Clarification of the C-35 stereochemistries of dinophysistoxin-1 and dinophysistoxin-2 and its consequences for binding to protein phosphatase.
Okadaic acid analogues are well known as protein phosphatase inhibitors and occur naturally in marine shellfish feeding on dinoflagellates of the genus Dinophysis, leading to diarrhetic shellfish poisoning of shellfish consumers. Knowledge of the correct structures for these toxins is important in understanding their toxicology, biochemistry, and biosynthesis. We have performed extensive NMR analyses on okadaic acid (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 and DTX-2 based on analysis of NMR coupling constants and NOE interactions. Our results revealed that DTX-2 (3) has a stereochemistry opposite to that of DTX-1 (2) at C-35. Molecular modeling of the docking of 1-3 with protein phosphatase-1 and protein phosphatase 2A (PP2A) suggested that the reduced affinity 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.
Larsen
Kristofer
K
Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, NO-0315 Oslo, Norway.
Petersen
Dirk
D
Wilkins
Alistair L
AL
Samdal
Ingunn A
IA
Sandvik
Morten
M
Rundberget
Thomas
T
Goldstone
David
D
Arcus
Vickery
V
Hovgaard
Peter
P
Rise
Frode
F
Rehmann
Nils
N
Hess
Philipp
P
Miles
Christopher O
CO
D000818:Animals; D002247:Carbon Isotopes; D019295:Computational Biology; D004141:Dinoflagellida / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008387:Marine Toxins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009587:Nitrogen Isotopes; D019319:Okadaic Acid / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000031:analogs & derivatives; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D011714:Pyrans / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D012997:Solvents / Q000737:chemistry
D002247:Carbon Isotopes; D008387:Marine Toxins; D009587:Nitrogen Isotopes; D011714:Pyrans; D012997:Solvents; D019319:Okadaic Acid; C051904:dinophysistoxin 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C076221:dinophysistoxin 2