Thiazole/oxazole-modified microcins: complex natural products from ribosomal templates

Melby, Joel O.; Nard, Nathan J; Mitchell, Douglas A.

doi:10.1016/j.cbpa.2011.02.027

Cited by 168 publications

(192 citation statements)

References 69 publications

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“…Another area of research in which HSEE may be valuable is in the analysis of the temporal installation of multiple PTMs, which provides important mechanistic insights into RiPP biosynthesis. To test this application, we first used HSEE to analyze the in vitro intermediates of the azole-forming enzymes BalhC/BalhD/BcerB (1,27). In this biosynthetic system, BalhC and BalhD catalyze the heterocyclization of three Cys thiols of the BalhA2 peptide onto the carbonyl groups of the preceding amino acids, followed by a net dehydration to form thiazoline rings.…”

Section: Resultsmentioning

confidence: 99%

Structural investigation of ribosomally synthesized natural products by hypothetical structure enumeration and evaluation using tandem MS

Zhang

Ortega

Shi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a growing class of natural products that are found in all domains of life. These compounds possess vast structural diversity and have a wide range of biological activities, promising a fertile ground for exploring novel natural products. One challenging aspect of RiPP research is the difficulty of structure determination due to their architectural complexity. We here describe a method for automated structural characterization of RiPPs by tandem mass spectrometry. This method is based on the combined analysis of multiple mass spectra and evaluation of a collection of hypothetical structures predicted based on the biosynthetic gene cluster and molecular weight. We show that this method is effective in structural characterization of complex RiPPs, including lanthipeptides, glycopeptides, and azole-containing peptides. Using this method, we have determined the structure of a previously structurally uncharacterized lanthipeptide, prochlorosin 1.2, and investigated the order of the posttranslational modifications in three biosynthetic systems.dehydration | genome mining | lantibiotics | directionality R ibosomally synthesized and posttranslationally modified peptides (RiPPs) are a major class of natural products as revealed by the genome-sequencing efforts of the past decade (1). RiPPs are biosynthesized from genetically encoded and ribosomally produced precursor peptides, which typically consist of a core peptide that is transformed to the final product and an N-terminal extension called the leader peptide that is usually important for recognition by the posttranslational modification (PTM) enzymes (1). Because of the highly diverse PTMs, these compounds possess vast structural diversity and have a wide range of biological activities, thus representing a fertile ground for exploration. Furthermore, the ribosomal origin of RiPPs makes them particularly well suited for genome mining efforts. By using genome mining to explicitly avoid species harboring biosynthetic gene clusters identical to those that produce known compounds, a combination of strain prioritization and mass spectrometry (MS)-based analysis offers a new route to discovering natural products that can overcome the burden of rediscovery that has increasingly hampered discovery efforts (2, 3). One challenging aspect of high-throughput genome mining for new natural products is the difficulty to determine their molecular structures in high throughput. We present here a method that allows automated RiPP structure elucidation.In contrast to nonribosomal peptides that have an average molecular weight of less than 1,000 Da, as documented in the NORINE database (4), RiPPs in many cases have molecular weights larger than 2,500 Da. Molecules of this size are difficult to rapidly analyze by NMR spectroscopy, rendering MS the most convenient tool for RiPP structural characterization. Even when the precursor peptide sequences are known and the types of PTMs can be predicted based on the sequen...

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Section: Resultsmentioning

confidence: 99%

Structural investigation of ribosomally synthesized natural products by hypothetical structure enumeration and evaluation using tandem MS

Zhang

Ortega

Shi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…mbs thus have a number of unusual structural features. Modifications of two residues to form oxazolone or imidazolone rings are rare but have been observed in several classes of ribosomally synthesized and posttranslationally modified peptide (RiPP) secondary metabolites (163)(164)(165)(166). Pyrazinedione rings are even more uncommon and have been detected only in the non-amino-acidcontaining molecules selerominol (167) and flutamide (168) from fungi.…”

