ALPHA-FLUORO ACID AND ALPHA-FLUORO AMIDE ANALOGS OF ACETYL-COA AS INHIBITORS OF CITRATE SYNTHASE - EFFECT OF PK(A) MATCHING ON BINDING-AFFINITY AND HYDROGEN-BOND LENGTH

An alpha-fluoro acid analog and an alpha-fluoro amide analog of acetyl -CoA have been synthesized. The ternary complexes of these inhibitors with oxaloacetate and citrate synthase have been crystallized and thei r structures analyzed at 1.7 Angstrom resolution. The structures are s imilar to those reported for the corresponding non-fluorinated analogs (Usher et al., 1994), with all forming unusually short hydrogen bonds to Asp 375. The alpha-fluoro amide analog binds with an affinity 1.5- fold lower than that of a previously described amide analog lacking th e alpha-fluoro group. The alpha-fluoro acid analog binds with a 50-fol d decreased affinity relative to the corresponding unfluorinated analo g. The binding affinities are consistent with increased strengths of h ydrogen bonds to Asp 375 with closer matching of pK(a) values between hydrogen bond donors and accepters. The results do not support any dir ect correlation between hydrogen bond strength and hydrogen bond lengt h in enzyme-inhibitor complexes.