Review Snake venom proteases a¡ecting hemostasis and thrombosis Taei Matsui a , Yoshihiro Fujimura b , Koiti Titani a ; * a Division of Biomedical Polymer Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan b Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan Abstract The structure and function of snake venom proteases are briefly reviewed by putting the focus on their effects on hemostasis and thrombosis and comparing with their mammalian counterparts. Up to date, more than 150 different proteases have been isolated and about one third of them structurally characterized. Those proteases are classified into serine proteases and metalloproteinases. A number of the serine proteases show fibrin(ogen)olytic (thrombin-like) activities, which are not susceptible to hirudin or heparin and perhaps to most endogenous serine protease inhibitors, and form abnormal fibrin clots. Some of them have kininogenase (kallikrein-like) activity releasing hypotensive bradykinin. A few venom serine proteases specifically activate coagulation factor V, protein C, plasminogen or platelets. The venom metalloproteinases, belonging to the metzincin family, generally show fibrin(ogen)olytic and extracellular matrix-degrading (hemorrhagic) activities. A few venom metalloproteinases show a unique substrate specificity toward coagulation factor X, platelet membrane receptors or von Willebrand factor. A number of the metalloproteinases have chimeric structures composed of several domains such as proteinase, disintegrin-like, Cys-rich and lectin-like domains. The disintegrin-like domain seems to facilitate the action of those metalloproteinases by interacting with platelet receptors. A more detailed analysis of snake venom proteases should find their usefulness for the medical and pharmacological applications in the field of thrombosis and hemostasis. ß 2000 Elsevier Science B.V. All rights reserved. Keywords : Snake venom; Serine protease; Metalloproteinase; Metzincin; Hemostasis; Thrombosis 1. Introduction At present, there are more than 200 species of venomous snakes on the earth. They are classi¢ed into four major families: (1) Hydrophiae, (2) Elapi- dae, (3) Viperidae and (4) Crotalidae. To provide victims with various damages, they have a venom gland that synthesizes, stores and secretes about 50^60 protein/peptide components with di¡erent structures and functions, as either the active or the inactive precursor form, into the site of their bite. The precursor forms of components are activated by a special mechanism after the secretion. The ven- om components seem to be fairly common and sim- ilar to one another within each family of snakes (e.g., nerve toxins are generally found in the Hydrophidae and Elapidae venoms and hemorrhagic and myone- crotic toxins are generally found in the venoms of the other two families of snakes), but they are basically di¡erent depending on each snake species [1,2]. There are several unique components that have been so far isolated from the venom of only one snake species. Recently Daltry et al. [3] have published an interest- ing report that venom components have a consider- able geographical variation even within each snake species in close association with its diet, in accord 0167-4838 / 00 / $ ^ see front matter ß 2000 Elsevier Science B.V. All rights reserved. PII:S0167-4838(99)00268-X * Corresponding author. Fax: +81-562-938832; E-mail : ktitani@fujita-hu.ac.jp Biochimica et Biophysica Acta 1477 (2000) 146^156 www.elsevier.com/locate/bba