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Chapter 23 : The A Factor Regulatory Cascade That Triggers Secondary Metabolism and Morphological Differentiation in Streptomyces
Category: Microbial Genetics and Molecular Biology; Bacterial Pathogenesis
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The A Factor Regulatory Cascade That Triggers Secondary Metabolism and Morphological Differentiation in Streptomyces, Page 1 of 2< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815578/9781555814045_Chap23-1.gif /docserver/preview/fulltext/10.1128/9781555815578/9781555814045_Chap23-2.gif
This chapter deals with the study of the biology and chemistry of γ-butyrolactone-type autoregulators that switch on secondary metabolism and morphological differentiation in Streptomyces. The A factor and receptor system in Streptomyces griseus acts as an all-or-nothing switch for both morphological and physiological differentiation. Escherichia coli carrying afsA produces two new substances that are absent in the broth of E. coli without afsA with their m/z 241 and 213 and the same MS/MS fragmentation pattern as A factor. AfsA is thus the key enzyme for the biosynthesis of γ-butyrolactones. Interestingly, a database search predicts that afsA and its homologs are distributed only in actinomycetes. In S. griseus, A factor production is controlled directly or indirectly by adpA in a two-step regulatory feedback loop. The major streptomycin resistance determinant, aphD, located just downstream of strR, encoding streptomycin-6-phosphotransferase, is also transcribed by read-through from the A factor-dependent strR promoter. The cotranscription of strR and aphD accounts for the prompt induction of streptomycin resistance by A factor and achieves a rapid increase in self-resistance just before induction of streptomycin biosynthesis.
γ-Butyrolactones in Streptomyces. The differences in chemical structure among the γ-butyrolactones are the length and branching of the acyl chain and the reduction state, either a keto or a hydroxyl group, at position 6.
The A factor regulatory cascade. The A factor signal, starting with the A factor biosynthesis gene afsA, is transferred to the receptor ArpA, to a transcriptional activator AdpA, and finally to a variety of genes required for morphological development and secondary metabolite formation. See the text for details of the target genes of AdpA. Through this cascade, morphological and physiological differentiation occurs at a specific time of growth, when the intracellular concentration reaches a critical level at or near the middle of the exponential growth.
The whole A factor biosynthesis pathway. The major pathway, highlighted by shadowing, and an alternative pathway are shown. In the major pathway, AfsA catalyzes the condensation of DHAP  and a β-keto acid derivative  to yield an 8-methyl-3-oxononanoyl-DHAP ester . The fatty acid ester is nonenzymatically converted to a butenolide phosphate  by intramolecular aldol condensation. The butenolide phosphate is then reduced by BprA to yield a butanolide . The last dephosphorylation step yields A factor . In the alternative pathway, the 8-methyl-3-oxononanoyl-DHAP ester  is first dephosphorylated to yield a dephosphorylated ester , which is then nonenzymatically condensed, resulting in a butenolide . The C=C double bond of the butenolide  is reduced to yield A factor .