Cascades and Networks of Regulatory Genes That Control Antibiotic Biosynthesis
Onset of the biosynthesis of bioactive secondary metabolites in batch cultures of actinomycetes occurs after the rapid growth phase, following a transition phase which involves complex metabolic changes. This transition is triggered by nutrient starvation
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Cascades and Networks of Regulatory Genes That Control Antibiotic Biosynthesis Juan F. Martín and Paloma Liras
Abstract Onset of the biosynthesis of bioactive secondary metabolites in batch cultures of actinomycetes occurs after the rapid growth phase, following a transition phase which involves complex metabolic changes. This transition is triggered by nutrient starvation or by other environmental stress signals. Expression of genes encoding bioactive secondary metabolites is governed by cascades of pathway specific regulators and networks of cross-talking global regulators. Pathway specific regulators such as Streptomyces antibiotic regulatory proteins, LAL-type and LysR-type regulators respond to autoregulatory proteins that act in concert with their cognate ligands (e.g. g-butyrolactone receptor proteins and their cognate g-butyrolactone ligands). Global regulators such as PhoR-PhoP and other two component systems and orphan response regulators, such as GlnR, control set of genes affecting primary and secondary metabolism. GlnR and, therefore, nitrogen metabolism genes are under phosphate control exerted by binding of PhoP to PHO boxes located in the promoter region of GlnR. A few pleiotropic regulatory genes, such as areB (ndgR), dmdR1 or dasR connect primary metabolism (amino acid biosynthesis, N-acetylglucosamine or iron levels) with antibiotic biosynthesis. Some atypical response regulators that require specific small ligands appear to be involved in feedback control of antibiotic production. All these mechanisms together modulate, in a coordinated manner, different aspects of Streptomyces metabolism as a real “protection net” that prevents drastic changes in metabolism that may be deleterious for cell survival. Keywords Antibiotic biosynthesis pathways • Phosphate and nitrogen control • Pathway-specific regulators • Streptomyces regulatory mechanisms • Two component systems
J.F. Martín (*) • P. Liras Department of Molecular Biology, University of León, León 24071, Spain e-mail: [email protected]; [email protected] X. Wang et al. (eds.), Reprogramming Microbial Metabolic Pathways, Subcellular Biochemistry 64, DOI 10.1007/978-94-007-5055-5_6, © Springer Science+Business Media Dordrecht 2012
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J.F. Martín and P. Liras
Abbreviations ARE ARR BRP CDA EMSA GlcNac HTH i-TRAQ LAL LC-MS/MS PHO box Q-RT-PCR SARP TCS
6.1
autoregulatory element atypical response regulators butyrolactone receptor protein calcium-dependent antibiotic electrophoretic mobility shift assay N-acetyl-glucosamine helix-turn-helix isobaric tags for relative and absolute quantification large ATP-binding regulators of the LuxR family liquid chromatography mass spectrometry sequence for PhoP binding quantitative reverse polymerase chain reaction Streptomyces antibiotic regulatory protein two component systems
Secondary Metabolite Gene Clusters
Secondary metabolites of microorganisms include antibacterial, antifungal, antiviral and antitumor agents, insecticides, pigments, inmunomodulators (including potent inmunosupressor
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