Interplay between carbon, nitrogen and phosphate utilization in the control of secondary metabolite production in Streptomyces
Streptomyces species are a wide and diverse source of many therapeutic agents (antimicrobials, antineoplastic and antioxidants, to name a few) and represent an important source of compounds with potential applications in medicine. The effect of nitrogen, phosphate and carbon on the production of secondary metabolites has long been observed, but it was not until recently that the molecular mechanisms on which these effects rely were ascertained. In addition to the specific macronutrient regulatory mechanisms, there is a complex network of interactions between these mechanisms influencing secondary metabolism. In this article, we review the recent advances in our understanding of the molecular mechanisms of regulation exerted by nitrogen, phosphate and carbon sources, as well as the effects of their interconnections, on the synthesis of secondary metabolites by members of the genus Streptomyces.
KeywordsSecondary metabolism Antibiotic production Carbon regulation Regulation Streptomyces
This work was supported by Grant CB-219686 from Consejo Nacional de Ciencia y Tecnología, Mexico.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants or animals
This article does not contain any studies with animals performed by any of the authors.
- Allenby NEE, Laing E, Bucca G et al (2012) Diverse control of metabolism and other cellular processes in Streptomyces coelicolor by the PhoP transcription factor: genome-wide identification of in vivo targets. Nucleic Acids Res 40:9543–9556. https://doi.org/10.1093/nar/gks766 PubMedPubMedCentralGoogle Scholar
- Amin R, Franz-Wachtel M, Tiffert Y et al (2016) Post-translational serine/threonine phosphorylation and lysine acetylation: a novel regulatory aspect of the global nitrogen response regulator GlnR in S. coelicolor M145. Front Mol Biosci 3:1–14. https://doi.org/10.3389/fmolb.2016.00038 Google Scholar
- Běhal V, Hošťálek Z, Vaněk Z (1971) Anhydrotetracycline oxygenase activity and biosynthesis of tetracyclines in Streptomyces aureofaciens. Biotechnol Lett 1:177–182Google Scholar
- Demain AL (1989) Carbon source regulation of idiolite biosynthesis. In: Shapiro S (ed) Regulation of secondary metabolism of actinomycetes. CRC Press, Boca Raton, pp 127–134Google Scholar
- Díaz M, Esteban A, Fernández-Abalos JM, Santamaría RI (2005) The high-affinity phosphate-binding protein PstS is accumulated under high fructose concentrations and mutation of the corresponding gene affects differentiation in Streptomyces lividans. Microbiology 151:2583–2592. https://doi.org/10.1099/mic.0.27983-0 PubMedGoogle Scholar
- Fang A, Demain AL (1995) Exogenous shikimic acid stimulates rapamycin biosynthesis in Streptomyces hygroscopicus. Folia Microbiol 40:607–610Google Scholar
- Gubbens J, Janus M, Florea BI et al (2012) Identification of glucose kinase-dependent and -independent pathways for carbon control of primary metabolism, development and antibiotic production in Streptomyces coelicolor by quantitative proteomics. Mol Microbiol 6:1490–1507. https://doi.org/10.1111/mmi.12072 Google Scholar
- Guzman S, Carmona A, López R, Escalante L, Ruiz B, Rodríguez-Sanoja R, Sánchez S, Langley E (2005) Pleiotropic effect of the sco2127 gene on the glucose uptake, glucose kinase activity and carbon catabolite repression in Streptomyces peucetius var. caesius. Microbiology-SGM 151:1717–1723Google Scholar
