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James W. Campbell
Professor Emeritus
e-mail:[email protected]
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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.