Fibrinopeptide A

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. 

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.

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...

Substitution of particular amino acids in the fibrinopeptides and at thrombin s cleavage sites in recombinant fibrinogen has been used to understand thrombin specificity, the relative rates of fibrinopeptide cleavage, and effects on polymerization. If fibrinopeptide B is replaced with a fibrinopeptide-A-like peptide, fibrinopeptide release is similar to release from the Aa chain (Mullin et al., 2000). Thus, the ordered release of fibrinopeptides is dictated by the specificity of thrombin for its substrates. 

There is evidence for the involvement of the N-terminal B/3 chain in fibrin polymerization (Pandya et at, 1985 Siebenlist et al., 1990). A recombinant fibrinogen with His substituted for Arg at the B/3 thrombin-cleavage site led to a 300-fold decrease in the rate of fibrinopeptide B release, whereas the rate of fibrinopeptide A release was normal (Moen et al., 2003). As a consequence, thrombin- or batroxobin-catalyzed or desA monomer polymerization was impaired, due to the histidine substitution itself. Thus, it appears that the N-terminus of the B/3 chain is involved in the lateral aggregation of normal desA protofibrils. 

Mutations of the Bj3 chain are less common. Substitution of Cys for Gly at amino acid 15 results in prolonged polymerization from delayed release of fibrinopeptide B (Yoshida et al., 1991). Mutation of Ala68 to Thr results in defective binding of thrombin to fibrin and consequent thrombosis (Koopman et al., 1992). Deletion of residues 9-72, which includes a cysteine that is normally part of a disulfide bond, results in delayed release of both fibrinopeptides A and B (Liu et al., 1985). 

I 5 Neri Serneri GG, Gensini Gp Abbate R, et al, Is raised plasma fibrinopeptide A a marker of acute coronary insufficiency Lancet 1980 11 982. 

I 6 Theroux R Latour JG, Leger-Gautier C, et al, Fibrinopeptide A plasma levels and platelet factor 4 levels in unstable angina pectoris. Circulation 1987 75 156-162. 

Van Hulsteijn H, Kolff J, Briet E, et al. Fibrinopeptide A and 13-thromboglobulin in patients angina pectoris and acute myocardial infarction. Am Heart J 1984 107 39—45. 

Ardissino D, Gamba MG, Merlini PA, et al, Fibrinopeptide A excretion in urine a marker of cumulative thrombin activity in stable versus unstable angina patients. Am J Cardiol 1991 68 58B-63B. 

Inserted emitter, silver glue coated, PMMA chip ESI-ITMS BSA, fibrinopeptide A, osteocalcin fragment 7-19, bradykinin (all 10 pmol/jxL) Trypsin, off-chip Nil 814... 

Hie serine protease thrombin takes a central position in the clotting system. It splits off fibrinopeptides A and B from the amino terminal ends of the a- and -chains of fibrinogen. The resulting fibrin monomer then undergoes polymerization to forma fibrin dot. Via activation of the clotting factors V and VIII, further thrombin is Generated from wothramhin. and via activation of blood dale lets and... 

Figure 2.30. Domain structure of fibrinogen. The fibrinogen molecule is composed of globular end regions separated from a central domain by helical threads. The central domain has cross-links that hold all the polypeptide chains together. Fibrinopeptides A and B (FPA and FPB) are found in the central domain.

Fibrinogen is a plasma protein, formed in the liver that is the basis for the formation of a blood clot. The blood concentration of this protein is about 3% and in the presence of other blood proteins pieces of the fibrinogen molecule, fibrinopeptides A and B, are cleaved and fibrinogen is polymerized to form a fibrin clot (Figure 2.30). 

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