- Hindle Z, Smith CP (1994) Substrate induction and catabolite repression of the Streptomyces coelicolor glycerol operon are mediated through the GylR protein. Mol Microbiol 12:737–745. https://doi.org/10.1111/j.1365-2958.1994.tb01061.x PubMedGoogle Scholar
- Hodgson DA (2000) Primary metabolism and its control in streptomycetes: a most unusual group of bacteria. Adv Microb Phys 42:47–238Google Scholar
- Kusano T, Suzuki H (eds) (2015) Polyamines a universal molecular nexus for growth, survival and specialized metabolism. Springer, BerlinGoogle Scholar
- Mahr K, van Wezel GP, Svensson C et al (2001) Glucose kinase of Streptomyces coelicolor A3(2): large-scale purification and biochemical analysis. Antonie Van Leeuwenhoek 78:253–261Google Scholar
- Martín JF (1989) Molecular mechanisms for the control by phosphate of the biosynthesis of antibiotic and secondary metabolism. In: Shapiro S (ed) Regulation of secondary metabolism of actinomycetes1. CRC Press, Boca Raton, pp 213–237Google Scholar
- Rao NN, Gómez-García MR, Kornberg A (2009) Inorganic polyphosphate: essential for growth and survival. Annu Rev Biochem 78:605–647. https://doi.org/10.1146/annurev.biochem.77.083007.093039 PubMedGoogle Scholar
- Rigali S et al (2006) The sugar phosphotransferase system of Streptomyces coelicolor is regulated by the GntR-family regulator DasR and links N-acetylglucosamine metabolism to the control of development. Mol Microbiol 61:1237–1251. https://doi.org/10.1111/j.1365-2958.2006.05319.x PubMedGoogle Scholar
- Rodríguez-García A, Sola-Landa A, Apel K et al (2009) Phosphate control over nitrogen metabolism in Streptomyces coelicolor: direct and indirect negative control of glnR, glnA, glnII and amtB expression by the response regulator PhoP. Nucleic Acids Res 37:3230–3242. https://doi.org/10.1093/nar/gkp162 PubMedPubMedCentralGoogle Scholar
- Saito A, Shinya T, Miyamoto K et al (2007) The dasABC gene cluster, adjacent to dasR, encodes a novel ABC transporter for the uptake of N, N′-Diacetylchitobiose in Streptomyces coelicolor A3(2). Appl Environ Microbiol 73:3000–3008. https://doi.org/10.1128/aem.02612-06 PubMedPubMedCentralGoogle Scholar
- Segura D, Rodríguez R, Sandoval T et al (1996) Streptomyces mutants insensitive to glucose repression showed deregulation of primary and secondary metabolism. Asia Pacific J Mol Biotechnol 4:30–36Google Scholar
- Shu D, Chen L, Wang W et al (2009) afsQ1-Q2-sigQ is a pleiotropic but conditionally required signal transduction system for both secondary metabolism and morphological development in Streptomyces coelicolor. Appl Microbiol Biotechnol 81:1149–1160. https://doi.org/10.1007/s00253-008-1738-1 PubMedGoogle Scholar
- Świątek MA, Gubbens J, Bucca G et al (2013) The ROK family regulator Rok7B7 pleiotropically affects xylose utilization, carbon catabolite repression, and antibiotic production in Streptomyces coelicolor. J Bacteriol 195:1236–1248. https://doi.org/10.1128/JB.02191-12 PubMedPubMedCentralGoogle Scholar
- Tenconi E, Traxler MF, Hoebreck C, van Wezel GP, Rigali S (2018) Prodiginine production in Streptomyces coelicolor correlates temporally and spatially to programmed cell death. bioRxiv preprint first posted online Jan 19, 2018. https://doi.org/10.1101/240689
- Tierrafría VH, Licona-Cassani C, Maldonado-Carmona N et al (2016) Deletion of the hypothetical protein SCO2127 of Streptomyces coelicolor allowed identification of a new regulator of actinorhodin production. Appl Microbiol Biotechnol 100:9229–9237Google Scholar
- van Keulen G, Dyson PJ (2014) Chapter six—production of specialized metabolites by Streptomyces coelicolor A3(2), 1st edn. Elsevier Inc., AmsterdamGoogle Scholar