Clarification of the C-35 Stereochemistries of Dinophysistoxin-1 and Dinophysistoxin-2 and Its Consequences for Binding to Protein Phosphatase

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• 作者：Kristofer Larsen ; Dirk Petersen ; Alistair L. Wilkins ; Ingunn A. Samdal ; Morten Sandvik ; Thomas Rundberget ; David Goldstone ; Vickery Arcus ; Peter Hovgaard ; Frode Rise ; Nils Rehmann ; ^O ; Philip
• 刊名：Chemical Research in Toxicology
• 出版年：2007
• 出版时间：June 2007
• 年：2007
• 卷：20
• 期：6
• 页码：Hess,
• 全文大小：349K
• 年卷期：v.20,no.6(June 2007)
• ISSN：1520-5010

文摘

Okadaic acid analogues are well known as protein phosphatase inhibitors and occur naturally in marineshellfish feeding on dinoflagellates of the genus Dinophysis, leading to diarrhetic shellfish poisoning ofshellfish consumers. Knowledge of the correct structures for these toxins is important in understandingtheir toxicology, biochemistry, and biosynthesis. We have performed extensive NMR analyses on okadaicacid (1), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2) obtained from natural sources.Consequently, we were able to unambiguously deduce the stereochemistries at C-35 for DTX-1 andDTX-2 based on analysis of NMR coupling constants and NOE interactions. Our results revealed thatDTX-2 (3) has a stereochemistry opposite to that of DTX-1 (2) at C-35. Molecular modeling of thedocking of 1-3 with protein phosphatase-1 and protein phosphatase 2A (PP2A) suggested that the reducedaffinity of DTX-2 for PP2A may be due to the newly defined stereochemistry at the 35-methyl group.The implications of these findings for biosynthesis and toxicology are discussed.