Inhibition of Enzymes which Interact with Citrate by (—)Hydroxycitrate and 1,2,3,‐Tricarboxybenzene

The effects of two citrate analogues, (—)hydroxycitrate and 1,2,3‐tricarboxybenzene, were studied using rat liver enzymes which interact with citrate. The most pronounced effect of 1,2,3‐tricarboxybenzene was inhibition of acetyl‐CoA carboxylase (Ki 20 μM). It also inhibited the mitochondrial citrate transporter (50% inhibition at 3 mM), but was not a substrate for this transporter. ATP‐citrate lyase was markedly inhibited by both free (—)hydroxycitrate (Ki 8 μM) and (—)hydroxycitrate lactone (Ki 50 to 100 μM). Acetyl‐CoA carboxylase was activated by both the forms of (—)hydroxycitrate (Ka 0.7 mM and 1.6 mM, respectively). (—)Hydroxycitrate is a substrate for the mitochondrial citrate transporter, but its rate of transport is less than 10% of that of citrate. Other citrate metabolizing enzymes also were inhibited by 1,2,3‐tricarboxybenzene and (—)hydroxycitrate but much higher concentrations were required.