Gene Replacement Analysis of the Butyrolactone Autoregulator Receptor (FarA) Reveals that FarA Acts as a Novel Regulator in Secondary Metabolism ofStreptomyces lavendulaeFRI-5

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Abstract
IM-2 [(2R,3R,1′R)-2-1′-hydroxybutyl-3-hydroxymethyl γ-butanolide] is a γ-butyrolactone autoregulator which, inStreptomyces lavendulae FRI-5, switches off the production of d-cycloserine but switches on the production of a blue pigment and several nucleoside antibiotics. To clarify the in vivo function of an IM-2-specific receptor (FarA) in the IM-2 signaling cascade of S. lavendulae FRI-5, a farA deletion mutant was constructed by means of homologous recombination. On several solid media, no significant difference in morphology was observed between the wild-type strain and the farA mutant (strain K104), which demonstrated that the IM-2–FarA system does not participate in the morphological control of S. lavendulaeFRI-5. In liquid media, the farA mutant overproduced nucleoside antibiotics and produced blue pigment earlier than did the wild-type strain, suggesting that the FarA protein acts primarily as a negative regulator on the biosynthesis of these compounds in the absence of IM-2. However, contrary to the IM-2-dependent suppression ofd-cycloserine production in the wild-type strain, overproduction of d-cycloserine was observed in thefarA mutant, indicating for the first time that the presence of both IM-2 and intact FarA are necessary for the suppression of d-cycloserine biosynthesis.