A chemocentric view of the natural product inventory

Walsh, Christopher T.

doi:10.1038/nchembio.1894

Cited by 55 publications

(41 citation statements)

References 34 publications

(15 reference statements)

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“…oxygenases catalyzing key chemical steps in biosynthetic pathways, various glycosylases, enzymes catalyzing complex cyclizations, polycyclic fungal alkaloid biosynthetic pathways, and so-called hybrid assembly lines, were described. In a highly stimulating conclusion, the author indicated future perspectives in this field (Walsh 2015).…”

Section: The Present Timementioning

confidence: 98%

“…The enzymes for the production of secondary metabolites, or natural products, are generally encoded by biosynthetic gene clusters (Walsh 2015). The importance of genome mining, including the research programs capable of sequencing whole culture collections of bacterial and fungal strains and identification of biosynthetic gene clusters in genome sequences, was accentuated.…”

Section: The Present Timementioning

confidence: 99%

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Biogenesis of antibiotics—viewing its history and glimpses of the future

et al. 2016

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This review aims at comparing some historical data with the current situation in the study of biogenesis of natural compounds, antibiotics in the first place. Biogenesis of tetracyclines and cycloheximide and related compounds serves as example. Examples of molecular biological and bioinformatics methods used in the study of antibiotic biogenesis are described both in terms of its historical aspects and the current knowledge.

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Section: The Present Timementioning

confidence: 98%

Section: The Present Timementioning

confidence: 99%

Biogenesis of antibiotics—viewing its history and glimpses of the future

et al. 2016

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“…Production of these compounds allows cells to adapt to new environments and to compete against other organisms. This latter property confers important biological functions that have been exploited in the development of natural products into important pharmaceutically active molecules [1,2]. …”

Section: The Modular Basis For Nonribosomal Peptide Synthesismentioning

confidence: 99%

Structural insight into the necessary conformational changes of modular nonribosomal peptide synthetases

Gulick

2016

Current Opinion in Chemical Biology

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Nonribosomal peptide synthetases (NRPSs) catalyze the assembly line biosynthesis of peptide natural products that play important roles in microbial signaling and communication. These multidomain enzymes use an integrated carrier protein that delivers the growing peptide to the catalytic domains, requiring coordinated conformational changes that allow the proper sequence of synthetic steps. Recent structural studies of NRPSs have described important conformational states and illustrate the critical role of a small subdomain within the adenylation domains. This subdomain alternates between catalytic conformations and also serves as a linker domain, providing further conformational flexibility to enable the carrier to project from the core of NRPS. These studies are described along with remaining questions in the study of the structural dynamics of NRPSs.

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“…13–22 For the latter, permissive catalysts involved in late-stage NP tailoring modifications (acylation, alkylation, glycosylation, oxidation) have been particularly enabling in NP core scaffold diversification. 5,15,23–30 The demonstrated impact of glycosylation within this context is diverse and includes influencing NP or small-molecule drug potency, mechanism, pharmacodynamics, pharmacokinetics, and ADME properties 29–39 where the advent of permissive chemoenzymatic strategies complement and/or circumvent key limitations of conventional chemical glycosylation as a medicinal chemistry tool. 29,40–51 Such chemoenzymatic strategies have benefited from the development of donor/acceptor permissive glycosyltransferases via directed evolution and a corresponding screening platform enabled by the use of simple activated glycoside donors that drive the equilibrium of glycosyltransferase-catalyzed reactions toward product formation and provide real-time indicators of sugar-nucleotide utilization in parallel (Figure 1).…”

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confidence: 99%

Identification of Neuroprotective Spoxazomicin and Oxachelin Glycosides via Chemoenzymatic Glycosyl-Scanning

et al. 2016

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The assessment of glycosyl-scanning to expand the molecular and functional diversity of metabolites from the underground coal mine fire-associated Streptomyces sp. RM-14-6 is reported. Using the engineered glycosyltransferase OleD Loki and a 2-chloro-4-nitrophenylglycoside-based screen, six metabolites were identified as substrates of OleD Loki, from which 12 corresponding metabolite glycosides were produced and characterized. This study highlights the first application of the 2-chloro-4-nitrophenylglycoside-based screen toward an unbiased set of unique microbial natural products and the first reported application of the 2-chloro-4-nitrophenylglycoside-based transglycosylation reaction for the corresponding preparative synthesis of target glycosides. Bioactivity analysis (including antibacterial, antifungal, anticancer, and EtOH damage neuroprotection assays) revealed glycosylation to attenuate the neuroprotective potency of 4, while glycosylation of the structurally related inactive spoxazomicin C (3) remarkably invoked neuroprotective activity.

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A chemocentric view of the natural product inventory

Cited by 55 publications

References 34 publications

Biogenesis of antibiotics—viewing its history and glimpses of the future

Biogenesis of antibiotics—viewing its history and glimpses of the future

Structural insight into the necessary conformational changes of modular nonribosomal peptide synthetases

Identification of Neuroprotective Spoxazomicin and Oxachelin Glycosides via Chemoenzymatic Glycosyl-Scanning

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