Proteases from South American Snake Venoms Affecting Fibrinolysis

Abstract

Venoms of the viperidae (vipers and pit vipers) snakes are rich sources of proteinases which render fibrinogen incoagulable and solubilize fibrin. Many of these compounds have profound effects (stimulating or inhibiting) on the hemostatic mechanism, including, blood coagulation cascade, fibrinolysis, hypotension, vascular integrity and platelet function. The lethality of a venom often appears to be due to the combined action of several of these components, but severe consequences are frequently connected with hemostatic disorders. Viperid snake bite accidents in human and other large animals are characterized by localized or generalized bleeding and or thrombotic sequelae. This review is focused on the structural properties and features of a number of South American snake venom enzymes possessing clearly defined (pro)fibrinolytic activity. Under physiological conditions the venom proteins active on the plasminogen/fibrinolytic system can be grouped into two main categories: 1) direct-acting fibrinolytic endoproteinases which are related in amino acid sequence to the major family of metalloproteinases known as the metzincins. The members of this group are zinccontaining metalloproteinases (SVMPs) varying in size from 20 to 100 kDa and often more than one example is present in the same venom. 2) serine proteinases which specifically activate plasminogen into plasmin, and contain at least one catalytic domain structurally similar to trypsin. A number of these proteinases have been isolated and their mechanism of action established. Both direct and indirect endoproteinases on their own are practically nontoxic; however, they may act synergistically with other factors aggravating their toxic effects. Moreover, these proteinases are characterized by a relatively high degree of substrate specificity and resistance to physiological inhibitors. Indeed, some of these venom components are thought to hold promise as agents for medical applications in the field of thrombosis and diagnosis, or to hold the key for the design of pharmaceuticals. Keywords: Fibrinolysis, Snake venoms, Hemostasis, Serine proteinases, Metalloproteinases