The galloyl moiety of green tea catechins is the critical structural feature to inhibit fatty-acid synthase.
It has been reported that inhibition of fatty-acid synthase (FAS) is selectively cytotoxic to human cancer cells. Considerable interest has developed in identifying novel inhibitors of this enzyme complex. Our previous work showed that green tea (-)-epigallocatechin gallate can inhibit FAS in vitro. To elucidate the structure-activity relationship of the inhibitory effects of tea polyphenols, we investigated the inhibition kinetics of the major catechins and analogues. Ungallated catechins from green tea do not show obvious inhibition compared with gallated catechins. Another gallated catechin, (-)-epicatechin gallate, was also found as a potent inhibitor of FAS and its inhibition characteristics are similar to (-)-epigallocatechin gallate. Furthermore, the analogues of galloyl moiety without the catechin skeleton such as propyl gallate also showed obvious slow-binding inhibition, whereas the green tea ungallated catechin not. Atomic orbital energy analyses suggest that the positive charge is more distinctly distributed on the carbon atom of ester bond of galloyl moiety of gallate catechins, and that gallated forms are more susceptible for a nucleophilic attack than other catechins. Here we identify the galloyl moiety of green tea catechins as critical in the inactivation of the ketoacyl reductase activity of FAS for the first time.
Wang
Xuan
X
Department of Biology, Graduate School of Chinese Academy of Sciences, Beijing 100039, PR China.
Song
Ke-Sheng
KS
Guo
Qing-Xiang
QX
Tian
Wei-Xi
WX
D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D002645:Chickens; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D059808:Polyphenols; D013329:Structure-Activity Relationship; D013662:Tea / Q000737:chemistry*
D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D013662:Tea; D002392:Catechin; C062669:epicatechin gallate; C045651:epigallocatechin gallate; D064429:Fatty Acid Synthases