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(Received for publication, September 16, 1996, and in revised form, December 9, 1996)
From the Department of Biochemistry and Molecular Biology, The
Albany Medical College, Albany, New York 12208
Fatty acyl-CoA synthetase (fatty acid:CoA ligase,
AMP-forming; EC 6.2.1.3) catalyzes the formation of fatty acyl-CoA by a
two-step process that proceeds through the hydrolysis of pyrophosphate. In Escherichia coli this enzyme plays a pivotal role in the
uptake of long chain fatty acids (C12-C18) and in the regulation of
the global transcriptional regulator FadR. The E. coli
fatty acyl-CoA synthetase has remarkable amino acid similarities and
identities to the family of both prokaryotic and eukaryotic fatty
acyl-CoA synthetases, indicating a common ancestry. Most notable in
this regard is a 25-amino acid consensus sequence,
DGWLHTGDIGXWXPXGXLKIIDRKK, common to all fatty acyl-CoA synthetases for which sequence information is available. Within this consensus are 8 invariant and 13 highly conserved amino acid residues in the 12 fatty acyl-CoA synthetases compared. We propose that this sequence represents the fatty acyl-CoA synthetase signature motif (FACS signature motif). This region of fatty
acyl-CoA synthetase from E. coli,
431NGWLHTGDIAVMDEEGFLRIVDRKK455, contains 17 amino acid residues that are either identical or highly conserved to
the FACS signature motif. Eighteen site-directed mutations within the
fatty acyl-CoA synthetase structural gene (fadD)
corresponding to this motif were constructed to evaluate the
contribution of this region of the enzyme to catalytic activity. Three
distinct classes of mutations were identified on the basis of growth
characteristics on fatty acids, enzymatic activities using cell
extracts, and studies using purified wild-type and mutant forms of the
enzyme: 1) those that resulted in either wild-type or nearly wild-type
fatty acyl-CoA synthetase activity profiles; 2) those that had little
or no enzyme activity; and 3) those that resulted in lowering and
altering fatty acid chain length specificity. Among the 18 mutants
characterized, 7 fall in the third class. We propose that the FACS
signature motif is essential for catalytic activity and functions in
part to promote fatty acid chain length specificity and thus may
compose part of the fatty acid binding site within the enzyme.
Volume 272, Number 8,
Issue of February 21, 1997
pp. 4896-4903
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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