TetR Regulators: A Structural and Functional Perspective

Bhukya, Hussain; Anand, Ruchi

doi:10.1007/s41745-017-0025-5

Cited by 16 publications

(12 citation statements)

References 51 publications

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“…The TetR family repressors consist of a helix-turn-helix DNA binding domain and a receptor domain that responds to the presence of a small molecule ligand [ 150 ]. In the absence of the specific signaling molecule, TetR dimers bind to DNA and prevent transcription of downstream genes.…”

Section: Strategies For the Activation Of Unknown Metabolic Pathwaysmentioning

confidence: 99%

Activation of microbial secondary metabolic pathways: Avenues and challenges

Baral

Akhgari

Metsä‐Ketelä

2018

Synthetic and Systems Biotechnology

160

146

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Microbial natural products are a tremendous source of new bioactive chemical entities for drug discovery. Next generation sequencing has revealed an unprecedented genomic potential for production of secondary metabolites by diverse micro-organisms found in the environment and in the microbiota. Genome mining has further led to the discovery of numerous uncharacterized ‘cryptic’ metabolic pathways in the classical producers of natural products such as Actinobacteria and fungi. These biosynthetic gene clusters may code for improved biologically active metabolites, but harnessing the full genetic potential has been hindered by the observation that many of the pathways are ‘silent’ under laboratory conditions. Here we provide an overview of the various biotechnological methodologies, which can be divided to pleiotropic, biosynthetic gene cluster specific, and targeted genome-wide approaches that have been developed for the awakening of microbial secondary metabolic pathways.

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Section: Strategies For the Activation Of Unknown Metabolic Pathwaysmentioning

confidence: 99%

Activation of microbial secondary metabolic pathways: Avenues and challenges

Baral

Akhgari

Metsä‐Ketelä

2018

Synthetic and Systems Biotechnology

160

146

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“…The inactivation of a TetR transcriptional repressor gene arpRII in Streptomyces argillaceus promoted the activation of the cryptic gene cluster arp, and discovery of argimycins P, a natural product in polyketide alkaloid family . ScbR, another TetRlike transcriptional repressor, has been confirmed to directly control the expression of the cryptic type I polyketide BGC by binding at two different positions of kasO promoter in S. coelicolor (Takano et al, 2005;Xu D. et al, 2010;Bhukya and Anand, 2017). GdmRIII, a TetR family transcriptional regulator, was connected with the biosynthetic pathways of geldanamycin and elaiophylin in Streptomyces autolyticus CGMCC0516 (Jiang et al, 2017).…”

Section: Activation Of the Cryptic Gene Clusters By Manipulation Of Tmentioning

confidence: 98%

“…TetR family of transcription regulators, which participate in the regulatory pathways associated with the efflux of antibiotic, cell-cell signaling, antibiotic biosynthesis, biofilm formation, etc., is one of the most predominant families of transcription factors in the prokaryotic system (Bhukya and Anand, 2017). The TetR family members usually serve as repressors which possess a N-terminal DNA-binding domain and a C-terminal signal reception domain (Cuthbertson and Nodwell, 2013).…”

Section: Activation Of the Cryptic Gene Clusters By Manipulation Of Tmentioning

confidence: 99%

The Application of Regulatory Cascades in Streptomyces: Yield Enhancement and Metabolite Mining

Xia

et al. 2020

Front. Microbiol.

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Streptomyces is taken as an important resource for producing the most abundant antibiotics and other bio-active natural products, which have been widely used in pharmaceutical and agricultural areas. Usually they are biosynthesized through secondary metabolic pathways encoded by cluster situated genes. And these gene clusters are stringently regulated by interweaved transcriptional regulatory cascades. In the past decades, great advances have been made to elucidate the regulatory mechanisms involved in antibiotic production in Streptomyces. In this review, we summarized the recent advances on the regulatory cascades of antibiotic production in Streptomyces from the following four levels: the signals triggering the biosynthesis, the global regulators, the pathway-specific regulators and the feedback regulation. The production of antibiotic can be largely enhanced by rewiring the regulatory networks, such as overexpression of positive regulators, inactivation of repressors, fine-tuning of the feedback and ribosomal engineering in Streptomyces. The enormous amount of genomic sequencing data implies that the Streptomyces has potential to produce much more antibiotics for the great diversities and wide distributions of biosynthetic gene clusters in Streptomyces genomes. Most of these gene clusters are defined cryptic for unknown or undetectable natural products. In the synthetic biology era, activation of the cryptic gene clusters has been successfully achieved by manipulation of the regulatory genes. Chemical elicitors, rewiring regulatory gene and ribosomal engineering have been employed to crack the potential of cryptic gene clusters. These have been proposed as the most promising strategy to discover new antibiotics. For the complex of regulatory network in Streptomyces, we proposed that the discovery of new antibiotics and the optimization of industrial strains would be greatly promoted by further understanding the regulatory mechanism of antibiotic production.

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“…[α] 25 +4.96 (c 1.0, CHCl 3 ); 1HNMR (500 MHz, CDCl 3 ) 3.47 (brs, 2H), 3.43 (d, J = 11.1 Hz, 1H), 3.37 (d, J =11.1 Hz, 1H), 1.51 (q, J =7.3 Hz, 2H), 1.10 (s, 3H), 0.89 (t, J =7.6 Hz, 3H); 13C-NMR (125 MHz, CDCl 3 ) 73.6, 69.3, 31.2, 22.5, 8.2 HRMS (ESI+, TFA-Na) calcd for C 5 H 12 NaO 2 127.0735 [M+Na] + , found m/z 127.0740.…”

Section: Methodsmentioning

confidence: 99%

Biochemical Basis for the Regulation of Biosynthesis of Antiparasitics by Bacterial Hormones

Kapoor

Olivares

Nair

2020

Preprint

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small molecule microbial hormones drastically alter the expression profiles of 21 antibiotics and other drugs in actinobacteria. For example, avenolide (a butenolide) 22 regulates production of avermectin, derivatives of which are used in the treatment of river 23 blindness and other parasitic diseases. Butenolides and γ-butyrolactones control 24 production of pharmaceutically important secondary metabolites by binding to TetR 25 family transcriptional repressors. Here, we describe a concise, 22-step synthetic strategy 26 for the production of avenolide. We present crystal structures of the butenolide receptor 27 AvaR1 in isolation, and in complex with avenolide, as well as AvaR1 bound to an 28 oligonucleotide derived from its operator. Biochemical studies guided by the co-crystal 29 structures enable identification of 90 new actinobacteria that may be regulated by 30 butenolides, two of which are experimentally verified. These studies provide a foundation 31 for understanding regulation of microbial secondary metabolite production, which may be 32 exploited for the discovery and production of novel medicines. 33 34 35

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TetR Regulators: A Structural and Functional Perspective

Cited by 16 publications

References 51 publications

Activation of microbial secondary metabolic pathways: Avenues and challenges

Activation of microbial secondary metabolic pathways: Avenues and challenges

The Application of Regulatory Cascades in Streptomyces: Yield Enhancement and Metabolite Mining

Biochemical Basis for the Regulation of Biosynthesis of Antiparasitics by Bacterial Hormones

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