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J. Biol. Chem., Vol. 276, Issue 40, 37051-37059, October 5, 2001
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From the Exogenous long-chain fatty acids are activated to
coenzyme A derivatives prior to metabolic utilization. In the yeast
Saccharomyces cerevisiae, the activation of these compounds
prior to metabolic utilization proceeds through the fatty acyl-CoA
synthetases Faa1p and Faa4p. Faa1p or Faa4p are essential for
long-chain fatty acid import, suggesting that one or both of these
enzymes are components of the fatty acid transport system, which also
includes Fat1p. By monitoring the intracellular accumulation of the
fluorescent long-chain fatty acid analogue
4,4-difluoro-5-methyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoic acid, long-chain fatty acid transport was shown to be severely restricted in a faa1
The Acyl-CoA Synthetases Encoded within FAA1 and
FAA4 in Saccharomyces cerevisiae
Function as Components of the Fatty Acid Transport System Linking
Import, Activation, and Intracellular Utilization*
§,,,
Center for Cardiovascular Sciences, Albany
Medical College, Albany, New York 12208 and the ¶ Institute of
Biochemistry and Molecular Biology, University of Southern Denmark,
Odense M, Denmark DK 5220
faa4 strain. These
data established for the first time a mechanistic linkage between the
import and activation of exogenous fatty acids in yeast. To investigate
this linkage further, oleoyl CoA levels were defined following
incubation of wild type and mutant cells with limiting concentrations
of exogenous oleate. These studies demonstrated oleoyl CoA levels were
reduced to less than 10% wild-type levels in faa1 and
faa1 faa4 strains. Defects in metabolic
utilization and intracellular trafficking were also found in the fatty
acyl-CoA synthetase-deficient strains. The faa1
faa4 strain had a marked reduction in endogenous
acyl-CoA pools, suggesting these enzymes play a role in maintenance of endogenous acyl-CoA pools, metabolism and trafficking. In addition, this strain had levels of in vivo 
-oxidation of
exogenous oleate reduced 3-fold when compared with the isogenic parent.
Northern analyses demonstrated an additional defect in fatty acid
trafficking as FAA1 or FAA4 were required for
the transcriptional regulation of the genes encoding the peroxisomal
enzymes acyl-CoA oxidase (POX1) and medium-chain acyl-CoA
synthetase (FAA2). These data support the hypothesis that
fatty acyl-CoA synthetase (Faa1p or Faa4p) functions as a component of
the fatty acid import system by linking import and activation of
exogenous fatty acids to intracellular utilization and signaling.
*
This work was supported in part by National Institutes of
Health Grant GM56840 (to P. N. B. and C. C. D.) and
by American Heart Association Grant 9750550N (to C. C. D.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Center for
Cardiovascular Sciences, Albany Medical College MC-8, 47 New Scotland Ave., Albany, NY 12208. Tel.: 518-262-6435; Fax: 518-262-8101; E-mail: dirussc@mail.amc.edu.
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