Chain Termination Steps in Nonribosomal Peptide Synthetase Assembly Lines: Directed Acyl-S-Enzyme Breakdown in Antibiotic and Siderophore Biosynthesis

Keating, Thomas A.; Ehmann, David E.; Kohli, Rahul M.; Marshall, C. Gary; Trauger, John W.; Walsh, Christopher T.

doi:10.1002/1439-7633(20010202)2:2<99::aid-cbic99>3.0.co;2-3

Cited by 80 publications

(58 citation statements)

References 43 publications

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“…Specifically, the third NRPS module is missing of the adenylation domain, but has a functionally unknown HxxPF repeat domain in front of two repeated T domains. A condensation domain is found at the C-terminus instead of a TE or a reductase domain, suggesting that the peptide product may be released from the NRPS machinery by a condensation reaction as reported previously28.…”

Section: Resultssupporting

confidence: 63%

Genome mining unveils widespread natural product biosynthetic capacity in human oral microbe Streptococcus mutans

Liu

Hao

Xie

et al. 2016

Sci Rep

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Streptococcus mutans is a major pathogen causing human dental caries. As a Gram-positive bacterium with a small genome (about 2 Mb) it is considered a poor source of natural products. Due to a recent explosion in genomic data available for S. mutans strains, we were motivated to explore the natural product production potential of this organism. Bioinformatic characterization of 169 publically available genomes of S. mutans from human dental caries revealed a surprisingly rich source of natural product biosynthetic gene clusters. Anti-SMASH analysis identified one nonribosomal peptide synthetase (NRPS) gene cluster, seven polyketide synthase (PKS) gene clusters and 136 hybrid PKS/NRPS gene clusters. In addition, 211 ribosomally synthesized and post-translationally modified peptides (RiPPs) clusters and 615 bacteriocin precursors were identified by a combined analysis using BAGEL and anti-SMASH. S. mutans harbors a rich and diverse natural product genetic capacity, which underscores the importance of probing the human microbiome and revisiting species that have traditionally been overlooked as “poor” sources of natural products.

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Section: Resultssupporting

confidence: 63%

Genome mining unveils widespread natural product biosynthetic capacity in human oral microbe Streptococcus mutans

Liu

Hao

Xie

et al. 2016

Sci Rep

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“…Structural characterization would be necessary to determine spatial proximity. Finally, after the incorporation of L-valine into the peptide chain, the C and PCP domain of the last module catalyze the cyclization of the peptide leading to the final cyclic structure, as previously observed in other NRPS systems [34], [35]. It should be stressed that non-linear NRPS organizations are a very heterogenous group of NRPS systems which deviate from the colinearity rule thus showing various unusual mechanisms [6].…”

Section: Discussionmentioning

confidence: 58%

A Non-Canonical NRPS Is Involved in the Synthesis of Fungisporin and Related Hydrophobic Cyclic Tetrapeptides in Penicillium chrysogenum

et al. 2014

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The filamentous fungus Penicillium chrysogenum harbors an astonishing variety of nonribosomal peptide synthetase genes, which encode proteins known to produce complex bioactive metabolites from simple building blocks. Here we report a novel non-canonical tetra-modular nonribosomal peptide synthetase (NRPS) with microheterogenicity of all involved adenylation domains towards their respective substrates. By deleting the putative gene in combination with comparative metabolite profiling various unique cyclic and derived linear tetrapeptides were identified which were associated with this NRPS, including fungisporin. In combination with substrate predictions for each module, we propose a mechanism for a ‘trans-acting’ adenylation domain.

