Genomic analysis of a Streptomyces tsukubaensis mutant with reduced FR900525 production isolated by selection for S-(2-aminoethyl) L-cysteine resistance

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FK506 (tacrolimus), a macrolide compound with immunosuppressant activity, has been shown to be of clinical importance and has been manufactured industrially since 1993 using mutants with high FK506 production ability. These mutants have been developed from the wild strain Streptomyces tsukubaensis No. 9993. FR900525 is one of the by-products of FK506 production, and we previously established a mutant strain that produces reduced levels of FR900525 by selecting for S-(2-aminoethyl) l-cysteine (AEC) resistance. In this study, we conducted a genomic analysis of this strain to identify the changes associated with AEC resistance and to determine its metabolism. Three mutated genes were identified by comparing the genome sequences of the parental strain (A) and the AEC-resistant mutant (B). From the metabolite pathway, it was speculated that citric acid synthase was the most relevant to AEC resistance. To investigate the effect of the mutation in citric acid synthase, we added citric acid, an inhibitor of citric acid synthase, to strain A culture, which induced strain A to exhibit a strain B-like phenotype. We conclude that the mutation in citric acid synthase enhances the carbon flow into aspartic acid, increasing lysine synthesis and resulting in AEC resistance in strain B, as well as high production of FK506 and low production of FR900525.

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