Penicilliols A and B, novel inhibitors specific to mammalian Y-family DNA polymerases.
Penicilliols A (1) and B (2) are novel 5-methoxy-3(2H)-furanones isolated from cultures of a fungus (Penicillium daleae K.M. Zalessky) derived from a sea moss, and their structures were determined by spectroscopic analyses. These compounds selectively inhibited activities of eukaryotic Y-family DNA polymerases (pols) (i.e., pols eta, iota and kappa), and compound 1 was a stronger inhibitor than compound 2. Among mammalian Y-family pols, mouse pol iota activity was most strongly inhibited by compounds 1 and 2, with IC(50) values of 19.8 and 32.5 microM, respectively. On the other hand, activities of many other pols, such as A-family (i.e., pol gamma), B-family (i.e., pols alpha, delta and epsilon) or X-family (i.e., pols beta, lambda and terminal deoxynucleotidyl transferase), and some DNA metabolic enzymes, such as calf primase of pol alpha, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, mouse IMP dehydrogenase (type II), human topoisomerases I and II, T4 polynucleotide kinase or bovine deoxyribonuclease I, are not influenced by these compounds. In conclusion, this is the first report on potent inhibitors of mammalian Y-family pols.
Kimura
Takuma
T
Department of Applied Biological Science, Science University of Tokyo, Noda, Chiba, Japan.
Takeuchi
Toshifumi
T
Kumamoto-Yonezawa
Yuko
Y
Ohashi
Eiji
E
Ohmori
Haruo
H
Masutani
Chikahide
C
Hanaoka
Fumio
F
Sugawara
Fumio
F
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
D000818:Animals; D002417:Cattle; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007783:Lactones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors; D010407:Penicillium / Q000737:chemistry*
D004791:Enzyme Inhibitors; D007783:Lactones; D019384:Nucleic Acid Synthesis Inhibitors; C540736:penicilliol A; C540735:penicilliol B; D004259:DNA-Directed DNA Polymerase