Complexity generation during natural product biosynthesis using redox enzymes

Wang, Peng; Gao, Xue; Tang, Yi

doi:10.1016/j.cbpa.2012.04.008

Cited by 37 publications

(10 citation statements)

References 49 publications

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“…FAD serves as a cofactor to acetyl-CoA dehydrogenase. FAD-dependent redox enzymes play indispensable roles in generating structural complexity during natural product biosynthesis [ 41 ]. In our comparative proteomics analysis, the FAD-dependent oxidoreductase superfamily (spot 29) was 2.32–fold overrepresented in the HY strain, which may promote ATP formation and contribute to enhanced CPC production.…”

Section: Discussionmentioning

confidence: 99%

Acthi, a thiazole biosynthesis enzyme, is essential for thiamine biosynthesis and CPC production in Acremonium chrysogenum

et al. 2015

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BackgroundThe filamentous fungus Acremonium chrysogenum is an important industrial fungus and is used in the production of the β-lactam antibiotic cephalosporin C. Little is known regarding the molecular and biological mechanisms of how this industrial strain was improved by mutagenesis and molecular breeding. Comparative proteomics is one of the most powerful methods to evaluate the influence of gene expression on metabolite production.ResultsIn this study, we used comparative proteomics to investigate the molecular mechanisms involved in the biosynthesis of cephalosporin C between a high-producer (HY) strain and a wide-type (WT) strain. We found that the expression levels of thiamine biosynthesis-related enzymes, including the thiazole biosynthesis enzyme (Acthi), pyruvate oxidase, flavin adenine dinucleotide (FAD)-dependent oxidoreductase and sulfur carrier protein-thiS, were up-regulated in the HY strain. An Acthi-silencing mutant of the WT strain grew poorly on chemically defined medium (MMC) in the absence of thiamine, and its growth was recovered on MMC medium supplemented with thiamine. The intracellular thiamine content was changed in the Acthi silencing or over-expression mutants. In addition, we demonstrated that the manipulation of the Acthi gene can affect the hyphal growth of Acremonium chrysogenum, the transcription levels of cephalosporin C biosynthetic genes, the quantification levels of precursor amino acids for cephalosporin C synthesis and the expression levels of thiamine diphosphate-dependent enzymes. Over-expression of Acthi can significantly increase the cephalosporin C yield in both the WT strain and the HY mutant strain.ConclusionsUsing comparative proteomics, four differently expressed proteins were exploited, whose functions may be involved in thiamine diphosphate metabolism. Among these proteins, the thiazole biosynthesis enzyme (ActhiS) may play an important role in cephalosporin C biosynthesis. Our studies suggested that Acthi might be involved in the transcriptional regulation of cephalosporin C biosynthesis. Therefore, the thiamine metabolic pathway could be a potential target for the molecular breeding of this cephalosporin C producer for industrial applications.

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Section: Discussionmentioning

confidence: 99%

Acthi, a thiazole biosynthesis enzyme, is essential for thiamine biosynthesis and CPC production in Acremonium chrysogenum

et al. 2015

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“…transformations, including halogenation and hydroxylation reactions. [2] A particularly interesting oxidative tailoring step gives rise to a large number of medically important secondary metabolites by introducing single or multiple biaryl linkages. Such modifications can be found in many natural product families across phylogenetically diverse producing organisms and occur both inter-and intramolecularly.…”

Section: Introductionmentioning

confidence: 99%

The Biocatalytic Repertoire of Natural Biaryl Formation

2014

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The catalytic and selective construction of carbon-carbon bonds for the generation of complex molecules is one of the most important tasks in organic chemistry. This was clearly highlighted by the 2010 Nobel Prize in Chemistry, which was awarded for the development of Pd-catalyzed cross-coupling reactions. The underlying concept of cross-linking building blocks to generate molecular complexity can also be widely found in natural product biosynthesis. Impressive examples for such natural cross-coupling reactions are biosynthetic processes for the assembly of biaryl moieties in natural products--highly efficient enzymatic reactions that often achieve synthetically yet unmatched selectivities. This Minireview highlights selected examples that showcase these fascinating biotransformations.

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“… Secondary metabolites synthesized by nonribosomal peptide synthetases (NRPSs) display diverse and complex topologies and possess an impressive range of biological activities 1,2 Much of this diversity derives from a synthetic strategy that entails the oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds pre- 3 and post-assembly 2 . The vancomycin biosynthetic pathway is an excellent example of the range of oxidative transformations that can be performed by the iron-containing enzymes involved in its biosynthesis.…”

mentioning

confidence: 99%

Oxidative diversification of amino acids and peptides by small-molecule iron catalysis

Osberger

Rogness

Kohrt

et al. 2016

Nature

236

124

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Secondary metabolites synthesized by nonribosomal peptide synthetases (NRPSs) display diverse and complex topologies and possess an impressive range of biological activities1,2 Much of this diversity derives from a synthetic strategy that entails the oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds pre-3 and post-assembly2. The vancomycin biosynthetic pathway is an excellent example of the range of oxidative transformations that can be performed by the iron-containing enzymes involved in its biosynthesis.4 However, because of the challenges associated with using such oxidative enzymes to carry out chemical transformations in vitro, chemical syntheses guided by these principles have not been fully realized outside of nature.5 In this manuscript, we report that two small-molecule iron catalysts are capable of facilitating the targeted C—H oxidative modification of amino acids and peptides with preservation of α-center chirality. Oxidation of proline to 5-hydroxyproline furnishes a versatile intermediate that can be transformed to rigid arylated derivatives or flexible linear carboxylic acids, alcohols, olefins, and amines in both monomer and peptide settings. The value of this C—H oxidation strategy is demonstrated in its capacity for generating diversity: four 'chiral pool' amino acids are transformed to twenty-one chiral unnatural amino acids (UAAs) representing seven distinct functional group arrays; late-stage C—H functionalizations of a single proline-containing tripeptide furnish eight tripeptides, each having different UAAs. Additionally, a macrocyclic peptide containing a proline turn element is transformed via late-stage C—H oxidation to one containing a linear UAA.

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Complexity generation during natural product biosynthesis using redox enzymes

Cited by 37 publications

References 49 publications

Acthi, a thiazole biosynthesis enzyme, is essential for thiamine biosynthesis and CPC production in Acremonium chrysogenum

Acthi, a thiazole biosynthesis enzyme, is essential for thiamine biosynthesis and CPC production in Acremonium chrysogenum

The Biocatalytic Repertoire of Natural Biaryl Formation

Oxidative diversification of amino acids and peptides by small-molecule iron catalysis

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