Snake inhibitors of phospholipase A(2) enzymes.
Phospholipase A(2) (PLA(2)) enzymes consist of a large family of proteins which share the same enzymatic function and display considerable sequence homology. These enzymes have been identified and characterised in mammalian tissue and snake venoms. Numerous physiological functions have been attributed 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 probably mediated via membrane receptors. Snake PLA(2) inhibitors (PLIalpha), with a similar structure to the M-type receptor, have been identified as soluble complexes in the serum of viperinae and crotalinae snakes. These inhibitors showed selective binding to crotalid group II PLA(2)s and appeared to be restricted to the serum of this snake family. Analysis of PLA(2) binding to recombinant fragments of PLIalpha indicated that the CRD region was most likely responsible for enzyme inhibition. A second type of inhibitor, PLIbeta, has been identified in serum from one viperid snake and consists of a leucine-rich structure. The third type of inhibitor, PLIgamma, was found in the serum of five snake families and contains a pattern of cysteine residues that define a three-finger structure. PLIgamma inhibitors isolated from the serum of Elapidae, Hydrophidae, Boidae and Colubridae families were able to inhibit a broad range of enzymes including the nontoxic mammalian group IB and IIA PLA(2)s, and bee venom group III PLA(2). However, differences in the binding affinities indicated specificity for particular PLA(2)s. A different representation has emerged for crotalid and viperid snakes. Their PLIgammas did not inhibit bee venom group III, mammalian group IB and IIA enzymes. Furthermore, inhibition data for the gamma-type inhibitor from Crotalus durissus terrificus (CICS) showed that this inhibitor was specific for viperid beta-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 distribution of these inhibitors, their specificities and the structural features involved in binding are discussed in this review.
Dunn
R D
RD
Department of Cell and Molecular Biology, University of Technology, Sydney, Westbourne Street, 2065, Gore Hill, NSW, Australia.
Broady
K W
KW
D000818:Animals; D004791:Enzyme Inhibitors / Q000097:blood / Q000145:classification* / Q000378:metabolism; D006023:Glycoproteins / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D020033:Protein Isoforms / Q000145:classification / Q000235:genetics; D012911:Snakes / Q000097:blood*; D013045:Species Specificity
D004791:Enzyme Inhibitors; D006023:Glycoproteins; D020033:Protein Isoforms; D010741:Phospholipases A