Molecular Pharmacology, Vol 2, 481-490, Copyright © 1966 by the American Society for Pharmacology and Experimental Therapeutics

Control of Ammonia Formation From ATP in a Multienzyme System of Liver in Presence of Uncouplers of Oxidative Phosphorylation

¹ Departments of Pharmacology and Biochemistry and the Cardiovascular Research Institute, School of Medicine, University of California, San Francisco Medical Center, San Francisco, California 94122

An in vitro system composed of isolated rat liver mitochondria and an AMP deaminase-containing cytoplasmic protein fraction has been employed for the study of the effect of uncouplers on the enzymic conversion of ATP to IMP + NH₄⁺. Under these conditions one main pathway of ATP degradation is operative. It was shown that this metabolic sequence is initiated by activation of latent mitochondrial ATPase by uncouplers. Under uncoupled conditions, mitochondrial adenylate kinase converts ADP to AMP, which is almost quantitatively converted to IMP + NH₄⁺ by cytoplasmic AMP deaminase. Oligomycin, which has no effect on AMP deaminase or adenylate kinase but counteracts the activating effect of uncouplers on mitochondrial ATPase, inhibits the ATP IMP + NH₄⁺ pathway by blocking the initiating step. An ATP-dependent activation of AMP-deaminase by Mg⁺⁺ has been demonstrated. Relevance of these mechanisms to molecular control of cellular events is discussed.

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ACKNOWLEDGMENTS This work was supported by research grants of the U.S. Public Health Service, RO1-CA-07955-03 and RO1-HD-01239-10, and of the National Science Foundation, GB-3488, and in part by U.S. Public Health Service training grant 2-T1-GM-475-06 (to Dr. El-Fiky).