Saturday, January 2, 2016

Sequestration of Defensive Bufadienolide Steroid Toxins by the Asian Tiger Keelback Snake

            The Yamakagashi or Asian Tiger Keelback Snake (Rhabdophis tigrinus, depicted above) is a venomous Asian snake found in East and Southeast Asia. Its dorsal color pattern is olive-drab green with black and bright orange crossbars or spots from the neck down the first third of the body and the average length of the distinctive snake is about two to three feet. The tiger keelback snake feeds mainly on small vertebrates, especially frogs and toads, and possesses unique defensive glands on the dorsal surface of its neck. These nuchal glands sequester and contain cardiotonic steroidal toxins known as bufadienolides, which are also abundant in the skin of toads. This species of snake uses the steroids primarily as irritants, relying more heavily on the deterrence provided by these glands. Although venomous, few deaths have been recorded due to its tendency to display passive anti-predator responses as opposed to striking.
            Researchers Deborah Hutchinson (Coastal Carolina University), Jerrold Meinwald (Cornell University) and colleagues have conducted extensive investigations of the chemical composition of the defensive glands of R. tigrinus (for leading references, see this recent review article). A series of fascinating feeding experiments have demonstrated that Japanese toads (Bufo japonicus) consumed as prey are the environmental sources of the bufadienolides in the defensive glands of the tiger keelback snake. Interestingly, snakes that reside on a toad-free Japanese island (Kinkasan, Miyagi Prefecture) lack these chemicals in their glands, which suggests that the species is unable to biosynthesize the steroidal toxins. When snakes from Kinkasan were fed toads in the laboratory, they accumulated bufadienolides in their nuchal glands, indicating that they retain the ability to sequester defensive compounds from prey. A separate line of experiments also showed that bufadienolides can be provisioned to offspring such that hatchlings are chemically defended prior to their first toad meal. Female R. tigrinus provision bufadienolides to their offspring in direct proportion to their own level of chemical defense.
            The major bufadienolides that are accumulated by the tiger keelback snake are derived from bufotoxins (representative structures depicted above) that occur in Japanese common (Bufo) toads. Bufotoxins are variously oxygenated bufadienolides that bear a suberoylarginine side chain (or similar), appended to the C3 b-hydroxyl via an ester linkage. Bufotoxins themselves have never been found in the snake’s nuchal glands, likely due to metabolic instability of the ester side chain in conjunction with the fact that bufotoxins are less toxic than parent bufadienolides such as gamabufotalin, which is the predominant compound accumulated by the snakes. The bufadienolide steroid toxins sequestered by R. tigrinus, in general, are the products of C3 ester hydrolysis (i.e. cleavage of the suberoylarginine side chain), hydroxylation and/or epimerization.

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