Characterization of the Amicetin Biosynthesis Gene Cluster from Streptomyces vinaceusdrappus NRRL 2363 Implicates Two Alternative Strategies for Amide Bond Formation

Zhang, Gaiyun; Zhang, Haibo; Li, Sumei; Xiao, Jianru; Zhang, Guangtao; Zhu, Yiguang; Niu, Siwen; Ju, Jianhua; Zhang, Changsheng

doi:10.1128/aem.07185-11

Cited by 41 publications

(34 citation statements)

References 60 publications

(61 reference statements)

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“…This protein activates 2-methyl-serine for incorporation into amicetin as the final step in the biosynthesis. 18 By the process of elimination, we propose that TbrN is involved in the incorporation of tambroline, although it remains to be shown whether this protein activates tambroline itself, or if the cyclization occurs while the uncyclized precursor is tethered to the NRPS.…”

Section: Resultsmentioning

confidence: 96%

Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer

et al. 2016

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For more than half a century the pharmaceutical industry has sifted through natural products produced by microbes, uncovering new scaffolds and fashioning them into a broad range of vital drugs. We sought a strategy to reinvigorate the discovery of natural products with distinctive structures using bacterial genome sequencing combined with metabolomics. By correlating genetic content from 178 actinomycete genomes with mass spectrometry-enabled analyses of their exported metabolomes, we paired new secondary metabolites with their biosynthetic gene clusters. We report the use of this new approach to isolate and characterize tambromycin, a new chlorinated natural product, composed of several nonstandard amino acid monomeric units, including a unique pyrrolidine-containing amino acid we name tambroline. Tambromycin shows antiproliferative activity against cancerous human B- and T-cell lines. The discovery of tambromycin via large-scale correlation of gene clusters with metabolites (a.k.a. metabologenomics) illuminates a path for structure-based discovery of natural products at a sharply increased rate.

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Section: Resultsmentioning

confidence: 96%

Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer

et al. 2016

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“…Of the aforementioned natural products containing PABA, only the aromatic amine of PABA from amecitin is modified to an amide as also observed in 3. In the case of amicetin, gene inactivation of aviN encoding a putative malonyl-CoA:ACP transacylase revealed it as the catalyst for amide bond formation (60). Contrastingly, the formation of amide bond for 2a is orchestrated by an unconventional mechanism featuring sequential catalysis by CapS and CapW (25).…”

Section: Discussionmentioning

confidence: 99%

The Biosynthesis of Capuramycin-type Antibiotics

Cai

Goswami

Yang

et al. 2015

Journal of Biological Chemistry

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Background: Several nucleoside antibiotics contain a uridine-5Ј-carboxamide core of unclear origin. Results: The A-102395 biosynthetic gene cluster was cloned, a genetic system was developed, and three enzymes were characterized in vivo and in vitro. Conclusion: Uridine-5Ј-carboxamide originates from UMP and L-Thr by sequential reactions catalyzed by a dioxygenase and transaldolase. Significance: The results provide the first opportunity to methodically interrogate the biosynthesis of these unusual antibiotics.

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“…TFRs are not limited to polyketide biosynthesis clusters but are found in biosynthesis clusters for nonribosomal peptides (e.g., acmP and acmU in the actinomycin cluster [94]) and nucleoside antibiotics (e.g., amiP in the amicetin cluster [95]). …”

Section: Tfrs Regulating Self-resistance In Antibiotic-producing Orgamentioning

confidence: 99%

The TetR Family of Regulators

Cuthbertson

Nodwell

2013

Microbiol Mol Biol Rev

451

513

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SUMMARY The most common prokaryotic signal transduction mechanisms are the one-component systems in which a single polypeptide contains both a sensory domain and a DNA-binding domain. Among the >20 classes of one-component systems, the TetR family of regulators (TFRs) are widely associated with antibiotic resistance and the regulation of genes encoding small-molecule exporters. However, TFRs play a much broader role, controlling genes involved in metabolism, antibiotic production, quorum sensing, and many other aspects of prokaryotic physiology. There are several well-established model systems for understanding these important proteins, and structural studies have begun to unveil the mechanisms by which they bind DNA and recognize small-molecule ligands. The sequences for more than 200,000 TFRs are available in the public databases, and genomics studies are identifying their target genes. Three-dimensional structures have been solved for close to 200 TFRs. Comparison of these structures reveals a common overall architecture of nine conserved α helices. The most important open question concerning TFR biology is the nature and diversity of their ligands and how these relate to the biochemical processes under their control.

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Characterization of the Amicetin Biosynthesis Gene Cluster from Streptomyces vinaceusdrappus NRRL 2363 Implicates Two Alternative Strategies for Amide Bond Formation

Cited by 41 publications

References 60 publications

Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer

Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer

The Biosynthesis of Capuramycin-type Antibiotics

The TetR Family of Regulators

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