Control of growth, secondary metabolism and sporulation in Streptomyces venezuelae ISP5230 by jadW 1, a member of the afsA family of γ-butyrolactone regulatory genes

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Abstract
Three new genes (jadW1,jadW2andjadW3) were isolated from a region of theStreptomyces venezuelaeISP5230 chromosome at the left-hand end of thejadcluster for jadomycin B (JdB) biosynthesis. The deduced amino acid sequence ofjadW1showed strong similarity to gene products associated in several streptomycetes withγ-butyrolactone autoregulators controlling morphological differentiation and secondary metabolism. Examination of JadW1for conserved domains detected a repeat sequence characteristic of proteins in the AfsA regulatory family. Insertional inactivation ofjadW1reduced the growth rate ofS. venezuelaecultures in aerated liquid media containing complex nitrogen sources and altered growth morphology in minimal medium. It also affected sporulation on agar media. Cultures ofjadW1-disrupted mutants grown under conditions supporting biosynthesis of JdB or chloramphenicol by the wild-type strain failed to produce either of the antibiotics. Complementing the disrupted strain by transformation with pJV435, containing a cloned copy of the gene, improved sporulation and restored antibiotic biosynthesis in transformants to titres close to those of the wild-type similarly transformed with pJV435 as a control. The results are consistent with a role forjadW1in regulating morphological and metabolic differentiation. Further sequence analysis ofjadR2, which functions withjadR1in stress-induced activation of JdB biosynthesis, indicated that this gene encodes aγ-butyrolactone receptor homologue. The growth-rate-sensitive phenotype of thejadW1-disrupted mutant, and the proximity ofjadW1tojadR2indicate that this region of thejadgene cluster contains a regulatory mechanism incorporatingγ-butyrolactone signalling and sensitivity to environmental stress.