Inhibitive effect of zinc ion on fatty acid synthase from chicken liver

Fatty acid synthase (FAS; acyl-CoA:malonyl-CoA C-acyltransferase [decarboxylating, oxoacyl- and enoyl-reducing and thioester-hydrolyzing], EC 2.3.1.85) is an important enzyme participating in energy metabolism in vivo which is related to adiposis and cancer [Cancer Lett. 167 (1) (2001) 99; Nat. Med. 8 (4) (2002) 335]. Tests of fast- and slow-binding inhibitions showed that fatty acid synthase of chicken liver is rapidly and irreversibly inactivated by low Zn(2+) concentrations. Electrophoresis and FPLC results showed that FAS cross-links occurred in the presence of high Zn(2+) concentrations (>4 microM) which may be another reason that FAS lost its activity. The modification velocity of FAS by DTNB decreased with increasing Zn(2+) concentration, which confirmed that Zn(2+) interacted with SH groups. Substrate protective experiments and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that all three substrates tested had some protective effects on FAS in the presence of Zn(2+), and malonyl-CoA was the most effective of the three substrates. In the presence of malonyl-CoA, the activity loss of FAS decreased sharply and almost no cross-link was observed in SDS-PAGE. This suggests that the phosphopantetheine SH group is the critical group in the cross-link and inhibition of FAS in the presence of Zn(2+).