Relationship between nitrogen assimilation and cephalosporin synthesis in Streptomyces clavuligerus

The levels of three enzymes of the beta-lactam antibiotic pathway and overall cephalosporin production were subject to nitrogen source repression in Streptomyces clavuligerus. The specific activities of isopenicillin N synthetase ("cyclase") and deacetoxycephalosporin C synthetase ("expandase") measured during the exponential phase depended on the nitrogen source employed, following a pattern that roughly correlated with the corresponding antibiotic production. The effects on isopenicillin N epimerase ("epimerase") activities were less marked than those on the cyclase and expandase. Production of cephalosporins and enzymatic activities were not related to the growth rate of the cultures. Glutamate, glutamine and alanine inhibited production when added to resting cell systems, while lysine and alpha-aminoadipate were stimulatory. No clear relationship could be drawn between cephalosporin production or beta-lactam synthetase activities and the activities of enzymes of ammonium assimilation (glutamine synthetase, glutamate synthase and alanine dehydrogenase). The intracellular pools of free glutamine, alanine and ammonium were the only ones markedly affected by the nitrogen source in the wild type and mutants, but these amino acids did not seem to play an obvious role as intracellular mediators of nitrogen control.