A structural basis for the reduced toxicity of dinophysistoxin-2.

Chemical Research in Toxicology
Jason HuhnChristopher O Miles

Abstract

Okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2) are algal toxins that can accumulate in shellfish and cause diarrhetic shellfish poisoning. Recent studies indicate that DTX-2 is about half as toxic and has about half the affinity for protein phosphatase 2A (PP2A) as OA. NMR structural studies showed that DTX-1 possessed an equatorial 35-methyl group but that DTX-2 had an axial 35-methyl group. Molecular modeling studies indicated that an axial 35-methyl could exhibit unfavorable interactions in the PP2A binding site, and this has been proposed as the reason for the reduced toxicity of DTX-2. Statistical analyses of published data indicate that the affinity of PP2A for DTX-1 is 1.6-fold higher, and for DTX-2 is 2-fold lower, than for OA. We obtained X-ray crystal structures of DTX-1 and DTX-2 bound to PP2A. The crystal structures independently confirm the C-35 stereochemistries determined in the earlier NMR study. The structure for the DTX-1 complex was virtually identical to that of the OA-PP2A complex, except for the presence of the equatorial 35-methyl on the ligand. The favorable placement of the equatorial 35-methyl group of DTX-1 against the aromatic pi-bonds of His191 may account for the increa...Continue Reading

References

Nov 10, 2006·Toxicon : Official Journal of the International Society on Toxinology·Tore AunePhilipp Hess
Sep 11, 2007·Toxicon : Official Journal of the International Society on Toxinology·Thomas RundbergetChristopher O Miles
Jan 30, 2008·Bioorganic & Medicinal Chemistry Letters·Craig J Forsyth, Ce Wang
Nov 13, 2008·Bioinformatics·Christopher ReynoldsSusan Jones
Aug 13, 2009·Toxicon : Official Journal of the International Society on Toxinology·Clara AlbanoGian Paolo Rossini

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Citations

Mar 19, 2011·Analytical and Bioanalytical Chemistry·Pearse McCarronPhilipp Hess
Nov 5, 2013·Marine Drugs·Vanessa ValdiglesiasBlanca Laffon
Mar 7, 2013·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Hao ZhangJian-Guo Yu
Mar 10, 2016·Toxicology in Vitro : an International Journal Published in Association with BIBRA·P J FerronL Le Hegarat
Aug 14, 2013·The FEBS Journal·Mengmeng ZhangYan Zhang
Jul 9, 2014·Biological Chemistry·Christian LöwPär Nordlund
Feb 4, 2011·Critical Reviews in Toxicology·Susana R PereiraAgostinho Antunes
Jan 13, 2021·Marine Drugs·M Carmen LouzaoLuis M Botana
Jan 18, 2022·Archives of Toxicology·Yang LiuWei-Dong Yang

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