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Antimicrobial Agents and Chemotherapy, March 2000, p. 720-726, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Enzymes Catalyzing the Early Steps of Clavulanic Acid Biosynthesis Are Encoded by Two Sets of Paralogous Genes in Streptomyces clavuligerus

Susan E. Jensen,^* Kenneth J. Elder, Kwamena A. Aidoo, and Ashish S. Paradkar

Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E9

Received 6 July 1999/Returned for modification 27 October 1999/Accepted 16 December 1999

Genes encoding the proteins required for clavulanic acid biosynthesis and for cephamycin biosynthesis are grouped into a "supercluster" in Streptomyces clavuligerus. Nine open reading frames (ORFs) associated with clavulanic acid biosynthesis were located in a 15-kb segment of the supercluster, including six ORFs encoding known biosynthetic enzymes or regulatory proteins, two ORFs that have been reported previously but whose involvement in clavulanic acid biosynthesis is unclear, and one ORF not previously reported. Evidence for the involvement of these ORFs in clavulanic acid production was obtained by generating mutants and showing that all were defective for clavulanic acid production when grown on starch asparagine medium. However, when five of the nine mutants, including mutants defective in known clavulanic acid biosynthetic enzymes, were grown in a soy-based medium, clavulanic acid-producing ability was restored. This ability to produce clavulanic acid when seemingly essential biosynthetic enzymes have been mutated suggests that paralogous genes encoding functionally equivalent proteins exist for each of the five genes but that these paralogues are expressed only in the soy-based medium. The five genes that have paralogues encode proteins involved in the early steps of the pathway common to the biosynthesis of both clavulanic acid and the other clavam metabolites produced by this organism. No evidence was seen for paralogues of the four remaining genes involved in late, clavulanic acid-specific steps in the pathway.

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^* Corresponding author. Mailing address: Department of Biological Sciences, CW-405 Biological Sciences Building, University of Alberta, Edmonton, Alberta T6G 2E9, Canada. Phone: (780) 492-0672. Fax: (780) 492-2216. E-mail: susan.jensen{at}ualberta.ca.

Present address: Diversa Corporation, San Diego, CA 92121.

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Antimicrobial Agents and Chemotherapy, March 2000, p. 720-726, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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