Y-carboxyglutamate

Hydroxylated amino acids (eg, 4-hydroxyproline, 5-hydroxylysine) and A/-methylated amino acids (eg, /V-methylhistidine) are obtained by the acid hydrolysis of proteins. y-Carboxyglutamic acid occurs as a component of some sections of protein molecules it decarboxylates spontaneously to L-glutamate at low pH. These examples are formed upon the nontranslational modification of protein and are often called secondary protein amino acids... 

Aminoadipic acid y-Carboxyglutamic acid Pyroglutatnic acid Phosphoserine Phospho threonine Phospho tyrosine... 

Anticoagulants. Figure 2 Coumarin (Warfarin) and the vitamin K cycle. Abbreviations glu, glutamate gla, y-carboxyglutamate. (Modified from [2], with permission from Chest.)... 

K Phylloquinone, menaquinones Coenzyme in formation of y-carboxyglutamate in enzymes of blood clotting and bone matrix Impaired blood clotting, hemorrhagic disease... 

Prothrombin and several other proteins of the blood clotting system (Factors VII, IX and X, and proteins C and S) each contain between four and six y-carboxygluta-mate residues which chelate calcium ions and so permit the binding of the blood clotting proteins to membranes. In vitamin K deficiency or in the presence of warfarin, an abnormal precursor of prothrombin (preprothrombin) containing little or no y-carboxyglutamate, and incapable of chelating calcium, is released into the circulation. 

Osteocalcin (bone Gla protein) Contains y-carboxyglutamate residues that bind to hydroxyapatite. Bone-specific. 

Protein S Acts as a cofactor of protein C both proteins contain Gla (y-carboxyglutamate) residues. 

Factor XIa in the presence of activates factor IX (55 kDa, a zymogen containing vitamin K-dependent y-carboxyglutamate [Gla] residues see Chapter 45), to the serine protease, factor IXa. This in turn cleaves an Arg-Ile bond in factor X (56 kDa) to produce the two-chain serine protease, factor Xa. This latter reaction requires the assembly of components, called the tenase... 

Figure 2.11 y-Carboxylation of glutamate residues (Glu) yields y-carboxyglutamate (Gla), whereas (3-hydroxy lation of aspartate (Asp) yields (3-hydroxyaspartate (Hya) and (3-hydroxylation of asparagine (Asn) yields 3-hydroxyasparagine (Hyn)... 

Prothrombin (factor II) is a 582 amino acid, 72.5 kDa glycoprotein, which represents the circulating zymogen of thrombin (Ha). It contains up to six y-carboxyglutamate residues towards its N-terminal end, via which it binds several Ca2+ ions. Binding of Ca2+ facilitates prothrombin binding to factor Xa at the site of vascular injury. The factor Xa complex then proteolytically... 

Asp-M Monodentate Asp-M Bidentate, chelating Asp-M Bidentate, bridging y-Carboxyglutamate... 

Figure 3.1 Principal protein amino acid side-chain metal-ion binding modes (the metal ion represented as a dark filled circle) and (right) the structure of the Ca2+-binding y-carboxyglutamate found in proteins of the blood-clotting cascade.

Vitamin K is a component of the carboxylase enzyme that carboxylates the amino acid glutamate in proteins to form y-carboxyglutamate, which binds calcium ions i.e. it catalyses a post-transcriptional modification. Proteins so carboxylated include clotting factors (Factors 11, Vll, IX, and X) and two proteins in bone oesteocalcin (known as matrix-gln-protein) and bone gin protein (BGP). The... 

The mechanism of action of warfarin becomes apparent from the molecular details of the blood clotting process. The clotting factors VII, IX, and X require Ca ions for maximum activity. These proteins possess a novel amino acid which binds Ca ions. It is a modified form of the amino acid glutamate, as y-carboxyglutamate (Gla) which possesses two... 

C2 domains, 46 460-465 y-carboxyglutamic acid sites, 46 465 70 Calcium nitrate, preparation of, 6 125 Calcium pentaphosphate, 4 37-38 Calcium phthalocyanine, preparation of, 7 ... 

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