Journal of Bacteriology, August 1998, p. 4068-4079, Vol. 180, No. 16
0021-9193/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E9
Received 24 March 1998/Accepted 4 June 1998
As part of a search for transcriptional regulatory genes, sequence
analysis of several previously unsequenced gaps in the cephamycin
biosynthetic cluster has revealed the presence in Streptomyces clavuligerus of seven genes not previously described. These
include genes encoding an apparent penicillin binding protein and a
transport or efflux protein, as well as the CmcI and CmcJ proteins,
which catalyze late reactions in the cephamycin biosynthetic pathway. In addition, we discovered a gene, designated pcd, which
displays significant homology to genes encoding semialdehyde
dehydrogenases and may represent the gene encoding the
long-sought-after dehydrogenase involved in the conversion of lysine to
-aminoadipate. Finally, two genes, sclU and
rhsA, with no obvious function in cephamycin biosynthesis
may define the end of the cluster. The previously described CcaR
protein displays homology to a number of Streptomyces pathway-specific transcriptional activators. The ccaR gene
was shown to be essential for the biosynthesis of cephamycin,
clavulanic acid, and non-clavulanic acid clavams. Complementation of a
deletion mutant lacking ccaR and the adjacent
orf11 and blp genes showed that only
ccaR was essential for the biosynthesis of cephamycin, clavulanic acid, and clavams and that mutations in orf11 or
blp had no discernible effects. The lack of cephamycin
production in ccaR mutants was directly attributable to the
absence of biosynthetic enzymes responsible for the early and middle
steps of the cephamycin biosynthetic pathway. Complementation of the
ccaR deletion mutant resulted in the return of these
biosynthetic enzymes and the restoration of cephamycin production.
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