ABSTRACT

Zinc-dependent metalloproteinases are abundant components in snake venoms, especially in those of species of the families Viperidae and Colubridae. Four main classes of snake venom metalloproteinases (SVMPs) have been described on the basis of their domain constitution. The large diversity of SVMPs is the consequence of an accelerated evolutionary process that occurred in their genes after an early recruitment of an ADAM-like gene before the radiation of the advanced snakes. The largest diversication of SVMPs occurred in the family Viperidae. From a biological standpoint, SVMPs have two fundamental roles, associated with prey immobilization and digestion. SVMPs play a key role in viperid snakebite envenomations, since they induce a complex series of local and systemic pathophysiological effects. At the site of injection, SVMPs induce hemorrhage, edema, myonecrosis, blistering, dermonecrosis, and a prominent inammatory reaction. Hemorrhage induced by SVMPs is a consequence of their ability to hydrolyze key components of the basement membrane that surrounds, and gives support to, endothelial cells in capillaries. The consequent weakening in

I. Introduction .......................................................................................................................... 116 II. Classication of SVMPs ...................................................................................................... 116 A. Class P-I ......................................................................................................................... 116 B. Class P-II ........................................................................................................................ 117 C. Class P-III ....................................................................................................................... 118 D. Class P-IV....................................................................................................................... 119 III. SVMPs from a Biological Perspective ................................................................................. 119 IV. SVMPs in the Context of the Pathophysiology of Snakebite Envenomation ....................... 122 A. The Role of SVMPs in the Hemorrhagic Syndrome in Viperid Envenomations ........... 122 B. Why Are P-III SVMPs More Hemorrhagic Than P-I SVMPs? .....................................124 C. SVMPs Induce Blistering and Myonecrosis, and Impair Muscle Regeneration ............ 126 D. SVMPs Contribute to the Hemostatic Alterations in Viperid Envenomations .............. 126 E. The Role of SVMPs in Venom-Induced Local Inammation ....................................... 127 V. Concluding Remarks ............................................................................................................ 128 Acknowledgments .......................................................................................................................... 129 References ...................................................................................................................................... 130

capillary mechanical stability prompts the distention and eventual disruption of the capillary wall due to the hemodynamic biophysical forces normally operating in the microcirculation. As a consequence of their drastic effects in the microvasculature, SVMPs induce a severe impairment in the process of skeletal muscle regeneration, thus contributing to the permanent tissue loss characteristic with viperid envenomations. Moreover, SVMPs induce systemic hemorrhage and coagulopathy, thus contributing to hypovolemia and cardiovascular collapse. Owing to their primary role in the pathophysiology of snakebite envenomation, the search for novel natural and synthetic inhibitors of SVMPs is a relevant task in the improvement of snakebite envenomation therapy.