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J Biol Chem, Vol. 274, Issue 6, 3402-3406, February 5, 1999
-Oxidation on Cytosolic Sources of
NADPH
From the Department of Biochemistry, University of Texas Health
Science Center, San Antonio, Texas 78284-7760
Growth of Saccharomyces cerevisiae
with a fatty acid as carbon source was shown previously to require
function of either glucose-6-phosphate dehydrogenase (ZWF1) or
cytosolic NADP+-specific isocitrate dehydrogenase (IDP2),
suggesting dependence of 
-oxidation on a cytosolic source of NADPH.
In this study, we find that 
IDP2ZWF1 strains
containing disruptions in genes encoding both enzymes exhibit a rapid
loss of viability when transferred to medium containing oleate as the
carbon source. This loss of viability is not observed following
transfer of a IDP3 strain lacking peroxisomal isocitrate
dehydrogenase to medium with docosahexaenoate, a nonpermissive carbon
source that requires function of IDP3 for -oxidation. This suggests
that the fatty acid
phenotype of
IDP2ZWF1 strains is not a simple defect in
utilization. Instead, we propose that the common function shared by
IDP2 and ZWF1 is maintenance of significant levels of NADPH for
enzymatic removal of the hydrogen peroxide generated in the first step
of peroxisomal -oxidation in yeast and that inadequate levels of the
reduced form of the cofactor can produce lethality. This proposal is
supported by the finding that the sensitivity to exogenous hydrogen
peroxide previously reported for ZWF1 mutant strains is
less pronounced when analyses are conducted with a nonfermentable carbon source, a condition associated with elevated expression of IDP2.
Under those conditions, similar slow growth phenotypes are observed for
ZWF1 and IDP2 strains, and co-disruption
of both genes dramatically exacerbates the
H2O2s phenotype. Collectively,
these results suggest that IDP2, when expressed, and ZWF1 have critical
overlapping functions in provision of reducing equivalents for defense
against endogenous or exogenous sources of
H2O2.
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