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Engineering of Primary Carbon Metabolism for Improved Antibiotic Production in Streptomyces lividans

Michael J. Butler,^1* Per Bruheim,² Srdjan Jovetic,³ Flavia Marinelli,³ Pieter W. Postma,^4, and Mervyn J. Bibb^1,

Department of Molecular Microbiology, John Innes Centre, Norwich, NR4 7UH, United Kingdom,¹ Department of Biotechnology, Norwegian University of Science and Technology, N7491 Trondheim, Norway,² Biosearch Italia S.p.A., 21040 Gerenzano (VA), Italy,³ E. C. Slater Institute, Faculty of Chemistry, University of Amsterdam, 1018WS Amsterdam, The Netherlands⁴

Received 29 March 2002/ Accepted 11 July 2002

Deletions were made in Streptomyces lividans in either of two genes (zwf1 and zwf2) encoding isozymes of glucose-6-phosphate dehydrogenase, the first enzyme in the oxidative pentose phosphate pathway (PPP). Each mutation reduced the level of Zwf activity to approximately one-half that observed in the wild-type strain. When the mutants were transformed with multicopy plasmids carrying the pathway-specific transcriptional activator genes for either the actinorhodin (ACT) or undecylprodigiosin (RED) biosynthetic pathway, they produced higher levels of antibiotic than the corresponding wild-type control strains. The presumed lower flux of carbon through the PPP in each of the zwf mutants may allow more efficient glucose utilization via glycolysis, resulting in higher levels of antibiotic production. This appears to occur without lowering the concentration of NADPH (the major biochemical product of the oxidative PPP activity) to a level that would limit antibiotic biosynthesis. Consistent with this hypothesis, deletion of the gene (devB) encoding the enzyme that catalyzes the next step in the oxidative PPP (6-phosphogluconolactonase) also resulted in increased antibiotic production. However, deletion of both zwf genes from the devB mutant resulted in reduced levels of ACT and RED production, suggesting that some of the NADPH made by the PPP is utilized, directly or indirectly, for antibiotic biosynthesis. Although applied here to the model antibiotics ACT and RED, such mutations may prove to be useful for improving the yield of commercially important secondary metabolites.

This paper is dedicated to the memory of Pieter Postma for his immense contribution to the field of bacterial physiology. He was a true friend and colleague who will be missed enormously.

Deceased.

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

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