HEMORRHAGIC METALLOPROTEINASES FROM SNAKE-VENOMS

One of the more significant consequences of crotalid envenomation is h emorrhage. Over the past 50 years of investigation, it is clear that t he primary factors responsible for hemorrhage are metalloproteinases p resent in the venom of these snakes. The biochemical basis for their a ctivity is the proteolytic destruction of basement membrane and extrac ellular matrix surrounding capillaries and small vessels. These protei nase toxins may also interfere with coagulation, thus complementing lo ss of blood from the vasculature. Structural studies have shown that t hese proteinases are synthesized as zymogens and are processed at both the amino and carboxy termini to give the mature protein. The variety of hemorrhagic toxins found in snake venoms is due to the presence of structurally related proteins composed of various domains. The type o f domains found in each toxin plays an important role in the hemorrhag ic potency of the protein. Recently, structural homologs to the venom hemorrhagic metalloproteinases have been identified in several mammali an reproductive systems. The functional significance of the reproducti ve proteins is not clear, but in light of the presence of similar doma ins shared with the venom metalloproteinases, their basic biochemical activities may be similar but with very different consequences. This r eview discusses the history of hemorrhagic toxin research with emphasi s on the Crotalus atrox proteinases. The structural similarities obser ved among the hemorrhagic toxins are outlined, and the structural rela tionships of the toxins to the mammalian reproductive proteins are des cribed.