Inhibitory effect of mispyric acid on mammalian DNA polymerases.
Mispyric acid is a novel natural triterpene dicarboxylic acid which has inhibitory activity against DNA polymerase beta (pol beta) isolated from the plant, Mischocarpus pyriformis. In this report, we examine the selectivity of the inhibitory activity against mammalian pols and the mode of inhibition in vitro. Natural mispyric acid (compound 1) inhibited the activities of all the mammalian pols tested (pol alpha, beta, gamma, delta and epsilon) with an IC50 value in the range of 3.6-44.5 microM. The inhibition was strongest for pol gamma among these five pols. The enantiomer of mispyric acid (compound 2, ent-mispyric acid) had similar effects to those of the natural compound. However, derivatives of compounds 1 and 2 with hydroxyl groups instead of carboxyl groups (i.e., compounds 3 and 4, respectively) exhibited no inhibitory effect on mammalian pols. The moiety of two carboxylic acids in mispyric acid was important for the inhibition of pols, and the stereoisomers of mispyric acid had no inhibitory effect.
Mizushina
Yoshiyuki
Y
Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Hyogo, Japan. mizushin@nutr.kobegakuin.ac.jp
Takikawa
Hirosato
H
Imamura
Yusuke
Y
Sasaki
Mitsuru
M
Mori
Kenji
K
Yoshida
Hiromi
H
D000818:Animals; D002417:Cattle; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors*; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D014315:Triterpenes / Q000494:pharmacology*
D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D014315:Triterpenes; C505735:mispyric acid; D004256:DNA Polymerase I; D019951:DNA Polymerase beta