Inhibitory effect of conjugated eicosapentaenoic acid on human DNA topoisomerases I and II

Yuko Yonezawa, Tsuyoshi Tsuzuki, Takahiro Eitsuka, Teruo Miyazawa, Takahiko Hada, Keisuke Uryu, Chikako Murakami-Nakai, Hiroshi Ikawa, Isoko Kuriyama, Masaharu Takemura, Masahiko Oshige, Hiromi Yoshida, Kengo Sakaguchi, Yoshiyuki Mizushina

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

DNA topoisomerases (topos) and DNA polymerases (pols) are involved in many aspects of DNA metabolism such as replication reactions. We reported previously that long chain unsaturated fatty acids such as polyunsaturated fatty acids (PUFA) (i.e., eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA)) inhibited the activities of eukaryotic pols in vitro [Biochim. Biophys. Acta 1336 (1997) 509]. In the present study, we found that PUFA also inhibited human topos I and II activities, and the inhibitory effect of conjugated fatty acids converted from EPA and DHA (cEPA and cDHA) on pols and topos was stronger than that of normal EPA and DHA. cEPA and cDHA inhibited the activities of mammalian pols and human topos, but did not affect the activities of plant and prokaryotic pols or other DNA metabolic enzymes tested. cEPA was a stronger inhibitor than cDHA with IC50 values for mammalian pols and human topos of 11.0-31.8 and 0.5-2.5 μM, respectively. Therefore, the inhibitory effect of cEPA on topos was stronger than that on pols. Preincubation analysis suggested that cEPA directly bound both topos I and II, but did not bind or interact with substrate DNA. This is the first report that conjugated PUFA such as cEPA act as inhibitors of pols and topos. The results support the therapeutic potential of cEPA as a leading anti-cancer compound that poisons pols and topos.

Original languageEnglish
Pages (from-to)197-206
Number of pages10
JournalArchives of Biochemistry and Biophysics
Volume435
Issue number1
DOIs
Publication statusPublished - 2005 Mar 1

Keywords

  • Conjugated fatty acids
  • DNA polymerases
  • DNA topoisomerases I and II
  • Docosahexanoic acid
  • Eicosapentaenoic acid
  • Polyunsaturated fatty acids

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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