Molecular Pharmacology, Vol 8, 139-148, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Studies with Specific Enzyme Inhibitors

XIV. The Effects of Enzymatically Synthesized (-)-erythro-Fluoromalic Acid on Malate Dehydrogenase and on Anion Carriers of Liver Mitochondria

¹ Departments of Pharmacology, Biochemistry, and Biophysics and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94122

Enzymatic synthesis and isolation of fluoromalate with a tentatively assigned (-)-erythro configuration is described. Fluoromalate inhibits purified malate dehydrogenase (K_i = 13 or 16 µM) but has no effect on the oxidation of pyruvate and succinate by liver mitochondria, indicating that fluoromalate does not penetrate the inner mitochondrial membrane. Oxidation of externally added L-malate is reversibly inhibited by fluoromalate when the latter is present at higher concentrations than malate. Oxidation of tricarboxylic acids and of -ketoglutarate is greatly increased under state 3 conditions by fluoromalate. The rate of citrate-isocitrate translocation in mitochondria is activated by fluoromalate to the same extent as the metabolism of tricarboxylic acids. It is concluded that fluoromalate competitively inhibits the malate carrier and activates the carriers of tricarboxylic acids and of -ketoglutarate.

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ACKNOWLEDGMENT We are indebted to Miss C. Fegte for typing the manuscript.