Molecular Evolution, Functional Variation, and Proposed Nomenclature of the Gene Family That Includes Sphingomyelinase D in Sicariid Spider Venoms

Abstract

The venom enzyme sphingomyelinase D (SMase D) in the spider family Sicariidae (brown or fiddleback spiders [Loxosceles] and six-eyed sand spiders [Sicarius]) causes dermonecrosis in mammals. SMase D is in a gene family with multiple venom-expressed members that vary in functional specificity. We analyze molecular evolution of this family and variation in SMase D activity among crude venoms using a data set that represents the phylogenetic breadth of Loxosceles and Sicarius. We isolated a total of 190 nonredundant nucleotide sequences encoding 168 nonredundant amino acid sequences of SMase D homologs from 21 species. Bayesian phylogenies support two major clades that we name alpha and beta, within which we define seven and three subclades, respectively. Sequences in the alpha clade are exclusively from New World Loxosceles and Loxosceles rufescens and include published genes for which expression products have SMase D and dermonecrotic activity. The beta clade includes paralogs from New World Loxosceles that have no, or reduced, SMase D and no dermonecrotic activity and also paralogs from Sicarius and African Loxosceles of unknown activity. Gene duplications are frequent, consistent with a birth-and-death model, and there is evidence of purifying selection with episodic positive directional selection. Despite having venom-expressed SMase D homologs, venoms from New World Sicarius have reduced, or no, detectable SMase D activity, and Loxosceles in the Southern African spinulosa group have low SMase D activity. Sequence conservation mapping shows >98% conservation of proposed catalytic residues of the active site and around a plug motif at the opposite end of the TIM barrel, but alpha and beta clades differ in conservation of key residues surrounding the apparent substrate binding pocket. Based on these combined results, we propose an inclusive nomenclature for the gene family, renaming it SicTox, and discuss emerging patterns of functional diversification.

Squeezers and Leaf-cutters: Differential Diversification and Degeneration of the Venom System in Toxicoferan Reptiles

“…Subsequently, the venom gland specific gene isoform is further duplicated, often explosively. Evidence of accelerated evolution and positive selection is characteristic of this "birth and death" model of venom protein evolution (1,(3)(4)(5)(6)(7)(8)(9)(10)(11). For example, the A-superfamily of conotoxin genes isolated from venomous cone snails is among the most rapidly evolving protein-coding gene family identified in metazoans to date (5).…”

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“…Structural comparisons suggest that bacterial and spider SMase Ds originated from the broadly conserved glycerophosphoryl diester phosphodiesterases (55). There are unique motifs present in bacterial and spider SMase Ds but not in the ancestral family, supporting their origin through a single divergence event followed by horizontal gene transfer (59).…”

Chemical Control of Spiders and Scorpions in Urban Areas

“…Preferred habitats includes rock piles, wood piles, rat holes, attic and basement crawl spaces, indoor trash and clothing piles, cardboard boxes, and storage sheds. Sicarius and Loxosceles are the only known spiders with venom able to cause necrotic arachnidism in humans [79]. Some biotechnological applications of Loxosceles genus venom www.intechopen.com toxins are being devised [80].…”

“…Some biotechnological applications of Loxosceles genus venom www.intechopen.com toxins are being devised [80]. Although several toxins have been isolated from Loxosceles venom and various enzymatic activities have been identified, the medically important component appears to be sphingomyelinase D [79]. This dermonecrotic venom component has been identified in all species thus far tested, and it would not be surprising if all Loxosceles spiders are capable of causing necrotic skin lesions [74,79].…”

“…Although several toxins have been isolated from Loxosceles venom and various enzymatic activities have been identified, the medically important component appears to be sphingomyelinase D [79]. This dermonecrotic venom component has been identified in all species thus far tested, and it would not be surprising if all Loxosceles spiders are capable of causing necrotic skin lesions [74,79]. Among the spiders that can cause serious health risks to humans, the brown spiders -particularly L. reclusa, L. laeta and L.intermedia -were the targets of the major control initiatives in the world.…”