Abstract
We reported previously that unsaturated linear-chain FA of the cis-configuration with a C18-hydrocarbon chain such as linoleic acid (18∶2Δ9c, 12c) could potently inhibit the activities of mammalian DNA polymerases and DNA topoisomerases, but their saturated forms could not. There are chemically two classes of unsaturated FA, normal and conjugated, but only the conjugated forms show potent antitumor activity. In this report, we study the inhibitory effects of chemically synthesized conjugated C18-FA on mammalian DNA polymerases and DNA topoisomerases as compared with normal unsaturated FA. The conjugated α-eleostearic acid (18∶3Δ9c, 11t, 13t) was the strongest of all the FA tested. For the inhibition, the conjugated form is crucially important. The energy-minimized 3-D structures of the FA were calculated, and both a length of less than 20 Å and a width of 8.13–9.24 Å in the C18-FA structure were found to be important for enzyme inhibition. The 3-D structure of the active site of both DNA polymerases and topoisomerases must have had a pocket to join α-eleostearic acid, and this pocket was 12.03 Å long and 9.24 Å wide.
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Abbreviations
- dsDNA:
-
double-stranded DNA
- dTTP:
-
[3h]2′-deoxythymidine 5′-triphosphate
- NP-40:
-
Nonidet P-40
- oligo(dT)12–18 :
-
oligo(12–18) deoxyribothymidylic acid
- pol:
-
DNA-directed DNA polymerase (EC 2.7.7.7)
- poly(dA):
-
polydeoxyriboadenylic acid
- poly(rC):
-
polycytidylic acid
- topo:
-
DNA topoisomerase
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Mizushina, Y., Tsuzuki, T., Eitsuka, T. et al. Inhibitory action of conjugated C18-fatty acids on DNA polymerases and DNA topoisomerases. Lipids 39, 977–983 (2004). https://doi.org/10.1007/s11745-004-1319-y
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DOI: https://doi.org/10.1007/s11745-004-1319-y