The central carbon metabolism of the nystatin-producing strain Streptomyces noursei ATCC 11455 was evaluated by 13C-labelling experiments. A batch fermentation was examined during the idiophase by GC-MS measurements of the labelling patterns of amino acids in the biomass. The labelling patterns of the amino acids and calculated fluxes of the central metabolism showed that changes in the primary and secondary metabolisms occurred simultaneously. Changes in the profiles for the integrated fluxes showed a decreased flux through the pentose phosphate pathway and an increased flux in the tricarboxylic acid cycle relative to the glucose uptake rate when the culture entered a phase with reduced specific growth rate and enhanced nystatin yield. The flux through the pentose phosphate pathway seemed to be adjusted according to the NADPH requirement during the different phases of the batch fermentation.
Cell growth and production of nystatin by Streptomyces noursei (ATCC11455) were investigated on the three different nitrogen sources, ammonium sulphate, ammonium nitrate and sodium nitrate. S. noursei was able to utilise all of the three tested nitrogen sources for the growth and production of nystatin. High ammoniumconcentration had a negative effect on production of nystatin whenphosphate and glucose was in excess. There was an increased production of nystatin whenthe cultures becameammonium limited. Cultivation with sodium nitrate as the nitrogen source resulted in a prolonged lag-phase for growth and about 50%lower final nystatin titres comparedwith cultures grownon nitrogen sources containing ammonium. Nystatin production was shownto be related to the specific growth rate, its production was increased at decreasing specific growth rates.Nystatin is an industrially important secondary metabolite produced by Streptomyces noursei with a world market of more than 250million US dollars per year.Nystatin belongs to the polyene macrolide antibiotics, which is a subgroup of the polyketides. It has a lactone ring of 37 carbon atoms which consists of a diene-tetraene chromophore. The aminosugar mycosamine is linked to the lactone ring1^. Nystatin antifungal's activity is expressed through its binding to sterols in cell membranes that affect the permeability and in turn leads to leakage of intracellular compounds2).Microbial secondary metabolites are usually produced only at low specific growth rates3). Specific growth rate is important in controlling the onset of secondary metabolism, but the mechanisms involved are unknown. Deficiencies in certain nutritional factors are important as well, and many secondary metabolic pathways are negatively affected by nitrogen sources favourable for growth4). Streptomyces venezuelae grown on a mediumcontaining ammoniumand nitrate showed a delayed production of chloramphenicol until ammoniumhad been consumed, and the growth remained slow until subsequent depletion of nitrate5). There have been no reports on the possible nitrogen regulation of the production of nystatin or aminosugars of polyenes.S. noursei JA 3890b is a spontaneous mutant of S. noursei ATCC 11455 and produces a different type of antibiotic, nourseothricin (streptothricin)6).This strain was found to have a strong repression of the NADP+-dependent glutamate dehydrogenase and enhanced the capacity to oxidative deamination of alanine via the NAD+-dependent alanine dehydrogenase during excess of ammoniumand alanine, where low nourseothricin titres were obtained. A decrease in the intracellular level of ammoniumcaused by ammoniumlimitation increased the activity of NADP+-dependent glutamate dehydrogenase and repressed the NAD+-dependent alanine dehydrogenase, and this was associated with increased production of nourseothricin. S. noursei ATCC 11455 failed to demonstrate a similar response on NADP+-dependent glutamate dehydrogenase and NAD+-dependent alanine dehydrogenase during
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