Glutamyl carboxylase

FIGURE 18.40 The glutamyl carboxylase reaction is vitamin K-dependent. This enzyme activity is essential for the formation of 7-car-boxyglutamyl residues in several proteins of the blood-clotting cascade (Figure 15.5), accounting for the vitamin K dependence of coagulation. 

BIFUNCTIONAL ENZYME GLUTAMINYL-tRNA SYNTHETASE AMINOACYL-tRNA SYNTHETASES y-Glutamyl carboxylase,... 

VISCOSITY COEFFICIENT VITAMIN A GROUP VITAMIN D GROUP VITAMIN D 25-HYDROXYLASE VITAMIN K-DEPENDENT y-GLUTAMYL CARBOXYLASE... 

Shikata E, leiri I, Ishiguru S, et al. Association of pharmacokinetics (CYP2C9) and pharmacodynamics (factors II, VII, IX, and X protein S and C and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004 103 2630-2635. 

Mutucumarana VP, Stafford DW, Stanley TB, Jin DY, Solera J, Brenner B, Azerad R, and Wu SM (2000) Expression and characterization of the naturally occurring mutation L394R in human gamma-glutamyl carboxylase. Journal of Biological Chemistry 275, 32572-7. 

Chen LY, Eriksson N, Gwilliam R, et al. Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing. Blood 200.5 106( I ()) 3673 4. 

Kimura R, Miyashita K, Kokubo Y, et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res 2007 120(2) 181—6. 

In bone, a CaBP called osteocalcin contains 49 amino acids (M.W. 5500-6000). Its synthesis is stimulated by 1,25-(0H)2D. Osteocalcin contains four residues of y-carboxyglutamic acid, which require vitamin K for their synthesis and are important as binding sites for calcium (Chapter 36). Although vitamin K deficiency reduces the osteocalcin content of bone, it does not cause functional bone defects. For this reason, osteocalcin may function in calcium mobilization rather than deposition. Alternatively, as an effective inhibitor of hydroxyapatite formation, it may prevent overmineralization of bone. 1,25-(OH)2D increases y-glutamyl carboxylase activity in the renal cortex. The relationship between vitamin D and vitamin K needs clarification. 

FIGURE 54-6 The vitamin K cycle y-glutamyl carboxy lotion of vitamin K-dependentpr( eins. The enzyme -glutamyl carboxylase couples the oxidation of the reduced hydroquinone form (KH2) of vitamin Kj or K2, to -carboxylation of Glu residues on vitamin K-dependent proteins, generating the epoxide of vitamin K (KO) and 7-carboxyglutamate (Gla) residues in vitamin K-dependent precursor proteins in the endoplasmic reticulum. A 2,3-epoxide reductase regenerates vitamin KH2 and is the warfarin-sensitive step. The R on tiie vitamin K molecule represents a 20-carbon phytyl side chain in vitamin and a 5- to 65-carbon prenyl side chain in vitamin K2. 

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