Human Molecular Genetics, Vol 6, 963-968, Copyright © 1997 by Oxford University Press
H Morizono, CD Listrom, BS Rajagopal, M Aoyagi, MT McCann, NM Allewell and M Tuchman
Although many mutations in the ornithine transcarbamylase gene have been
correlated with 'late onset' of hyperammonemia in patients, the effects of
these mutations on enzyme function are largely unknown. Three recurrent
mutations (R40H, R277W and R277Q) found in patients with 'late onset'
disease were incorporated into 'mature' human ornithine transcarbamylase
cDNA and overexpressed in Escherichia coli. The three recombinant mutant
enzymes were purified to homogeneity on an affinity column and their
biochemical characteristics were compared to the wild type enzyme. The
R277W and R277Q mutants display markedly reduced affinity for L-ornithine,
loss of substrate inhibition, alkaline shift of pH optimum, and reduced
thermal stability compared to the wild type enzyme. These differences,
particularly the reduced affinity for L-ornithine, are sufficient to
account for their biochemical effects. In contrast, the 'mature' R40H
mutant was biochemically indistinguishable from the wild type enzyme in
vitro.
ARTICLES
'Late onset' ornithine transcarbamylase deficiency: function of three purified recombinant mutant enzymes
Department of Biochemistry, College of Biological Sciences, University of Minnesota, St Paul 55108, USA.
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