Inhibitory action of C22-fatty acids on DNA polymerases and DNA topoisomerases.
We reported previously that unsaturated linear-chain fatty acids of the cis-configuration with a C18-hydrocarbon chain such as linoleic acid (cis-9, 12-octadecadienoic acid, C18:2) could potently inhibit the activity of mammalian DNA polymerases (Biochim Biophys Acta 1308: 256-262, 1996). In this study, we investigated the inhibitory effects of cis-type C22-fatty acids including cis-7,10,13,16,19-docosapentaenoic acid (DPA, C22:5) and cis-4,7,10,13,16,19-docosahexaenoic acid (DHA, C22:6) on mammalian DNA polymerases and human DNA topoisomerases. Cis-13,16-docosadienoic acid (C22:2) was the strongest inhibitor of both DNA polymerases and topoisomerases of all C22-fatty acids tested. The inhibitory tendency by the fatty acids on DNA polymerases was the same as that of DNA topoisomerases, and the second strongest inhibitor was cis-13,16,19-docosatrienoic acid (C22:3). The energy-minimized three-dimensional structures of the fatty acids were calculated and it was found that a length of 19-21 Angstrom and width of more than 7 Angstrom in C22-fatty acid structure were important for enzyme inhibition. The three-dimensional structure of the active site of both DNA polymerases and topoisomerases must have a pocket to join C22:2, and this pocket was 19.41 Angstrom long and 9.58 Angstrom wide.
Yonezawa
Yuko
Y
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Hyogo 651-2180, Japan.
Hada
Takahiko
T
Uryu
Keisuke
K
Iijima
Hiroshi
H
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
D000818:Animals; D002417:Cattle; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D026942:DNA Topoisomerases / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology*; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D019384:Nucleic Acid Synthesis Inhibitors; D059003:Topoisomerase Inhibitors
D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D007527:Isoenzymes; D019384:Nucleic Acid Synthesis Inhibitors; D059003:Topoisomerase Inhibitors; D004281:Docosahexaenoic Acids; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D026942:DNA Topoisomerases; C026219:docosapentaenoic acid