Dynamical modelling of secondary metabolism and metabolic switches in Streptomyces xiamenensis 318

Abstract

The production of secondary metabolites, while important for bioengineering purposes, presents a paradox in itself. Though widely existing in plants and bacteria, they have no definite physiological roles. Yet in both native habitats and laboratories, their production appears robust and follows apparent metabolic switches. We show in this work that the enzyme-catalysed process may improve the metabolic stability of the cells. The latter can be responsible for the overall metabolic behaviours such as dynamic metabolic landscape, metabolic switches and robustness, which can in turn affect the genetic formation of the organism in question. Mangrove-derived Streptomyces xiamenensis 318, with a relatively compact genome for secondary metabolism, is used as a model organism in our investigation. Integrated studies via kinetic metabolic modelling, transcriptase measurements and metabolic profiling were performed on this strain. Our results demonstrate that the secondary metabolites increase the metabolic fitness of the organism via stabilizing the underlying metabolic network. And the fluxes directing to NADH, NADPH, acetyl-CoA and glutamate provide the key switches for the overall and secondary metabolism. The information may be helpful for improving the xiamenmycin production on the strain.

Constructing Microbial Hosts for the Production of Benzoheterocyclic Derivatives

“…A benzastatin derivative (15) containing a tetrahydroquinoline scaffold was detected at a yield of 25.9 mg/L by feeding 9 (Figure 3A, Table 1), as confirmed by UPLC-QTOF-MS and NMR analyses (Figure S6−S12, Table S2). Moreover, three analogues of p-aminobenzoic acid, i.e., 4-aminosalicylic acid (26), 4-amino-2-chlorobenzoic acid (27), and 4-amino-2methylbenzoic acid (28), were fed into the medium at a final concentration of 100 mg/L after 24 h cultivation of strain XL01, respectively. The products (29, 31, and 33) containing a tetrahydroquinoline scaffold were detected by UPLC-MS (Figure S13).…”

“…Putative promoters of 18 highly expressed genes were selected on the basis of a transcriptomics data set (Table S1, Figure S1). The promoters were cloned into the reporter plasmid pDR3 and evaluated using catechol 2,3-dioxygenase (XylE) activity, and the two widely used promoters, ermE p* and kasO p*, were tested for comparison.…”

Systems and synthetic biology to elucidate secondary metabolite biosynthetic gene clusters encoded inStreptomycesgenomes

“…69,78,85,86 During the metabolic switch, downregulation of translation machinery genes and up-regulation of genes related to stress response, especially nutrient depletion, were consistent between time-course transcriptomic profiling studies. 69,85 Most Streptomyces species, including S. coelicolor, 78 S. lividans, 86 S. clavuligerus, 69 S. xiamenensis, 87 and S. fungicidicus 88 are continually up-regulated in the expression of smBGC-encoded genes after exponential growth. However, not all smBGCs were activated during the metabolic switch.…”

Bursts in biosynthetic gene cluster transcription are accompanied by surges of natural compound production in the myxobacteriumSorangiumsp

“…Notably, the depletion of phosphate (Martín, 2004;Thomas et al, 2012), nitrogen (Voelker & Altaba, 2001), or carbon sources (Sánchez et al, 2010), among other stress factors, was identified to stimulate the biosynthesis of antibiotics and other 'secondary metabolites' (van Wezel & McDowall, 2011;Wohlleben et al, 2017). In Streptomyces spp., the transcriptional activity of genes encoding enzymes for synthesizing natural compounds was mostly observed at later stages of batch cultivation, after nutrients had been depleted, whereas it was repressed during exponential bacterial growth (Nieselt et al, 2010;X.-M. Zhu et al, 2019). It is not clear, however, to what extent a generalization of this observation from actinobacteria is justified for other microorganisms, since, for example, myxobacteria produce several natural compounds preferably during growth in nutrient-rich media (Gerth et al, 1982;Kegler et al, 2006;Kunze et al, 1984;Rachid et al, 2007).…”

“…Investigations into the cellular regulation of BGC activities could facilitate control over the production of novel bioactive compounds, either by targeted molecular manipulation (Mungan et al, 2022;van der Heul et al, 2018) or by providing suitable extracellular cues (Okada & Seyedsayamdost, 2017). Transcriptional activities of BGCs and their regulation have been studied in Streptomyces (Hwang et al, 2019;Nieselt et al, 2010;X.-M. Zhu et al, 2019) and related actinobacteria (Tocchetti et al, 2015), and in a few other model organisms (Neubacher et al, 2020;Wu et al, 2020). Insights into genetic regulatory circuits of natural compound synthesis in myxobacteria are more limited at present.…”