Structure-activity relationship of polyphenols that inhibit fatty acid synthase.

Many flavone derivatives inhibit FAS, and their A and B rings play an important role, but is the C ring necessary for the inhibition of FAS? Here, using nordihydroguaiaretic acid (NDGA), with two phenyl rings connected by a four-carbon chain, as a representative, the structural basis for the inhibition of animal fatty acid synthase (FAS) by polyphenols was investigated. NDGA potently inhibits the overall reaction of FAS (IC(50) = 9.3 +/- 0.1 muM). The kinetic study indicated that NDGA inhibits FAS competitively with respect to acetyl-CoA, noncompetitively with respect to malonyl-CoA, and in a mixed manner with respect to NADPH. The inhibitory mechanism is the same as that of FAS flavonoid inhibitors. This suggests that the C ring of flavonoids is not essential for their FAS inhibitory effect. This conclusion was further confirmed by the results obtained for different polyphenols. A structure-activity relationship study indicated that a biphenyl core exists in all FAS polyphenol inhibitors. Thus, we propose a common model possibly shared by all FAS polyphenol inhibitors. The model includes two almost planar aromatic rings with their respective hydroxyl groups, and a proper ester linkage between the two rings that possibly causes the inhibition of FAS by irreversibly inhibiting the beta-ketoacyl reductase domain.