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© 1993 Oxford University Press

RESEARCH-ARTICLE

Expression and processing of human ornithine-{delta}-aminotransferase in Saccharomyces cerevisiae

Kristiann M. Dougherty, Deborah A. Swanson, Lawrence C. Brody1 and David Valle1

Predoctoral Training Program in Human Genetics 1Howard Hughes Medical Institute, Johns Hopkins University School of Medicine Baltmore, MD 21205, USA

Received July 20, 1993; Revised August 18, 1993; Accepted August 18, 1993

Ornithlne-{delta}-aminotransferase catalyzes the conversion of omithine to glutamate-{gamma}-semialdehyde. In humans, deficiency of this mitochondrial matrix enzyme results in the progressive blinding disorder, gyrate atrophy of the chorold and retina. To explore yeast as an expression system, we introduced a cDNA encoding human ornithine-{delta}-aminotransferase into an ornithine aminotransferase-deficient strain of Saccharomyces cerevlslae. The human enzyme was expressed at high levels, with activity 20-fold greater than that of wild-type yeast and 10-fold higher than in human fibroblasts. Although the normal location of ornithine-{delta}-aminotransferase in S.cerevislae is cytosolic, human ornithine-{delta}-aminotransferase expressed in S.cerevislae was localized to the mitochondrial matrix with correct proteolytic processing of its mitochondrial leader sequence. Despite this anomalous location in yeast, human omithine-{delta}-aminotransferase complemented the phenotype of the mutant strain, restoring its ability to utilize omithine as a sole nitrogen source. We also expressed a vitamin B6-responsive missense allele of ornithine-{delta}-aminotransferase (V332M) and showed that the biochemical phenotype of this allele is easily demonstrated confirming the usefulness of this system for examining mutations causing gyrate atrophy.


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