Prothrombin, structure

Suttie JW and Jackson CM (1977) Prothrombin structure, activation, and biosynthesis. Physiological Reviews 57, 1-70. 

Figure 13 shows the structure and absolute configuration of (2R,3S)-(-) vitamin K3 epoxide. This epoxide, prepared in optically active form by us (70) in 1976, had been known as a racemate since 1939 (78). It has recently been implicated (79) in prothrombin biosynthesis (80). The absolute configuration as shown in Figure 13 is based on the work of Snatzke (76) and the absolute rotation is [ ]436 = — 124° (acetone) and [a] = 0° ( ) (acetone). 

The last of the fat-soluble vitamins to be identified was vitamin K, found by Dam to be an anti-hemorrhagic factor for young chicks, distinct from vitamin C. Its structure was determined by Dam in collaboration with Karrer. Interest in the vitamin was intensified when it was discovered (Link, 1941) that dicoumarol, present in spoiled sweet clover, was the agent producing hypothrombinemia (giving prolonged blood-clotting time) in cattle. Since vitamin K is structurally similar to dicoumarol, the vitamin was presumptively implicated in thrombin formation. This has been fully substantiated by recent work on the role of vitamin K in the synthesis of prothrombin in the liver. 

In normal individuals phytonadione and the menaquinones have no activity while in vitamin K deficiency the vitamin promotes the hepatic biosynthesis of factor II (prothrombin), factor VII, factor IX and factor X. Vitamin K functions as an essential cofactor for the enzymatic activation of precursors of these vitamin K dependent clotting factors. The quinone structure of the active form of vitamin K, i.e. reduced vitamin K or hydroquinone. 

Ami RK, Padmanabhan K, Padmanabhan KP, Wu TP, Tulinsky A. The structure of the non-covalent complex of prothrombin kringle 2 with PPACK-thrombin. Chem Phys Lipids 1994 67-68 59-66. 

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. 

VITAMIN K. Sometimes referred to as the antihemmorhagic vitamin, and. earlier in its development, the prothrombin factor or Koagulations-vitamin, vitamin Kis a substituted derivative of naphthoquinone and occurs in several forms. The designationphylloquinone. or Ki, refers to 2-methyl-3-phytyl-l,4 naphthoquinone the designations famoquinone and prertyl-menaquinone, or K2, refer to 2-difarnesyl-3-methyl-1, 4-naphthoquinone. Menadione, sometimes called oil-soluble vitamin K3, is 2-methyl-1,4-naphthoquinone. The structure of phylloquinone is ... 

From the previous results one can draw some conclusions with regard to the structure and the arrangements of the prothrombin molecules interacting with a lipid layer consisting of PS. A model based on these conclusions are presented schematically in Figure 7. As seen in this drawing... 

Both the intrinsic and extrinsic systems ultimately lead to the conversion of prothrombin to thrombin.92 Thrombin is an enzyme that quickly converts the inactive fibrinogen molecule to fibrin. Individual strands of fibrin bind together to form a meshlike structure, which ultimately forms the framework for the blood clot. Other cellular components, especially platelets, help reinforce the clot by sticking to the fibrin mesh. 

Heparin acts by binding to anti thrombin III, which serves as a major inhibitor of serine protease clotting enzymes. Abruptly ending heparin treatment can be hazardous because of reduced levels of antithrombin III. Coumarins, typified by warfarin, are structurally similar to vitamin K, which plays an important role in blood coagulation. By interfering with the function of vitamin K, vitamin K-dependent proteins such as clotting factors VII, IX, X and prothrombin are reduced. 

Q14 Warfarin is an orally active anticoagulant used in the treatment of valvular disease and atrial fibrillation. It is structurally similar to vitamin K, a compound which is required for the synthesis of prothrombin and several other clotting factors in the liver. Warfarin interferes with the actions of vitamin K and so reduces the risk of blood clotting. When taken by mouth, its effect is not immediate and it takes several days to achieve the maximal clinical effect. 

The coagulation and anticoagulation proteases, factors VII, IX, and X, and protein C, have a common domain structure with an N-terminal gamma-carboxyglutamic acid (Gla)-containing domain that is followed by two EGF-like modules, whereas the C-terminal half of each protein is occupied by a trypsin-like serine protease domain. Prothrombin also has an N-terminal Gla domain and a C-terminal serine protease... 

Figure 10.41. Modular Structure of Prothrombin. Cleavage of two peptide bonds yields thrombin. All the y-carboxyglutamate residues are in the gla domain.

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. 

All of these proteins are synthesized in the liver, and they have coasiderable structural homology. All contain 10 to 12 Gla residues. " " The coagulation activity is proportional to the number of Gla residues present. For example, prothrombin has 10 Gla residues. Loss of just two residues decreases activity by 80%. " ... 

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