Inhibition of rat liver acetyl-CoA carboxylase by β,β′-tetramethyl-substituted hexadecanedioic acid (MEDICA 16)

Abstract

Rat liver acetyl-CoA carboxylase activity was inhibited by the free as well as the CoA monothioester of β,β'-methylsubstituted hexadecanedioic acid (MEDICA 16) (Bar-Tana, J., Rose-Kahn, G. and Srebnik, M. (1985) J. Biol. Chem. 260, 8404–8410 (1985). (1) The CoA monothioester of MEDICA 16 served as a dead-end inhibitor with an apparent K i of 2 μM and 58 μM for the biotin-carboxylated and noncarboxylated enzyme forms, respectively. MEDICA 16-CoA binding was not mutually exclusive with that of citrate and did not affect the avidin-resistance of rat liver acetyl-CoA carboxylase. (2) The free dioic acid of MEDICA 16 was competitive to citrate, having an apparent K i of about 70 μM, as compared to a K a of 2–8 mM for the citrate activator. Inhibition of the carboxylase by the free dioic acid of MEDICA 16 was accompanied by an increase in its avidin resistance. The resultant inhibition of acetyl-CoA carboxylase by MEDICA 16 and its CoA thioester, together with the previously reported citrate-competitive inhibition of ATP-citrate lyase by MEDICA 16, may account for the observed hypolipidemic effect of MEDICA 16 under dietary conditions where liver lipogenesis constitutes a major flux of liver lipid synthesis.