title: Evidence for an enantioselective pumiliotoxin 7-hydroxylase in dendrobatid poison frogs of the genus Dendrobates.
abstract: Dendrobatid poison frogs readily accumulate alkaloids from diet into skin, where such compounds serve as a chemical defense against predators. Arthropods seem to be the source of decahydroquinolines (DHQs), several izidines, coccinellines, spiropyrrolizidines, pumiliotoxins (PTXs), and allopumiliotoxins (aPTXs). A DHQ iso-223F, and PTX (+)-251D were fed to poison frogs of the dendrobatid genera Dendrobates, Epipedobates, and Phyllobates. The two alkaloids were accumulated in skin unchanged except for the three species of Dendrobates, where approximately 80% of accumulated PTX (+)-251D was stereoselectively hydroxylated to aPTX (+)-267A. The unnatural enantiomer PTX (-)-251D was accumulated efficiently when fed to Dendrobates auratus, but was not hydroxylated. The enantiomers of PTX 251D and their desmethyl analogs were synthesized from N-Boc-protected (-)- and (+)-proline methyl esters. Both PTX (+)-251D and aPTX (+)-267A proved to be potent convulsants in mice, with (+)-267A being approximately 5-fold more toxic than (+)-251D. Both alkaloids were hyperalgesic at the site of injection. The unnatural PTX (-)-251D caused no overt effect in mice. Thus, the evolutionary development of a pumiliotoxin 7-hydroxylase would have provided frogs of the genus Dendrobates with a means of enhancing the antipredator potency of ingested PTXs.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-0820, USA. jdaly@nih.gov
authors.forename: John W
authors.initials: JW
authors.lastname: Daly
authors.forename: H Martin
authors.initials: HM
authors.lastname: Garraffo
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Spande
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Clark
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Ma
authors.forename: Herman
authors.initials: H
authors.lastname: Ziffer
authors.forename: John F
authors.initials: JF
authors.lastname: Cover
mesh_terms: D000818:Animals; D001001:Anura; D006900:Hydroxylation; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D006899:Mixed Function Oxygenases