Substrate specificity of nonribosomal peptide synthetase modules responsible for the biosynthesis of the oligopeptide moiety of cephabacin in<i>Lysobacter lactamgenus</i>

Demirev, Atanas V.; Lee, Chu-Hee; Jaishy, Bharat P.; Nam, Doo-Hyun; Ryu, Dewey D. Y.

doi:10.1111/j.1574-6968.2005.00067.x

Cited by 12 publications

(7 citation statements)

References 27 publications

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“…The four A domains were biochemically characterized, with A 1 activating L-arginine and the other three A domains all activating L-alanine. 48 The in vitro results confirmed that these four NRPS modules are responsible for the oligopeptide chain incorporation in cephabacin biosynthesis. The function of the PKS in the hybrid PKS-NRPS was also probed by in vitro expression of KS, ACP and AT domains independently in E. coli .…”

Section: Structure Activity and Biosynthesis Of Lysobacter Naturalmentioning

confidence: 54%

Bioactive natural products from Lysobacter

et al. 2012

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The gliding Gram-negative Lysobacter bacteria are emerging as a promising source of new bioactive natural products. These ubiquitous freshwater and soil microorganisms are fast growing, simple to use and maintain, and genetically amenable for biosynthetic engineering. This Highlight reviews a group of biologically active and structurally distinct natural products from the genus Lysobacter, with a focus on their biosyntheses. Although Lysobacter sp. are known as prolific producers of bioactive natural products, detailed molecular mechanistic studies of their enzymatic assembly have been surprisingly scarce. We hope to provide a snapshot of the important work done on the lysobacterial natural products and to provide useful information for future biosynthetic engineering of novel antibiotics in Lysobacter.

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Section: Structure Activity and Biosynthesis Of Lysobacter Naturalmentioning

confidence: 54%

Bioactive natural products from Lysobacter

et al. 2012

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“…Several reports had examined the biocontrol efficacy of Lysobacter species and their colonization in soil and roots/rhizosphere, and recent research on Lysobacter has focused on the identification and utilization of the bioactive molecules [5], [13], [15], [19], [28], [31], [55], [56], [57], [58], [59]. Relatively little has been carried out to investigate the biology of these ubiquitous microorganisms.…”

Section: Resultsmentioning

confidence: 99%

Biosynthetic Mechanism for Sunscreens of the Biocontrol Agent Lysobacter enzymogenes

Yan

Qian

et al. 2013

PLoS ONE

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Lysobacter are ubiquitous environmental bacteria emerging as novel biocontrol agents and new sources of anti-infectives. So far, very little effort has been invested in the study of the biology of these Gram-negative gliding bacteria. Many Lysobacter species are characterized by their yellow-orange appearance. Using transposon mutagenesis, we identified a stand-alone polyketide synthase (PKS) gene cluster required for the pigment production in L. enzymogenes OH11. The yellow pigments were abolished in the “white” mutants generated by target-specific deletions of ketosynthase (KS), acyl carrier protein, or ketoreductase. Spectroscopic data suggested that the pigments belong to xanthomonadin-like aryl polyenes. Polyene-type polyketides are known to be biosynthesized by modular PKS (Type I), not by stand-alone PKS (Type II) which always contain the heterodimer KS-CLF (chain-length factor) as the key catalytic component. Remarkably, this aryl polyene PKS complex only contains the KS (ORF17), but not the CLF. Instead, a hypothetical protein (ORF16) is located immediately next to ORF17. ORF16–17 homologs are widespread in numerous uncharacterized microbial genomes, in which an ORF17 homolog is always accompanied by an ORF16 homolog. The deletion of ORF16 eliminated pigment production, and homology modeling suggested that ORF16 shares a structural similarity to the N-terminal half of CLF. A point-mutation of glutamine (Q166A) that is the conserved active site of known CLF abolished pigment production. The “white” mutants are significantly more sensitive to UV/visible light radiation or H2O2 treatment than the wild type. These results unveil the first example of Type II PKS-synthesized polyene pigments and show that the metabolites serve as Lysobacter “sunscreens” that are important for the survival of these ubiquitous environmental organisms.

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“…Lysobacter is fast-growing, simple to use and maintain, and readily accessible to genetic tools, with capacities for posttranslational modifications and availability of the substrate pool for polyketides and nonribosomal peptide biosynthesis. Furthermore, Lysobacter is known as a prolific producer of bioactive compounds, such as cephabacins (11,28), HSAF (33,52), lysobactin (5,7,20,37), and tripropeptins (18,19). So far, none of these pathways has been genetically manipulated for new antibiotic production.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of the Anti-Methicillin-Resistant Staphylococcus aureus WAP-8294A2 Biosynthetic Gene Cluster from Lysobacter enzymogenes OH11

Zhang

Qian

et al. 2011

Antimicrob Agents Chemother

154

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Lysobactor enzymogenes strain OH11 is an emerging biological control agent of fungal and bacterial diseases. We recently completed its genome sequence and found it contains a large number of gene clusters putatively responsible for the biosynthesis of nonribosomal peptides and polyketides, including the previously identified antifungal dihydromaltophilin (HSAF). One of the gene clusters contains two huge open reading frames, together encoding 12 modules of nonribosomal peptide synthetases (NRPS). Gene disruption of one of the NRPS led to the disappearance of a metabolite produced in the wild type and the elimination of its antibacterial activity. The metabolite and antibacterial activity were also affected by the disruption of some of the flanking genes. We subsequently isolated this metabolite and subjected it to spectroscopic analysis. The mass spectrometry and nuclear magnetic resonance data showed that its chemical structure is identical to WAP-8294A2, a cyclic lipodepsipeptide with potent antimethicillin-resistant Staphylococcus aureus (MRSA) activity and currently in phase I/II clinical trials. The WAP-8294A2 biosynthetic genes had not been described previously. So far, the Gram-positive Streptomyces have been the primary source of anti-infectives. Lysobacter are Gram-negative soil/water bacteria that are genetically amendable and have not been well exploited. The WAP-8294A2 synthetase represents one of the largest NRPS complexes, consisting of 45 functional domains. The identification of these genes sets the foundation for the study of the WAP-8294A2 biosynthetic mechanism and opens the door for producing new anti-MRSA antibiotics through biosynthetic engineering in this new source of Lysobacter.

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Substrate specificity of nonribosomal peptide synthetase modules responsible for the biosynthesis of the oligopeptide moiety of cephabacin inLysobacter lactamgenus

Cited by 12 publications

References 27 publications

Bioactive natural products from Lysobacter

Bioactive natural products from Lysobacter

Biosynthetic Mechanism for Sunscreens of the Biocontrol Agent Lysobacter enzymogenes

Identification and Characterization of the Anti-Methicillin-Resistant Staphylococcus aureus WAP-8294A2 Biosynthetic Gene Cluster from Lysobacter enzymogenes OH11

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