shtofman, R.L., Runge, K.W. and Berkner, K.L. Bronsted analysis reveals Lys218 as the carboxylase active site base that deprotonates vitamin K hydroquinone to initiate vitamin K-dependent protein carboxylation. Biochemistry 45 (2006) 13239–13248. [PMID: 17073445]
4.  Silva, P.J. and Ramos, M.J. Reaction mechanism of the vitamin K-dependent glutamate carboxylase: a computational study. J. Phys. Chem. B 111 (2007) 12883–12887. [PMID: 17935315]
5.  Decottignies-Le Maréchal, P., Ducrocq, C., Marquet, A. and Azerad, R. The stereochemistry of hydrogen abstraction in vitamin K-dependent carboxylation. J. Biol. Chem. 259 (1984) 15010–15012. [PMID: 6150930]
6.  Dubois, J., Dugave, C., Foures, C., Kaminsky, M., Tabet, J.C., Bory, S., Gaudry, M. and Marquet, A. Vitamin K dependent carboxylation: determination of the stereochemical course using 4-fluoroglutamyl-containing substrate. Biochemistry 30 (1991) 10506–10512. [PMID: 1931973]
7.  Rishavy, M.A. and Berkner, K.L. Vitamin K oxygenation, glutamate carboxylation, and processivity: defining the three critical facets of catalysis by the vitamin K-dependent carboxylase. Adv Nutr 3 (2012) 135–148. [PMID: 22516721]
[EC created 2009, modified 2011]

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