Fibrinopeptide

Using Table 5.6 (see p. 156), propose a sequence for glu-fibrinopeptide B based on the product-ion MS-MS spectrum shown in Figure 4.20. 

Thrombin (34 kDa), a serine protease formed by the prothrombinase complex, hydrolyzes the four Arg-Gly bonds between the fibrinopeptides and the a and P portions of the Aa and BP chains of fibrinogen (Figure 51-5A). The release of the fibrinopeptides by thrombin generates fibrin monomer, which has the subunit stmc-... 

Figure 51-4. Diagrammatic representation (not to scaie) of fibrinogen showing pairs of Aa, B 3, and y chains iinked by disuifide bonds. (FPA, fibrinopeptide A FPB, fibrinopeptide B.)...

Fig. 3. Fibrinogen molecule with its two A a, two B 3, and two -y chains. Thrombin (Ha) acts on the A a chain to generate fibrinopeptide A (FPA) and the a-chain. It also cleaves the B 3 chain to generate fibrinopeptide B (FPB) and the p-chain. S-S represents disulfide bonds. Altogether, 29 disulfide bonds hold together the six polypeptide chains that make up the fibrinogen molecule.

Thrombin [EC 3.4.21.5], also known as fibrinogenase, catalyzes the hydrolysis of peptide bonds, exhibiting preferential cleavage for the Arg—Gly peptide bond. The enzyme, a member of the peptidase family SI, activates fibrinogen to fibrin and releases fibrinopeptide A and B. Thrombin, formed from prothrombin, is more selective in peptide hydrolysis than trypsin or plasmin. 

Fibrinolysis. The hydrolysis of an elastic, filamentous protein (fibrin) derived from fibrinogen by the action of thrombin, which releases fibrinopeptides A and B (co-fibrins A and B) from fibrinogen in co-agulation of the blood. 

After the early discovery of a tyrosine 0-sulfate residue in bovine fibrinopeptide B, 15 this posttranslational modification which occurs ubiquitously in proteins was also detected in a series of biologically active peptides such as the neurohormones of the gastrin/cholecysto-kinin (CCK) family of peptides, phyllokinin, Leu-enkephalin, and the thrombin inhibitor hirudin listed in Table 1. 

III. Thrombin Inhibitors Directed at the Fibrinopeptide a Binding Pocket... 

Schematic diagram of binding determinants within the fibrinopeptide A binding pocket of thrombin and their utilization by N-acetyl-(D-Phe)-Pro-boroArg-OH.

Table 2 Bivalent Thrombin Inhibitors Interacting with both Fibrinopeptide and Fibrinogen Recognition Binding Sites...

Fibrinogen is an elongated molecule with an (apy)2 structure.524,541,5413 Thrombin cleaves specific Arg-Gly bonds in the a and P chains releasing short (14- tol6-residue) "fibrinopeptides" from the N termini of the peptide chains. This leaves Gly-Pro-Arg "knobs" at... 

Peptide chimeras of this type have proven extremely valuable for the examination of an array of recognition events. In conjunction with molecular modeling, peptidomimetic substrates and inhibitors of human thrombin were designed and synthesized to evaluate our proposed structure for the thrombin-bound conformation of fibrinopeptide A (Scheme 2i)J%]... 

Scheme 21 Amino Acid Sequence of a Segment of Fibrinopeptide A and Its p-Turn Peptidomimeticsl%l...

Studies on pyrrolidone carboxylyl peptidase have shown that the enzyme can catalyze the removal of the terminal pyrrolidone carboxylyl residue from fibrinopeptides, fibrinogen (135, llfi), and human seromu-coid (135). 

Fig. 1. Basic scheme of fibrin polymerization and fibrinolysis. The clot is formed on the conversion of fibrinogen to fibrin by cleavage of the fibrinopeptides by thrombin, followed by stabilization of the network with isopeptide bonds by the transglutaminase Factor XHIa. The clot is dissolved through proteolysis by the enzyme plasmin, which is activated on the fibrin surface by plasminogen activators. This process is controlled by several inhibitory reactions (black arrows).

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