Precursor-directed biosynthesis of 6-deoxyerythronolide B analogs in Streptomyces coelicolor : Understanding precursor effects

A fermentation process employing precursor-directed biosynthesis is being developed for the manufacture of 6-deoxyerythronolide B (6-dEB) analogues. Through a plasmid-based system in Streptomyces coelicolor, 6-dEB synthesis is catalyzed by 6-dEB synthase (DEBS). 6-dEB synthesis is abolished by inact...

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Bibliographic Details
Published in:Biotechnology progress 2000-07, Vol.16 (4), p.553-556
Main Authors: LEAF, T, CADAPAN, L, CARRERAS, C, REGENTIN, R, OU, S, WOO, E, ASHLEY, G, LICARI, P
Format: Article
Language:English
Subjects:
6-deoxyerythronolide B
6-deoxyerythronolide B synthase
Antibiotics
Bacteria
Biological and medical sciences
Biosynthesis
Biotechnology
Catalysis
Catalyst deactivation
Cell culture
Composition effects
Culture Media
Enzymes
Erythromycin - analogs & derivatives
Erythromycin - biosynthesis
Fermentation
Fundamental and applied biological sciences. Psychology
Growth kinetics
Health. Pharmaceutical industry
Hydrolysis
Industrial applications and implications. Economical aspects
Production of active biomolecules
Streptomyces - metabolism
Streptomyces coelicolor
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Summary:A fermentation process employing precursor-directed biosynthesis is being developed for the manufacture of 6-deoxyerythronolide B (6-dEB) analogues. Through a plasmid-based system in Streptomyces coelicolor, 6-dEB synthesis is catalyzed by 6-dEB synthase (DEBS). 6-dEB synthesis is abolished by inactivation of the ketosynthase (KS) 1 domain of DEBS but can be restored by providing synthetic activated diketides. Because of its inherent catalytic flexibility, the KS1-deficient DEBS is capable of utilizing unnatural diketides to form various 13-substituted 6-dEBs. Here we characterize process variables associated with diketide feeding in shake-flask experiments. 13-R-6-dEB production was found to depend strongly on diketide feed concentrations, on the growth phase of cultures at feeding time, and on the R-group present in the diketide moiety. In all cases a major portion of the fed diketides was degraded by the cells.
ISSN:8756-7938
1520-6033
DOI:10.1021/bp000063l