Section: Structural Properties Of Methanobactins Structural Diversitymentioning

confidence: 99%

“…The presence of heterocyclic rings would suggest a pathway similar to that of other postribosomal peptide synthesis (PRPS) proteins (163)(164)(165)(166)188 (163). In this reaction sequence, the cyclodehydrase catalyzes ring formation via the amine bond with the thiol or alcohol, followed by oxidation by an FMN dehydrogenase (163)(164)(165)(166). In mb, ring formation is initiated from an X-Cys dipeptide sequence, resulting in formation of either an oxazolone, imidazolone, or pyrazinedione ring with a neighboring thioamide group.…”

Section: Current Hypotheses On the Nature Of The Methanobactin Biosynmentioning

confidence: 99%

Methanobactin and the Link between Copper and Bacterial Methane Oxidation

DiSpirito

Semrau

Murrell

et al. 2016

Microbiol Mol Biol Rev

127

157

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SUMMARYMethanobactins (mbs) are low-molecular-mass (<1,200 Da) copper-binding peptides, or chalkophores, produced by many methane-oxidizing bacteria (methanotrophs). These molecules exhibit similarities to certain iron-binding siderophores but are expressed and secreted in response to copper limitation. Structurally, mbs are characterized by a pair of heterocyclic rings with associated thioamide groups that form the copper coordination site. One of the rings is always an oxazolone and the second ring an oxazolone, an imidazolone, or a pyrazinedione moiety. The mb molecule originates from a peptide precursor that undergoes a series of posttranslational modifications, including (i) ring formation, (ii) cleavage of a leader peptide sequence, and (iii) in some cases, addition of a sulfate group. Functionally, mbs represent the extracellular component of a copper acquisition system. Consistent with this role in copper acquisition, mbs have a high affinity for copper ions. Following binding, mbs rapidly reduce Cu2+to Cu1+. In addition to binding copper, mbs will bind most transition metals and near-transition metals and protect the host methanotroph as well as other bacteria from toxic metals. Several other physiological functions have been assigned to mbs, based primarily on their redox and metal-binding properties. In this review, we examine the current state of knowledge of this novel type of metal-binding peptide. We also explore its potential applications, how mbs may alter the bioavailability of multiple metals, and the many roles mbs may play in the physiology of methanotrophs.

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“…YcaO domain proteins activate backbone amide bonds by phosphorylation26, 27 or adenylation28 of the carbonyl oxygen, and all YcaO domain proteins with a characterized activity have a partner cyclodehydratase that aids catalysis of cyclization to oxazolines or thiazolines 29. The bottromycin gene cluster encodes two YcaO domain proteins, BtmE and BtmF, but no cyclodehydratases.…”

mentioning

confidence: 99%

Dissecting Bottromycin Biosynthesis Using Comparative Untargeted Metabolomics

et al. 2016

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Bottromycin A2 is a structurally unique ribosomally synthesized and post‐translationally modified peptide (RiPP) that possesses potent antibacterial activity towards multidrug‐resistant bacteria. The structural novelty of bottromycin stems from its unprecedented macrocyclic amidine and rare β‐methylated amino acid residues. The N‐terminus of a precursor peptide (BtmD) is converted into bottromycin A2 by tailoring enzymes encoded in the btm gene cluster. However, little was known about key transformations in this pathway, including the unprecedented macrocyclization. To understand the pathway in detail, an untargeted metabolomic approach that harnesses mass spectral networking was used to assess the metabolomes of a series of pathway mutants. This analysis has yielded key information on the function of a variety of previously uncharacterized biosynthetic enzymes, including a YcaO domain protein and a partner protein that together catalyze the macrocyclization.

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Thiazole/oxazole-modified microcins: complex natural products from ribosomal templates

Cited by 168 publications

References 69 publications

Structural investigation of ribosomally synthesized natural products by hypothetical structure enumeration and evaluation using tandem MS

Structural investigation of ribosomally synthesized natural products by hypothetical structure enumeration and evaluation using tandem MS

Methanobactin and the Link between Copper and Bacterial Methane Oxidation

Dissecting Bottromycin Biosynthesis Using Comparative Untargeted Metabolomics

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