Gobichelin A and B: mixed-ligandsiderophores discovered using proteomics

Chen, Yunqiu; Unger, Michelle; Ntai, Ioanna; McClure, Ryan A.; Albright, Jessica C.; Thomson, Regan J.; Kelleher, Neil L.

doi:10.1039/c2md20232h

Cited by 31 publications

(33 citation statements)

References 22 publications

(38 reference statements)

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“…12,14–16 In one such screen, the proteomics data for Streptomyces sp. NRRL F-6652 grown in MSB medium for 48 h identified peptides originating from two NRPS proteins from Streptomyces flavogriseus ATCC 33331 (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

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Proteomics Guided Discovery of Flavopeptins: Anti-proliferative Aldehydes Synthesized by a Reductase Domain-Containing Non-ribosomal Peptide Synthetase

et al. 2013

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Due to the importance of proteases in regulating cellular processes, the development of protease inhibitors has garnered great attention. Peptide-based aldehydes are a class of compounds that exhibit inhibitory activities against various proteases and proteasomes in the context of anti-proliferative treatments for cancer and other diseases. More than a dozen peptide-based natural products containing aldehydes have been discovered such as chymostatin, leupeptin, and fellutamide; however, the biosynthetic origin of the aldehyde functionality has yet to be elucidated. Herein we describe the discovery of a new group of lipopeptide aldehydes, the flavopeptins, and the corresponding biosynthetic pathway arising from an orphan gene cluster in Streptomyces sp. NRRL-F6652, a close relative of Streptomyces flavogriseus ATCC 33331. This research was initiated using a proteomics approach that screens for expressed enzymes involved in secondary metabolism in microorganisms. Flavopeptins are synthesized through a nonribosomal peptide synthetase containing a terminal NAD(P)H dependent reductase domain likely for the reductive release of the peptide with a C-terminal aldehyde. Solid phase peptide synthesis of several flavopeptin species and derivatives enabled structural verification and subsequent screening of biological activity. Flavopeptins exhibited submicromolar inhibition activities against cysteine proteases such as papain and calpain as well as the human 20S proteasome. They also showed anti-proliferative activities against multiple myeloma and lymphoma cell lines.

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Section: Resultsmentioning

confidence: 99%

“…13 Using the PrISM approach, several new natural products and their corresponding gene clusters have been discovered from bacteria possessing either previously sequenced or non-sequenced genomes. 14–16 …”

Section: Introductionmentioning

confidence: 99%

Proteomics Guided Discovery of Flavopeptins: Anti-proliferative Aldehydes Synthesized by a Reductase Domain-Containing Non-ribosomal Peptide Synthetase

et al. 2013

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“…Spearheading this renewed interest is the application of genome mining techniques (Bachmann, et al, 2014) and focused efforts to develop new discovery platforms including heterologous expression (Bonet, et al, 2014; Yamanaka, et al, 2014), the activation of silent gene clusters (Seyedsayamdost, 2014), peptidogenomics (Kersten, et al, 2011), glycogenomics (Kersten, et al, 2013), and proteomics (Chen, et al, 2013), all of which have helped to realize this potential. While there have been efforts to automate the process of genome mining (Medema, et al, 2014; Mohimani, et al, 2014; Zhang, et al, 2014), there remain major gaps between the detection of BGCs in genome sequence data and the identification of the metabolites they produce (Jensen, et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Molecular Networking and Pattern-Based Genome Mining Improves Discovery of Biosynthetic Gene Clusters and their Products from Salinispora Species

Duncan

Crüsemann

Lechner

et al. 2015

Chemistry & Biology

167

147

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Summary Genome sequencing has revealed that bacteria contain many more biosynthetic gene clusters than predicted based on the number of secondary metabolites discovered to date. While this biosynthetic reservoir has fostered interest in new tools for natural product discovery, there remains a gap between gene cluster detection and compound discovery. Here we apply molecular networking and the new concept of pattern-based genome mining to 35 Salinispora strains including 30 for which draft genome sequences were either available or obtained for this study. The results provide a method to simultaneously compare large numbers of complex microbial extracts, which facilitated the identification of media components, known compounds and their derivatives, and new compounds that could be prioritized for structure elucidation. These efforts revealed considerable metabolite diversity and led to several molecular family-gene cluster pairings, of which the quinomycin-type depsipeptide retimycin A was characterized and linked to gene cluster NRPS40 using pattern-based bioinformatic approaches.

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“…Early reports describe the detection of proteins associated with six orphan BGCs in M. xanthus [38]. More recently, the Kelleher group has pioneered the application of proteomics in NP discovery by capitalizing on the properties and size of non-ribosomal peptide synthetases and polyketide synthases (often >200 kDa) and their unique marker ions derived from phosphopantetheinyl cofactors[39,40]. The PrISM (Proteomic Investigation of Secondary Metabolism) platform (not to be confused with the more recent PRISM genome mining tool[11]) was developed to exploit this concept and represents a ‘protein-first’ strategy that is complementary to bioassay-guided and genomic approaches[41].…”

Section: Proteomicsmentioning

confidence: 99%

Omics-based natural product discovery and the lexicon of genome mining

Machado

Tuttle

Jensen

2017

Current Opinion in Microbiology

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Genome sequencing and the application of omic techniques are driving many important advances in the field of microbial natural products research. Despite these gains, there remain aspects of the natural product discovery pipeline where our knowledge remains poor. These include the extent to which biosynthetic gene clusters are transcriptionally active in native microbes, the temporal dynamics of transcription, translation, and natural product assembly, as well as the relationships between small molecule production and detection. Here we touch on a number of these concepts in the context of continuing efforts to unlock the natural product potential revealed in genome sequence data and discuss nomenclatural issues that warrant consideration as the field moves forward.

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Gobichelin A and B: mixed-ligandsiderophores discovered using proteomics

Cited by 31 publications

References 22 publications

Proteomics Guided Discovery of Flavopeptins: Anti-proliferative Aldehydes Synthesized by a Reductase Domain-Containing Non-ribosomal Peptide Synthetase

Proteomics Guided Discovery of Flavopeptins: Anti-proliferative Aldehydes Synthesized by a Reductase Domain-Containing Non-ribosomal Peptide Synthetase

Molecular Networking and Pattern-Based Genome Mining Improves Discovery of Biosynthetic Gene Clusters and their Products from Salinispora Species

Omics-based natural product discovery and the lexicon of genome mining

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