title: Exactin: A specific inhibitor of Factor X activation by extrinsic tenase complex from the venom of Hemachatus haemachatus.
abstract: Unwanted clots lead to heart attack and stroke that result in a large number of deaths. Currently available anticoagulants have some drawbacks including their non-specific actions. Therefore novel anticoagulants that target specific steps in the coagulation pathway are being sought. Here we describe the identification and characterization of a novel anticoagulant protein from the venom of Hemachatus haemachatus (African Ringhals cobra) that specifically inhibits factor X (FX) activation by the extrinsic tenase complex (ETC) and thus named as exactin. Exactin belongs to the three-finger toxin (3FTx) family, with high sequence identity to neurotoxins and low identity to the well-characterized 3FTx anticoagulants-hemextin and naniproin. It is a mixed-type inhibitor of ETC with the kinetic constants, Ki' and Ki determined as 30.62 ± 7.73 nM and 153.75 ± 17.96 nM, respectively. Exactin does not bind to the active site of factor VIIa and factor Xa based on its weak inhibition (IC50 ≫ 300 μM) to the amidolytic activities of these proteases. Exactin shows exquisite macromolecular specificity to FX activation as compared to factor IX activation by ETC. Exactin thus displays a distinct mechanism when compared to other anticoagulants targeting ETC, with its selective preference to ETC-FX [ES] complex.
authors: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 119260, Singapore.
authors: Vallerinteavide Mavelli
authors: VM
authors: Girish
authors: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 119260, Singapore.|Department of Biochemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.|University of South Australia, School of Pharmacy and Medical Sciences, Adelaide, South Australia 5001, Australia.
authors: R Manjunatha
authors: RM
authors: Kini
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D001780:Blood Coagulation Tests / Q000379:methods; D002942:Circular Dichroism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004546:Elapid Venoms / Q000737:chemistry*; D005170:Factor X / Q000037:antagonists & inhibitors*; D000073179:Hemachatus; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011517:Prothrombin Time; D020539:Sequence Analysis, Protein
chemical_list: D000925:Anticoagulants; D004546:Elapid Venoms; D009363:Neoplasm Proteins; D005170:Factor X; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant