Inhibitory Effects of Flavonoids on Animal Fatty Acid Synthase

The inhibitory effects of 15 flavonoids on animal fatty acid synthase (FAS, EC 2.3.1.85) were investigated, and 9 of them were found to inhibit FAS with IC(50) (the inhibitor concentration inhibiting 50% of the activity of FAS) values ranging from 2 to 112 microM. A structure-activity relationship study showed that the flavonoids containing two hydroxyl groups in the B ring and 5,7-hydroxyl groups in the A ring in combination with a C-2, 3 double bond were the most inhibitory. Morin (IC(50) = 2.33 +/- 0.09 microM) was further investigated kinetically to detail the inhibitory mechanism. The results showed that morin inhibited the overall reaction of FAS competitively with Ac-CoA, noncompetitively with Mal-CoA and in a mixed manner with NADPH. The study indicated that morin bound reversibly to the beta-ketoacyl synthase domain of FAS to inhibit the elongation of the saturated acyl groups in fatty acids synthesis.