Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products

Molloy, Evelyn M.; Tietz, Jonathan I.; Blair, Patricia M.; Mitchell, Douglas A.

doi:10.1016/j.bmc.2016.05.021

Cited by 17 publications

(20 citation statements)

References 103 publications

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“…The strong correlations between certain sequence motifs present in PKS domains and the stereochemistry of the resulting polyketide chains has been exploited in several cases to predict and/or corroborate absolute stereochemical assignments made on newly-discovered natural products (for example, elansolid [ 117 ], the disciformycins [ 118 ], hygrobafilomycin [ 119 ], phormidiolide [ 120 ], and haprolid [ 121 ]), either by manual inspection of domain sequences or by more sophisticated methods including hidden Markov model (HMM)-based sequence classification (e.g., ScoreDiff [ 90 ]). This is notably the case for the direction of ketoreduction by assignment of KRs as either A- or B-type.…”

Section: Reviewmentioning

confidence: 99%

Polyketide stereocontrol: a study in chemical biology

Weissman¹

2017

Beilstein J. Org. Chem.

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The biosynthesis of reduced polyketides in bacteria by modular polyketide synthases (PKSs) proceeds with exquisite stereocontrol. As the stereochemistry is intimately linked to the strong bioactivity of these molecules, the origins of stereochemical control are of significant interest in attempts to create derivatives of these compounds by genetic engineering. In this review, we discuss the current state of knowledge regarding this key aspect of the biosynthetic pathways. Given that much of this information has been obtained using chemical biology tools, work in this area serves as a showcase for the power of this approach to provide answers to fundamental biological questions.

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Section: Reviewmentioning

confidence: 99%

Polyketide stereocontrol: a study in chemical biology

Weissman¹

2017

Beilstein J. Org. Chem.

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“…Recent examples of this approach have utilized thiol-based probes to successfully target electron-deficient alkenes, β-lactams, β-lactones, and epoxides by nucleophilic addition, resulting in the discovery of several novel natural products. 14,15,16 Here we expand the scope of RBS to target additional functional groups as well as introduce a method for the straightforward identification of labeled compounds based on a unique isotopic signature (Figure 1). …”

Section: Introductionmentioning

confidence: 99%

Targeting Reactive Carbonyls for Identifying Natural Products and Their Biosynthetic Origins

et al. 2016

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Natural products serve important roles as drug candidates and as tools for chemical biology. However, traditional natural product discovery, largely based on bioassay-guided approaches, is biased towards abundant compounds and rediscovery rates are high. Orthogonal methods to facilitate discovery of new natural products are thus needed, and herein we describe an isotope tag-based expansion of reactivity-based natural product screening to address these shortcomings. Reactivity-based screening is a directed discovery approach in which a specific reactive handle on the natural product is targeted by a chemoselective probe to enable its detection by mass spectrometry. In this study, we have developed an aminooxy-containing probe to guide the discovery of aldehyde- and ketone-containing natural products. To facilitate the detection of labeling events, the probe was dibrominated, imparting a unique isotopic signature to distinguish labeled metabolites from spectral noise. As a proof of concept, the probe was then utilized to screen a collection of bacterial extracts, leading to the identification of a new analog of antipain, deimino-antipain. The bacterial producer of deimino-antipain was sequenced and the responsible biosynthetic gene cluster was identified by bioinformatic analysis and heterologous expression. These data reveal the previously undetermined genetic basis for a well-known family of aldehyde-containing, peptidic protease inhibitors, including antipain, chymostatin, leupeptin, elastatinal, and microbial alkaline protease inhibitor (MAPI), which have been widely used for over 40 years.

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“…RBS has enabled the discovery and subsequent characterization of RiPPs, non-ribosomal peptides, polyketides, and hybrids thereof (e.g. cyclothiazomycin C, 31 deimino-antipain, 32 hygrobafilomycin JBIR-100, 33 and tirandalydigin, 34 etc.). RBS is therefore a valuable tool for bridging bioinformatics-guided NP identification with NP production.…”

Section: Res-701-2)mentioning

confidence: 99%

Reactivity-based screening for citrulline-containing natural products reveals a family of bacterial peptidyl arginine deiminases

Harris

Saint-Vincent

Guo

et al. 2020

Preprint

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a family of natural products defined by a genetically encoded precursor peptide that is tailored by associated biosynthetic enzymes to form the mature product. Lasso peptides are a class of RiPP defined by an isopeptide linkage between the N-terminal amine and an internal Asp/Glu residue with the C-terminus threaded through the macrocycle. This unique lariat topology, which provides considerable stability towards heat and proteases, has stimulated interest in lasso peptides as potential therapeutics. Post-translational modifications beyond the class-defining, threaded macrolactam have been reported, including one example of arginine deimination to yield citrulline. Although a citrulline-containing lasso peptide (i.e., citrulassin) was serendipitously discovered during a genome-guided campaign, the gene(s) responsible for arginine deimination has remained unknown. Herein we describe the use of reactivity-based screening to discriminate bacteria that produce arginine-versus citrulline-bearing citrulassins, culminating in the discovery and characterization of 11 new lasso peptide variants. Phylogenetic profiling identified a distally encoded peptidyl arginine deiminase (PAD) gene ubiquitous to the citrulline-containing variants. Absence of this gene correlated strongly with citrulassin variants only containing arginine (des-citrulassin). Heterologous expression of the PAD in a non-citrulassin producer resulted in the production of the deiminated analog, confirming PAD involvement in arginine deimination. The family of PADs were then bioinformatically surveyed for a deeper understanding of its genomic context and potential role in post-translational modification of RiPPs.

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Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products

Cited by 17 publications

References 103 publications

Polyketide stereocontrol: a study in chemical biology

Polyketide stereocontrol: a study in chemical biology

Targeting Reactive Carbonyls for Identifying Natural Products and Their Biosynthetic Origins

Reactivity-based screening for citrulline-containing natural products reveals a family of bacterial peptidyl arginine deiminases

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