Inhibition of telomerase by linear-chain fatty acids: a structural analysis.
In the present study, we have found that mono-unsaturated linear-chain fatty acids in the cis configuration with C(18) hydrocarbon chains (i.e. oleic acid) strongly inhibited the activity of human telomerase in a cell-free enzymic assay, with an IC(50) value of 8.6 microM. Interestingly, fatty acids with hydrocarbon chain lengths below 16 or above 20 carbons substantially decreased the potency of inhibition of telomerase. Moreover, the cis-mono-unsaturated C(18) linear-chain fatty acid oleic acid was the strongest inhibitor of all the fatty acids tested. A kinetic study revealed that oleic acid competitively inhibited the activity of telomerase ( K (i)=3.06 microM) with respect to the telomerase substrate primer. The energy-minimized three-dimensional structure of the linear-chain fatty acid was calculated and modelled. A molecule width of 11.53-14.26 A (where 1 A=0.1 nm) in the C(16) to C(20) fatty acid structure was suggested to be important for telomerase inhibition. The three-dimensional structure of the telomerase active site (i.e. the substrate primer-binding site) appears to have a pocket that could bind oleic acid, with the pocket being 8.50 A long and 12.80 A wide.
Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation, Toda-shi, Saitama 335-8502, Japan.
Masako
M
Oda
Takamasa
T
Ueno
Nobuyuki
N
Kasai
Hirotada
H
Takahashi
Hiromi
H
Yoshida
Fumio
F
Sugawara
Kengo
K
Sakaguchi
Hideya
H
Hayashi
Yoshiyuki
Y
Mizushina
D001665:Binding Sites; D002474:Cell-Free System; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D019301:Oleic Acid / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D019301:Oleic Acid; D019098:Telomerase