Biosynthesis of Mupirocin by <i>Pseudomonas fluorescens</i> NCIMB 10586 Involves Parallel Pathways

Gao, Shu-Shan; Hothersall, Joanne; Wu, Jixuan; Murphy, Annabel C.; Song, Zhiyong; Stephens, Elton R.; Thomas, