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Vol. 8, Issue 11, 2281-2290, November 1997
9-Desaturase
Department of Biochemistry, University of Connecticut Health
Center, Farmington, Connecticut 06030
9-Desaturase is a key enzyme in the synthesis of
desaturated fatty acyl-CoAs. Desaturase is an integral membrane protein
induced in the endoplasmic reticulum by dietary manipulations and then rapidly degraded. The proteolytic machinery that specifically degrades
desaturase and other short-lived proteins in the endoplasmic reticulum
has not been identified. As the first step in identifying cellular
factors involved in the degradation of desaturase, liver subcellular
fractions of rats that had undergone induction of this enzyme were
examined. In livers from induced animals, desaturase was present in the
microsomal, nuclear (P-1), and subcellular fractions (P-2). Incubation
of desaturase containing fractions at physiological pH and temperature
led to the complete disappearance of the enzyme. Washing microsomes
with a buffer containing high salt decreased desaturase degradation
activity. N-terminal sequence analysis of desaturase freshly isolated
from the P-1 fraction without incubation indicated the absence of three
residues from the N terminus, but the mobility of this desaturase
preparation on SDS-PAGE was identical to the microsomal desaturase,
which contains a masked N terminus under similar purification
procedures. Addition of concentrated cytosol or the high-salt wash
fraction did not enhance the desaturase degradation in the washed
microsomes. Extensive degradation of desaturase in the high-salt washed
microsomes could be restored by supplementation of the membranes with
the lipid and protein components essential for the reconstituted
desaturase catalytic activity. Lysosomotrophic agents leupeptin and
pepstatin A were ineffective in inhibiting desaturase degradation. The
calpain inhibitor, N-acetyl-leucyl-leucyl-methional, or
the proteosome inhibitor, Streptomyces metabolite,
lactacystin, did not inhibit the degradation of desaturase in the
microsomal or the P-1 and P-2 fractions. These results show that the
selective degradation of desaturase is likely to be independent of the
lysosomal and the proteosome systems. The reconstitution of complete
degradation of desaturase in the high-salt-washed microsomes by the
components essential for its catalytic activity reflects that the
degradation of this enzyme may depend on a specific orientation of
desaturase and intramembranous interactions between desaturase and the
responsible protease.
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