Chemical properties of fatty acid derivatives as inhibitors of DNA polymerases.
In this study, the chemical properties of organic acids as DNA polymerase inhibitors were examined. In total, we assayed the inhibitory activities of 23 compounds. We found that the DNA synthesis activity of DNA polymerase was usually reduced to less than 50% in the presence of 100 microM monoprotic acids, which have a Clog P value greater than 7.0 and a pK(a) value less than 5.4. With a minor modification these chemical properties applied to several organic fatty acids previously reported as DNA polymerase inhibitors. Moreover, we also examined the inhibitory activities of perfluorooctadecanoic acid (PFOdA) and perfluorooctanesulfonic acid (PFOS) against DNA polymerase beta in detail. These compounds inhibited the polymerase activity of pol beta competitively with template-primer DNA, and non-competitively with dNTPs. In addition, the 8 kDa domain-defective pol beta was also sensitive to these compounds. Our results suggest that the inhibitory mode of action of PFOdA and PFOS is different from that mediated by the classic fatty acid inhibitors against DNA polymerase beta.
Nakamura
Ryoichi
R
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Takeuchi
Ryo
R
Kuramochi
Kouji
K
Mizushina
Yoshiyuki
Y
Ishimaru
Chisato
C
Takakusagi
Yoichi
Y
Takemura
Masaharu
M
Kobayashi
Susumu
S
Yoshida
Hiromi
H
Sugawara
Fumio
F
Sakaguchi
Kengo
K
D017738:Alkanesulfonic Acids / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003652:Decanoic Acids / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005466:Fluorocarbons / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D017738:Alkanesulfonic Acids; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D005466:Fluorocarbons; C036567:perfluorodecanoic acid; D004247:DNA; C427203:calf thymus DNA; C076994:perfluorooctane sulfonic acid; D004256:DNA Polymerase I; D019951:DNA Polymerase beta