Comprehensive study on regulatory systems for the initiation of secondary metabolism and morphological development in Streptomyces

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1.The overall picture of the A-factor regulatory cascade has been revealed by genetic and biological approaches. For example, the signal transduction from A-factor to the streptomycin biosynthesis genes starts with AfsA that catalyzes the biosynthesis of A-factor from a glycerol derivative and a β-keto acid. Once the intracellular concentration of A-factor reaches a critical level, its information is transferred to ArpA (A-factor receptor and transcriptional repressor) to AdpA (transcriptional activator) to StrR (pathway-specific transcriptional activator for streptomycin biosynthesis) to the streptomycin biosynthesis genes. In addition, X-ray crystallography of ArpA revealed how A-factor dissociates ArpA from the DNA. The detailed study of the hormonal regulation of secondary metabolism and morphological development in Streptomyces, a boundary microorganisms, has given a big impact on microbiology. This study is also useful for further detailed and comprehensive analysis of the A-factor regulatory cascade by using DNA microarray techniques.2.A transcriptional activator AfsR is phosphorylated on its threonine residue(s) by a serine/threonine kinase AfsK. AfsK self-activates its kinase activity by autophosphorylation on Thr-168. The phosphorylated AfsR activates the promoter of afsS, the gene product of which enhances secondary metabolism in some unknown way. The regulatory system involving AfsK/AfsR/AfsS is the most extensively studied system in the bacterial world.3.Catabolite repression by glucose is another regulatory system for secondary metabolism and morphogenesis in Streptomyces. Several mutants that produce antibiotics and spores in a high concentration of glucose were isolated, which I believe will be good material to study catabolite repression. In addition, cAMP and calmodulin-like protein were also found to control morphogenesis of Streptomyces. These regulatory systems will be studied by means of DNA microarray.