Snake inhibitors of phospholipase A(2) enzymes

Phospholipase A(2) (PLA(2)) enzymes consist of a large family of proteins w hich share the same enzymatic function and display considerable sequence ho mology. These enzymes have been identified and characterised in mammalian t issue and snake venoms. Numerous physiological functions have been attribut ed to mammalian PLA(2)s and they are nontoxic. In comparison, venom PLA(2)s are toxic and induce a variety of pharmacological effects that are probabl y mediated via membrane receptors. Snake PLA(2) inhibitors (PLI alpha), wit h a similar structure to the M-type receptor, have been identified as solub le complexes in the serum of viperinae and crotalinae snakes. These inhibit ors showed selective binding to crotalid group II PLA(2)s and appeared to b e restricted to the serum of this snake family. Analysis of PLA(2) binding to recombinant fragments of PLI alpha indicated that the CRD region was mos t likely responsible for enzyme inhibition. A second type of inhibitor, PLI beta, has been identified in serum from one viperid snake and consists of a leucine-rich structure. The third type of inhibitor, My, was found in the serum of five snake families and contains a pattern of cysteine residues t hat define a three-finger structure. PLI gamma inhibitors isolated from the serum of Elapidae, Hydrophidae, Boidae and Colubridae families were able t o inhibit a broad range of enzymes including the nontoxic mammalian group I B and IIA PLA(2)s, and bee venom group III PLA(2)s. However, differences in the binding affinities indicated specificity for particular PLA(2). A diff erent representation has emerged for crotalid and viperid snakes. Their PLI gammas did not inhibit bee venom group III, mammalian group IB and IIA enz ymes. Furthermore, inhibition data for the gamma -type inhibitor from Crota lus durissus terrificus (CICS) showed that this inhibitor was specific for viperid P-neurotoxins and did not inhibit beta -neurotoxins from elapids [1 ]. Further studies are required to determine if this phenomenon is true for all gamma -type inhibitors from Crotalidae snakes. The relative distributi on of these inhibitors, their specificities and the structural features inv olved in binding are discussed in this review. (C) 2001 Elsevier Science B. V. All rights reserved.