Evaluation of epigallocatechin gallate and related plant polyphenols as inhibitors of the FabG and FabI reductases of bacterial type II fatty-acid synthase.
Epigallocatechin gallate (EGCG) is the major component of green tea extracts and possesses antibacterial, antiviral, and antitumor activity. Our study focused on validating the inhibition of the bacterial type II fatty acid synthesis system as a mechanism for the antibacterial effects of EGCG and related plant polyphenols. EGCG and the related tea catechins potently inhibited both the FabG and FabI reductase steps in the fatty acid elongation cycle with IC(50) values between 5 and 15 microm. The presence of the galloyl moiety was essential for activity, and EGCG was a competitive inhibitor of FabI and a mixed type inhibitor of FabG demonstrating that EGCG interfered with cofactor binding in both enzymes. EGCG inhibited acetate incorporation into fatty acids in vivo, although it was much less potent than thiolactomycin, a validated fatty acid synthesis inhibitor, and overexpression of FabG, FabI, or both did not confer resistance. A panel of other plant polyphenols was screened for FabG/FabI inhibition and antibacterial activity. Most of these inhibited both reductase steps, possessed antibacterial activity, and inhibited cellular fatty acid synthesis. The ability of the plant secondary metabolites to interfere with the activity of multiple NAD(P)-dependent cellular processes must be taken into account when assessing the specificity of their effects.
Zhang
Yong-Mei
YM
Protein Science Division, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Rock
Charles O
CO
D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology*; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D029968:Escherichia coli Proteins; D054889:Fatty Acid Synthase, Type II; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010636:Phenols / Q000302:isolation & purification / Q000494:pharmacology*; D059808:Polyphenols; D013662:Tea / Q000737:chemistry
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D005419:Flavonoids; D009097:Multienzyme Complexes; D010636:Phenols; D059808:Polyphenols; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C023744:acetoacetyl-CoA reductase; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); C493924:fabI protein, E coli; D000123:Acetyltransferases; D054889:Fatty Acid Synthase, Type II