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“…Recombinant A-domains of modules 8,5,7,4, and 2 of the BT NRPS were produced and purified as described in Methods and Materials. Almost completely soluble recombinant A-domain proteins were obtained.…”

Section: Vol 71 2005 Peptide Structure and Nrps Operon Of Bt Antibimentioning

confidence: 99%

“…This process is the chain termination step and is usually catalyzed by a C-terminal thioesterase domain (TE-domain). Thioesterase-mediated release of the mature peptide from the NRPS enzyme involves transient formation of an acyl-O-TE intermediate that is then hydrolyzed or hydrolyzed and concomitantly cyclized to release the mature peptide (7). An alternative termination scheme involves reduction of the tethered C-terminal residue by a reductase domain (R-domain) that resides in the last NRPS module, resulting in release of a peptide with an alcoholic C-terminal residue (5,9).…”

mentioning

confidence: 99%

Structure and Biosynthesis of the BT Peptide Antibiotic from Brevibacillus texasporus

Xiaofeng

Ballard

Jiang

2005

Appl Environ Microbiol

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We isolated a novel gram-positive bacterium, Brevibacillus texasporus, that produces an antibiotic, BT. BT is a group of related peptides that are produced by B. texasporus cells in response to nutrient limitation. We report here purification and determination of the structure of the most abundant BT isomer, BT1583. Amino acid composition and tandem mass spectrometry experiments yielded a partial BT1583 structure. The presence of ornithine and D-form residues in the partial BT1583 structure indicated that the peptide is synthesized by a nonribosomal peptide synthetase (NRPS). The BT NRPS operon was rapidly and accurately identified by using a novel in silico NRPS operon hunting strategy that involved direct shotgun genomic sequencing rather than the unreliable cosmid library hybridization scheme. Sequence analysis of the BT NRPS operon indicated that it encodes a colinear modular NRPS with a strict correlation between the NRPS modules and the amino acid residues in the peptide. The colinear nature of the BT NRPS enabled us to utilize the genomic information to refine the BT1583 peptide sequence to Me 2 -4-methyl-4-In addition, we report the discovery of novel NRPS codons (sets of the substrate specificity-conferring residues in NRPS modules) for valine, lysine, ornithine, and tyrosine.Novel antibiotics are needed to combat infections caused by bacteria that are resistant to conventional antibiotics. It is well known that microbes produce a huge variety of antibiotics to wage chemical warfare against competing microbes. We screened soil microorganisms for strains that produce novel antibiotics. Bacillus sp. strain E58 (ϭ ATCC PTA-5854) was isolated for its ability to produce the antibiotic BT against Staphylococcus aureus strains that cause life-threatening infections (Jiang and Munoz-Romero, unpublished results). This strain was named Brevibacillus texasporus based on its relatedness to Brevibacillus laterosporus.Many peptide antibiotics of microbial origin (mostly from actinomycetes, bacilli, and fungi) are synthesized by nonribosomal peptide synthetases (NRPS), and they contain unusual amino acids. NRPS usually have a colinear modular architecture (15). The N-terminal to C-terminal order and the specificities of the individual modules correspond to the sequential order and identities of the amino acid residues in the peptide product. Each NRPS module recognizes a specific amino acid and catalyzes stepwise condensation to form a growing peptide chain. The identity of the amino acid recognized by a particular module can be predicted by comparisons to other modules having known specificities (3). Such strict correlation made it possible to identify genes encoding the NRPS enzymes for a number of microbial nonribosomal peptides with known structures, as demonstrated by identification of the mycobactin biosynthesis operon in the genome of Mycobacterium tuberculosis (18). Conversely, an NRPS operon may be a source of information that allows researchers to determine certain structural details of the peptide product. ...

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Chain Termination Steps in Nonribosomal Peptide Synthetase Assembly Lines: Directed Acyl-S-Enzyme Breakdown in Antibiotic and Siderophore Biosynthesis

Cited by 80 publications

References 43 publications

Genome mining unveils widespread natural product biosynthetic capacity in human oral microbe Streptococcus mutans

Genome mining unveils widespread natural product biosynthetic capacity in human oral microbe Streptococcus mutans

A Non-Canonical NRPS Is Involved in the Synthesis of Fungisporin and Related Hydrophobic Cyclic Tetrapeptides in Penicillium chrysogenum

Structure and Biosynthesis of the BT Peptide Antibiotic from Brevibacillus texasporus

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