A Sweet Origin for the Key Congocidine Precursor 4‐Acetamidopyrrole‐2‐carboxylate

Lautru, Sylvie; Song, Lijiang; Demange, Luc; Lombès, Thomas; Galons, Hervé; Challis, Gregory L.; Pernodet, Jean‐Luc

doi:10.1002/anie.201201445

Cited by 18 publications

(13 citation statements)

References 27 publications

(35 reference statements)

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“…In the biosynthesis of 1 , it was proposed that Cgc18 acts iteratively to load the PCP domain of itself and Cgc19 with the same pyrrole precursor, 4-acetylaminopyrrole-2-carboxylate, which is then deacetylated by Cgc14 prior to be assembled into the final skeleton [24], [25]. This model is also hypothesized to be suited to the biosynthesis of tripyrrole skeleton in 2 if the C domain of Cgc18 further catalyzes the condensation between the bipyrrole (the product of the first round of condensation) tethered with Cgc19 and the third pyrrol residue tethered with the PCP domain of Cgc18 [24].…”

Section: Resultsmentioning

confidence: 99%

“…demonstrated that congocidine is assembled by an iterative nonribosomal peptide synthetase (NRPS). In another work, nearly every gene in the congocidine gene cluster is separately inactivated, and LC-MS analysis of the related mutants showed that 4-acetamidopyrrole-2-carboxylate is the key precursor for pyrrolamide biosynthesis [25]. However, the main mechanism underlying the control of pyrrole polymerization, which may be the most intriguing question in oligo-pyrroles NP biosynthesis, has not yet been understood.…”

Section: Introductionmentioning

confidence: 99%

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Mining of the Pyrrolamide Antibiotics Analogs in Streptomyces netropsis Reveals the Amidohydrolase-Dependent “Iterative Strategy” Underlying the Pyrrole Polymerization

et al. 2014

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In biosynthesis of natural products, potential intermediates or analogs of a particular compound in the crude extracts are commonly overlooked in routine assays due to their low concentration, limited structural information, or because of their insignificant bio-activities. This may lead into an incomplete and even an incorrect biosynthetic pathway for the target molecule. Here we applied multiple compound mining approaches, including genome scanning and precursor ion scan-directed mass spectrometry, to identify potential pyrrolamide compounds in the fermentation culture of Streptomyces netropsis. Several novel congocidine and distamycin analogs were thus detected and characterized. A more reasonable route for the biosynthesis of pyrrolamides was proposed based on the structures of these newly discovered compounds, as well as the functional characterization of several key biosynthetic genes of pyrrolamides. Collectively, our results implied an unusual “iterative strategy” underlying the pyrrole polymerization in the biosynthesis of pyrrolamide antibiotics.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mining of the Pyrrolamide Antibiotics Analogs in Streptomyces netropsis Reveals the Amidohydrolase-Dependent “Iterative Strategy” Underlying the Pyrrole Polymerization

et al. 2014

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“…The metabolic pathways associated with congocidin [117] , chloramphenicol [118] , caprazamycin [119] , clorobiocin and coumermycin A1 production [120] , [121] have all been elucidated. Precursor metabolites for the production of congocidin (3-phospho-glycerate, N-acetyl-glucosamine, sedoheptulose-7-phosphate and cytosine), chloramphenicol (shikimic acid, dichloro-acetyl-CoA), and caprazamycin (uridine, glycine, S-adenosyl-methionine, 3-methyl glutaryl-CoA, fatty acyl-CoA, per-methylated rhamnose) are all derived from glucose-1-phosphate, molecules from the pentose phosphate pathway, 3-phospho-glycerate and acetyl-CoA.…”

Section: Discussionmentioning

confidence: 99%

Carbon-Flux Distribution within Streptomyces coelicolor Metabolism: A Comparison between the Actinorhodin-Producing Strain M145 and Its Non-Producing Derivative M1146

et al. 2013

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Metabolic Flux Analysis is now viewed as essential to elucidate the metabolic pattern of cells and to design appropriate genetic engineering strategies to improve strain performance and production processes. Here, we investigated carbon flux distribution in two Streptomyces coelicolor A3 (2) strains: the wild type M145 and its derivative mutant M1146, in which gene clusters encoding the four main antibiotic biosynthetic pathways were deleted. Metabolic Flux Analysis and 13C-labeling allowed us to reconstruct a flux map under steady-state conditions for both strains. The mutant strain M1146 showed a higher growth rate, a higher flux through the pentose phosphate pathway and a higher flux through the anaplerotic phosphoenolpyruvate carboxylase. In that strain, glucose uptake and the flux through the Krebs cycle were lower than in M145. The enhanced flux through the pentose phosphate pathway in M1146 is thought to generate NADPH enough to face higher needs for biomass biosynthesis and other processes. In both strains, the production of NADPH was higher than NADPH needs, suggesting a key role for nicotinamide nucleotide transhydrogenase for redox homeostasis. ATP production is also likely to exceed metabolic ATP needs, indicating that ATP consumption for maintenance is substantial.Our results further suggest a possible competition between actinorhodin and triacylglycerol biosynthetic pathways for their common precursor, acetyl-CoA. These findings may be instrumental in developing new strategies exploiting S. coelicolor as a platform for the production of bio-based products of industrial interest.

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“…27 It should however be noted that a unique pyrrole biosynthesis from fructose-6phosphate (27) was identied by Lautru and co-workers in 2012, operative in Streptomyces ambofaciens (Scheme 3). 28 Brimble's natural product synthesis and medicinal chemistry group in the School of Chemical Sciences. Aer obtaining his undergraduate and doctoral degrees at The University of Auckland, he carried out postdoctoral fellowships in the total synthesis of azaspiracid at Oregon State University (USA), and medicinal chemistry of novel opioid receptor ligands at the University of Bath (UK).…”

Section: Non-enzymatic Originmentioning

confidence: 99%

2-Formylpyrrole natural products: origin, structural diversity, bioactivity and synthesis

2019

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Covering: up to April 20182-Formylpyrroles are ubiquitous in nature, arising from the non-enzymatic Maillard reactions of amines and sugars. Often confused for secondary metabolites, these Maillard products display interesting biological activities including hepatoprotective, immunostimulatory, antiproliferative and antioxidant effects. This review presents all 2-formylpyrrole natural products reported to date and identifies structural sub-classes for their categorisation. The origin, biological activity and chemical syntheses of these natural products are discussed herein.

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A Sweet Origin for the Key Congocidine Precursor 4‐Acetamidopyrrole‐2‐carboxylate

Cited by 18 publications

References 27 publications

Mining of the Pyrrolamide Antibiotics Analogs in Streptomyces netropsis Reveals the Amidohydrolase-Dependent “Iterative Strategy” Underlying the Pyrrole Polymerization

Mining of the Pyrrolamide Antibiotics Analogs in Streptomyces netropsis Reveals the Amidohydrolase-Dependent “Iterative Strategy” Underlying the Pyrrole Polymerization

Carbon-Flux Distribution within Streptomyces coelicolor Metabolism: A Comparison between the Actinorhodin-Producing Strain M145 and Its Non-Producing Derivative M1146

2-Formylpyrrole natural products: origin, structural diversity, bioactivity and synthesis

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