Insight into binding of calyculin A to protein phosphatase 1: isolation of hemicalyculin a and chemical transformation of calyculin A.
Calyculin A isolated from the marine sponge Discodermia calyx is a potent inhibitor of protein phosphatases 1 and 2A. We attempted to elucidate its mode of binding to the enzymes by examining the activity of natural and chemically transformed derivatives. Ten natural derivatives including a new compound, hemicalyculin A, were provided. The structure of hemicalyculin A, which comprises the southern hemisphere of calyculin A, was firmly established by chemical methods. Six compounds were prepared by selective modifications of functional groups in calyculin A. The enzyme inhibitory activity of these compounds indicated that 17-phosphate, 13-hydroxyl, and the hydrophobic tetraene moieties were all necessary for binding to the enzymes. The derivatives lacking the peptide portion were less cytotoxic even when they possessed full enzyme inhibitory activity.
Wakimoto
Toshiyuki
T
Laboratory of Aquatic Natural Products Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Matsunaga
Shigeki
S
Takai
Akira
A
Fusetani
Nobuhiro
N
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007941:Leukemia P388; D008387:Marine Toxins; D051379:Mice; D010080:Oxazoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011161:Porifera / Q000737:chemistry; D054645:Protein Phosphatase 1; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1