PREFERENTIAL PRODUCTION OF RAPAMYCIN VS PROLYLRAPAMYCIN BY STREPTOMYCES-HYGROSCOPICUS

A trace of prolylrapamycin is often produced in rapamycin fermentation s carried out by strains of Streptomyces hygroscopicus. Prolylrapamyci n was produced as the major rapamycin when L-proline was added to the fermentation medium. Addition of proline plus thiazolidine-2-carboxyli c acid (T2CA), a sulfur-containing proline analog, prevented rapamycin production and stimulated prolylrapamycin production, thereby resulti ng in an even greater selective production of prolylrapamycin. T2CA ad dition inhibited rapamycin production even in the presence of L-lysine which is converted into pipecolic acid intracellularly and normally s timulates rapamycin formation. Addition of the rapamycin precursor, DL -pipecolic acid, surprisingly failed to stimulate rapamycin production . However, when DL-pipecolic acid was added with L-proline, it reduced the formation of prolylrapamycin and stimulated rapamycin production; this was evident especially in the presence of T2CA. The evidence sug gests that T2CA suppresses rapamycin production by inhibiting intracel lular conversion of L-lysine into pipecolate. Furthermore, the data su ggest that uptake of pipecolate into the cell is stimulated or induced by growth in the presence of L-proline and/or T2CA.