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J Biol Chem, Vol. 274, Issue 8, 4671-4683, February 19, 1999
From the Division of Life Sciences, the Bureau of Biological
Research, Nelson Laboratories, Rutgers University,
Piscataway, New Jersey 08854-808
The Saccharomyces cerevisiae
FAT1 gene appears to encode an acyl-CoA synthetase that is
involved in the regulation of very long chain
(C20-C26) fatty acids. Fat1p, has homology to
a rat peroxisomal very long chain fatty acyl-CoA synthetase. Very long chain acyl-CoA synthetase activity is reduced in strains containing a
disrupted FAT1 gene and is increased when FAT1
is expressed in insect cells under control of a baculovirus promoter.
Fat1p accounts for approximately 90% of the C24-specific
acyl-CoA synthetase activity in glucose-grown cells and approximately
66% of the total activity in cells grown under peroxisomal induction
conditions. Localization of functional Fat1p:green fluorescent protein
gene fusions and subcellular fractionation of C24 acyl-CoA
synthetase activities indicate that the majority of Fat1p is located in
internal cellular locations. Disruption of the FAT1 gene
results in the accumulation of very long chain fatty acids in the
sphingolipid and phospholipid fractions. This includes a 10-fold
increase in C24 acids and a 6-fold increase in
C22 acids. These abnormal accumulations are further
increased by perturbation of very long chain fatty acid synthesis.
Overexpression of Elo2p, a component of the fatty acid elongation
system, in fat1
cells causes
C20-C26 levels to rise to approximately 20%
of the total fatty acids. These data suggest that Fat1p is involved in
the maintenance of cellular very long chain fatty acid levels,
apparently by facilitating 
-oxidation of excess intermediate length
(C20-C24) species. Although fat1 cells were reported to grow poorly in oleic
acid-supplemented medium when fatty acid synthase activity is
inactivated by cerulenin, fatty acid import is not significantly
affected in cells containing disrupted alleles of FAT1 and
FAS2 (a subunit of fatty acid synthase). These results
suggest that the primary cause of the growth-defective phenotype is a
failure to metabolize the incorporated fatty acid rather than a defect
in fatty acid transport. Certain fatty acyl-CoA synthetase activities,
however, do appear to be essential for bulk fatty acid transport in
Saccharomyces. Simultaneous disruption of FAA1
and FAA4, which encode long chain
(C14-C18) fatty acyl-CoA synthetases,
effectively blocks the import of long chain saturated and unsaturated
fatty acids.
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