Biosynthesis of kitasamycin (leucomycin) by leucine analog-resistant mutants of Streptomyces kitasatoensis.
The biosynthesis of kitasamycin in Streptomyces kitasatoensis B-896 was profoundly influenced by the addition of precursors to complex and defined media: l-valine and l-leucine directed biosynthesis towards the pairs A(4)/A(5) (R(2) = butyryl) and A(1)/A(3) (R(2) = isovaleryl), respectively, and total kitasamycin titers were doubled and quadrupled, respectively. S. kitasatoensis B-896 was very resistant (>20 mg/ml) to alpha-aminobutyric acid, an analog of l-valine, but very susceptible to l-leucine analogs 5', 5', 5'-trifluoroleucine and 4-azaleucine (5 to 10 mug/ml). The inhibition by 4-azaleucine could be reversed by l-leucine, but by none of the other amino acids of the pyruvate family or the amino acids of the aspartate pathway. 4-Azaleucine-resistant mutants were isolated which in the absence of any precursors overproduced l-leucine and a kitasamycin complex mainly consisting of the pair A(1)/A(3). These 4-azaleucine-resistant mutants are presumed to be regulatory mutants in which alpha-isopropylmalate synthase, the first enzyme of the l-leucine pathway, has become either derepressed or desensitized to leucine feedback inhibition. l-Leucine-regulatory mutants have economic value: in the absence of expensive precursors, they produce a kitasamycin complex in which the most potent pair A(1)/A(3) is dominant and the least active components are absent.
D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D002087:Butyrates / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D005285:Fermentation; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007933:Leucomycins / Q000096:biosynthesis*; D009154:Mutation; D013302:Streptomyces / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002087:Butyrates; D007933:Leucomycins; D007930:Leucine; D014633:Valine