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Antimicrobial Agents and Chemotherapy, January 2004, p. 192-202, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.192-202.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Five Additional Genes Are Involved in Clavulanic Acid Biosynthesis in Streptomyces clavuligerus

S. E. Jensen,1* A. S. Paradkar,1,{dagger} R. H. Mosher,1,{ddagger} C. Anders,1 P. H. Beatty,1 M. J. Brumlik,1,§ A. Griffin,2 and B. Barton2

Department of Biological Sciences, University of Alberta, Edmonton T6G 2E9, Canada,1 Glaxo SmithKline Pharmaceuticals, Worthing, West Sussex BN14 8QH, England2

Received 27 March 2003/ Returned for modification 7 September 2003/ Accepted 28 September 2003

An approximately 12.5-kbp region of DNA sequence from beyond the end of the previously described clavulanic acid gene cluster was analyzed and found to encode nine possible open reading frames (ORFs). Involvement of these ORFs in clavulanic acid biosynthesis was assessed by creating mutants with defects in each of the ORFs. orf12 and orf14 had been previously reported to be involved in clavulanic acid biosynthesis. Now five additional ORFs are shown to play a role, since their mutation results in a significant decrease or total absence of clavulanic acid production. Most of these newly described ORFs encode proteins with little similarity to others in the databases, and so their roles in clavulanic acid biosynthesis are unclear. Mutation of two of the ORFs, orf15 and orf16, results in the accumulation of a new metabolite, N-acetylglycylclavaminic acid, in place of clavulanic acid. orf18 and orf19 encode apparent penicillin binding proteins, and while mutations in these genes have minimal effects on clavulanic acid production, their normal roles as cell wall biosynthetic enzymes and as targets for ß-lactam antibiotics, together with their clustered location, suggest that they are part of the clavulanic acid gene cluster.

* Corresponding author. Mailing address: Department of Biological Sciences, University of Alberta, Edmonton T6G 2E9, Canada. Phone: (780) 492-0830. Fax: (780) 492-9234. E-mail: susan.jensen{at}ualberta.ca.

{dagger} Present address: Diversa Corporation, San Diego, CA 92126.

{ddagger} Present address: Department of Biological Sciences, Wagner College, Staten Island, NY 10301.

§ Present address: Section of Hematology/Medical Oncology, Tulane School of Medicine, New Orleans, LA 70112-2699.

Antimicrobial Agents and Chemotherapy, January 2004, p. 192-202, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.192-202.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zelyas, N. J., Cai, H., Kwong, T., Jensen, S. E. (2008). Alanylclavam Biosynthetic Genes Are Clustered Together with One Group of Clavulanic Acid Biosynthetic Genes in Streptomyces clavuligerus. J. Bacteriol. 190: 7957-7965 [Abstract] [Full Text]  
  • Arulanantham, H., Kershaw, N. J., Hewitson, K. S., Hughes, C. E., Thirkettle, J. E., Schofield, C. J. (2006). ORF17 from the Clavulanic Acid Biosynthesis Gene Cluster Catalyzes the ATP-dependent Formation of N-Glycyl-clavaminic Acid. J. Biol. Chem. 281: 279-287 [Abstract] [Full Text]  
  • Tahlan, K., Anders, C., Jensen, S. E. (2004). The Paralogous Pairs of Genes Involved in Clavulanic Acid and Clavam Metabolite Biosynthesis Are Differently Regulated in Streptomyces clavuligerus. J. Bacteriol. 186: 6286-6297 [Abstract] [Full Text]  
  • Tahlan, K., Park, H. U., Wong, A., Beatty, P. H., Jensen, S. E. (2004). Two Sets of Paralogous Genes Encode the Enzymes Involved in the Early Stages of Clavulanic Acid and Clavam Metabolite Biosynthesis in Streptomyces clavuligerus. Antimicrob. Agents Chemother. 48: 930-939 [Abstract] [Full Text]  


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