Prothrombin, amino acid

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... 

Figure 12.5 Proteolytic cleavage of prothrombin by factor Xa, yielding active thrombin. Although prothrombin is a single-chain glycoprotein, thrombin consists of two polypeptides linked by what was originally the prothrombin intrachain disulfide bond. The smaller thrombin polypeptide fragment consists of 49 amino acid residues, and the large polypeptide chain contains 259 amino acids. The N-terminal fragment released from prothrombin contains 274 amino acid residues. Activation of prothrombin by Xa does not occur in free solution, but at the site of vascular damage...

Coumarins are competitive inhibitors of vitamin K, which is required for the formation in the liver of the amino acid, gamma-carboxyglutamic acid. This is necessary for the synthesis of prothrombin and factors VII, IX and X (Figure 17.1). After starting treatment the anticoagulant effect is delayed until the concentration of normal coagulation factors falls (36-72 h). The effects can be reversed by vitamin K (slow maximum effect only after 3-6 h) or by whole blood or plasma (fast). Gut bacteria synthesise vitamin K and thus are an important source of this vitamin. Consequently, antibiotics can cause excessive prolongation of the prothrombin time in patients otherwise adequately controlled on warfarin. 

II Prothrombin (Ila is thrombin) MW 66 kD, 582 amino acids with 12 disulfide... 

In addition to the 20 common amino acids, proteins may contain residues created by modification of common residues already incorporated into a polypeptide (Fig. 3-8a). Among these uncommon amino acids are 4-hydroxyproline, a derivative of proline, and 5-hydroxylysine, derived from lysine. The former is found in plant cell wall proteins, and both are found in collagen, a fibrous protein of connective tissues. 6-N-Methyllysine is a constituent of myosin, a contractile protein of muscle. Another important uncommon amino acid is y-carboxyglutamate, found in the bloodclotting protein prothrombin and in certain other proteins that bind Ca2+ as part of their biological function. More complex is desmosine, a derivative of four Lys residues, which is found in the fibrous protein elastin. 

The most obvious effect of a deficiency in vitamin K in animals is delayed blood clotting, which has been traced to a decrease in the activity of prothrombin and of clotting factors VII, IX, and X (Chapter 12, Fig. 12-17). Prothrombin formed by the liver in the absence of vitamin K lacks the ability to chelate calcium ions essential for the binding of prothrombin to phospholipids and to its activation to thrombin. The structural differences between this abnormal protein and the normal prothrombin have been pinpointed at the N terminus of the 560 residue glycoprotein.e f Tryptic peptides from the N termini differed in electrophoretic mobility. As detailed in Chapter 12, ten residues within the first 33, which were identified as glutamate residues by the sequence analysis on normal prothrombin, are actually y-carboxyglutamate (Gla). The same amino acid is present near the N termini of clotting factors VII, IX, and X. 

Compounds with vitamin K activity (Table 6.2) are required in our diets for y-carboxyglutamate biosynthesis (Table 4.1). This amino acid is produced from certain protein glutamyl residues by carboxylation. Proteins that contain y-carboxyglutamate are blood prothrombin and coagulation factors VII, IX, and X (see Chapter 7). Other proteins of this type are osteocalcin from bone and several kidney and muscle calcium-binding proteins. 

Figure 10.43. The Calcium-Biudiug Regiou of Prothrombiu. Prothrombin binds calcium ions with the modified amino acid y-carboxyglutamate (red).

Prothrombin (factor It) is a 581-amino-acid protein that contains one disulfide bond fFigure 9.30). Prothrombin is cleaved by factor in between two specifii... 

FIGURE 9.30 Structures of prothrombin and thrombin. Prothrombin is a protein consisting of 581 amino acids, while thrombin consists of 308 amino acids. Prothrombin is cleaved within the bloodstream, at the indicated peptide bonds, by the factor X /factor Vg complex. The intermediary form of thrombin is called meizothrombin. The activation peptide might be considered to be a waste product of the activation scheme. Please note that thrombin consists of two separate polypeptide chains, and that these are held together by a disulfide bond. Studies by researchers have revealed that prothrombin can also be activated by factor X alone, but here the pathway of peptide bond cleavage is somewhat different than that produced by the factor XJfactor complex. 

CHAPTER 36, FIGURE 21 Structure of a Gla domain of prothrombin. The Gla domains of the vitamin K-dependent proteins contain between 9 and 12 carboxyglutamic acid residues. Prothrombin contains 10 Gla residues pairs of adjacent Gla residues at positions 6 and 7 19 and 20 and 25 and 26 and four other Gla residues at positions 14, 16, 29, and 32. Factor VII also contains 10 Gla residues in the same positions as in prothrombin. Factor IX contains 12 Gla residues. Because factor IX has an additional amino acid between its amino terminal Tyr and the first Gla residue, the numbering of the residues is different from prothrombin and factor VII. However, the pattern is similar with pairs of adjacent Gla residues at positions 7 and 8 20 and 21 and 26 and 27. The six other Gla residues are at positions 15, 17, 30, 33, 36, and 40. The last two Gla residues account for 12 Gla residues in factor IX. Factor X contains 11 Gla residues pairs of adjacent Gla residues at positions 6 and 7 19 and 20 and 25 and 26, with five other Gla residues at positions 14, 16, 29, 32, and 39. Protein C contains 9 Gla residues pairs of adjacent Gla residues at positions 6 and 7 19 and 20 and 25 and 26, and the other Gla residues at positions 14, 16, and 29. The cartoon structures show helices in magenta, P sheets in yellow, p bends in blue, and Ca ions in gray. The space-filling dot surfaces for the residues of the Gla domains are standard CPK colors. 

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