Abstract
Thrombin is a multifunctional enzyme with a key role in the coagulation cascade. Its functional modulation can culminate into normal blood coagulation or thrombosis. Thus, the identification of novel potent inhibitors of thrombin are of immense importance. Sculptin is the first specific thrombin inhibitor identified in the transcriptomics analysis of tick’s salivary glands. It consists of 168 residues having four similar repeats and evolutionary diverged from hirudin. Sculptin is a competitive, specific and reversible inhibitor of thrombin with a Ki of 18.3 ± 1.9 pM (kon 4.04 ± 0.03 × 107 M−1 s−1 and koff 0.65 ± 0.04 × 10−3 s−1). It is slowly consumed by thrombin eventually losing its activity. Contrary, sculptin is hydrolyzed by factor Xa and each polypeptide fragment is able to inhibit thrombin independently. A single domain of sculptin alone retains ~45% of inhibitory activity, which could bind thrombin in a bivalent fashion. The formation of a small turn/helical-like structure by active site binding residues of sculptin might have made it a more potent thrombin inhibitor. In addition, sculptin prolongs global coagulation parameters. In conclusion, sculptin and its independent domain(s) have strong potential to become novel antithrombotic therapeutics.
Highlights
Blood coagulation is a dynamic process, which involves a cascade of proenzymes leading to the activation of downstream enzymes[1,2,3,4]
In the evolution tree, sculptin was closer to serine protease inhibitors of the antistasin family i.e. hirustasin, guamerin, bdellastasin, theromin and therostasin than classical hirudin from leech
Our data showed that each repeated domain of sculptin resemble the C-terminal cysteine-free half of leech hirudin
Summary
Blood coagulation is a dynamic process, which involves a cascade of proenzymes leading to the activation of downstream enzymes[1,2,3,4]. Almost all of those anticoagulants are associated with side effects such as the formation of irreversible hirudin-thrombin complex, short half-life of the hirulogs and their dosage needs to be strictly monitored[2, 5] Most of these thrombin inhibitors are from leeches and have been extensively investigated. Sculptin selectively and reversibly inhibited thrombin in a competitive manner It was slowly cleaved by thrombin and factor Xa. Based on mass spectrometry and Edman analysis, we propose the thrombin active site binding sequence, which has only few conserved residues compared to classical hirudin from the medicinal leech but present sthe same potency. Sculptin has strong potential to become an antithrombotic drug and it could replace the classical hirudin and its analogs
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