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James W. Campbell Professor Emeritus e-mail:[email protected] B.S. (1953) Southwest Missouri State University, Springfield M.S. (1955) University of Illinois, Urbana Ph.D. (1958) University of Oklahoma Research Areas Comparative biochemistry of nitrogen metabolism in vertebrate liver. Research Statement My current interest is the theoretical basis for ammonia detoxication in vertebrate liver. This ammonia may be of either hepatic or extrahe- patic origin. Liver tissue is the site of gluconeogenesis in higher vertebrates and, during this process, amino acids are deaminated, forming ammonia. Extrahepatic tissues, especially working muscle, form ammonia which must be returned to the liver for detoxication. Working muscle also forms glutamine which is deamidated in mammalian liver forming additional ammonia. In mammals, the site of detoxication is the mitochondrial matrix of hepatocytes. This is true for ammonia arising in this compartment, in the cytosol, or in extrahepatic tissues. The classical pathway for ammonia detoxication in mammals is the urea cycle. Carbamyl phosphate synthetase-I (CPS-1) and ornithine transcarbamylase (OTC), the first two enzymes of the pathway, are localized exclusively in the mitochondrial matrix. Their combined activities convert ammonia to the carbamyl function of citrulline which then exits to the cytosol for conversion to urea for excretion. Birds and reptiles do not express CPS-1 and are thus incapable of detoxifying ammonia via the urea cycle. Rather, ammonia arising in or entering the matrix of their hepatic mitochondria is converted to the amide function of glutamine by glutamine synthetase. Glutamine then exits to the cytosol where the amide function contributes N-3 and N-9 of the purine ring which is excreted as uric acid. A comparison of the chemistries of the citrulline carbamyl and glutamine amide functionalities has led to the formulation of the proton-neutral theory for ammonia detoxication. This theory derives directly from the chemiosmotic theory for oxidative and photosynthetic phosphorylation. According to the chemiosmotic theory, during electron transport, protons are pumped across either the mitochondrial inner membrane or the thylakoid membrane thus forming both a concentration and an electrical gradient. These gradients represent the proton-motive force for the conservation of the energy of oxidation or photosynthesis. During passage of the protons through the proton-specific channels of ATP synthase, this energy is utilized for the synthesis of ATP. Because of the relative alkalinity of the mitochondrial matrix and thylacoid stroma, a high percentage of ammonia in these compartments exists as NH3. This form of ammonia is known to uncouple phosphorylation by dissipating the proton gradient across membranes by binding protons to form NH4+. Neither the carbamyl nor amide functionalities protonate at physiological pHs so the conversion of NH3 to one or the other thus allows for the transit of a proton-neutral form of ammonia, thereby preventing uncoupling. Selected Publications Other Campbell, J.W. "Mitochondrial Ammonia Metabolism and the Proton-neutral Theory of Hepatic Ammonia Detoxication." J. Exp. Zool., 278 (1997) : 308-321.