Role of a Two-Component Signal Transduction System RspA1/A2 in Regulating the Biosynthesis of Salinomycin in Streptomyces albus

Zhang, Kuipu; Mohsin, Ali; Dai, Yichen; Ali, Muhammad Fahad; Chen, Zhongbing; Zhuang, Yingping; Chu, Ju; Guo, Meijin

doi:10.1007/s12010-020-03357-z

Cited by 6 publications

(2 citation statements)

References 24 publications

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“…Usually, antibiotic biosynthetic clusters are regulated by two types of transcriptional regulators: pathway-specific regulators (PSRs) and pleiotropic regulators [86]. At a lower level, PSRs are located inside the antibiotic biosynthetic cluster and these proteins can bind directly to the promoters of genes in the same biosynthetic pathway [87,88]. Similarly, at the top level, global regulators are known to control the production of antibiotics in the Streptomyces genus [87,88].…”

Section: Regulation Of the Ca Production In S Clavuligerusmentioning

confidence: 99%

Clavulanic Acid Production by Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing

2021

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Clavulanic acid (CA) is an irreversible β-lactamase enzyme inhibitor with a weak antibacterial activity produced by Streptomyces clavuligerus (S. clavuligerus). CA is typically co-formulated with broad-spectrum β‑lactam antibiotics such as amoxicillin, conferring them high potential to treat diseases caused by bacteria that possess β‑lactam resistance. The clinical importance of CA and the complexity of the production process motivate improvements from an interdisciplinary standpoint by integrating metabolic engineering strategies and knowledge on metabolic and regulatory events through systems biology and multi-omics approaches. In the large-scale bioprocessing, optimization of culture conditions, bioreactor design, agitation regime, as well as advances in CA separation and purification are required to improve the cost structure associated to CA production. This review presents the recent insights in CA production by S. clavuligerus, emphasizing on systems biology approaches, strain engineering, and downstream processing.

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Section: Regulation Of the Ca Production In S Clavuligerusmentioning

confidence: 99%

Clavulanic Acid Production by Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing

2021

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“…As the major type of pleiotropic regulator, two-component regulatory system consists of sensor kinase (SK) and response regulator (RR), which are usually adjacent together to sense and respond to various stresses [ 20 ], such as the well-known PhoR-PhoP system [ 21 ]. Two-component regulatory systems are important for signal transductions and generally participate in different global regulations, while a few of them could also modulate antibiotic productions like cephamycin C [ 22 ], salinomycin [ 23 ], oxytetracycline [ 24 ] and etc. On the other hand, the manipulation of pathway-specific regulator is a general strategy used for titer improvement of many important antibiotics such as platensimycin, a 9-membered enediyne C-1027 [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Deciphering the pathway-specific regulatory network for production of ten-membered enediyne Tiancimycins in Streptomyces sp. CB03234-S

et al. 2022

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Background The anthraquinone-fused 10-membered enediynes (AFEs), represented by tiancimycins (TNMs), possess a unique structural feature and promising potentials as payloads of antitumor antibody–drug conjugates. Despite many efforts, the insufficient yields remain a practical challenge for development of AFEs. Recent studies have suggested a unified basic biosynthetic route for AFEs, those core genes involved in the formation of essential common AFE intermediates, together with multiple regulatory genes, are highly conserved among the reported biosynthetic gene clusters (BGCs) of AFEs. The extreme cytotoxicities of AFEs have compelled hosts to evolve strict regulations to control their productions, but the exact roles of related regulatory genes are still uncertain. Results In this study, the genetic validations of five putative regulatory genes present in the BGC of TNMs revealed that only three (tnmR1, tnmR3 and tnmR7) of them were involved in the regulation of TNMs biosynthesis. The bioinformatic analysis also revealed that they represented three major but distinct groups of regulatory genes conserved in all BGCs of AFEs. Further transcriptional analyses suggested that TnmR7 could promote the expressions of core enzymes TnmD/G and TnmN/O/P, while TnmR3 may act as a sensor kinase to work with TnmR1 and form a higher class unconventional orphan two-component regulatory system, which dynamically represses the expressions of TnmR7, core enzymes TnmD/G/J/K1/K2 and auxiliary proteins TnmT2/S2/T1/S1. Therefore, the biosynthesis of TNMs was stringently restricted by this cascade regulatory network at early stage to ensure the normal cell growth, and then partially released at the stationary phase for product accumulation. Conclusion The pathway-specific cascade regulatory network consisting with TnmR3/R1 and TnmR7 was deciphered to orchestrate the production of TNMs. And it could be speculated as a common regulatory mechanism for productions of AFEs, which shall provide us new insights in future titer improvement of AFEs and potential dynamic regulatory applications in synthetic biology.

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AflQ1-Q2 represses lincomycin biosynthesis via multiple cascades in Streptomyces lincolnensis

Wang

Zhou

Kong

et al. 2023

Appl Microbiol Biotechnol

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Role of a Two-Component Signal Transduction System RspA1/A2 in Regulating the Biosynthesis of Salinomycin in Streptomyces albus

Cited by 6 publications

References 24 publications

Clavulanic Acid Production by Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing

Clavulanic Acid Production by Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing

Deciphering the pathway-specific regulatory network for production of ten-membered enediyne Tiancimycins in Streptomyces sp. CB03234-S

AflQ1-Q2 represses lincomycin biosynthesis via multiple cascades in Streptomyces lincolnensis

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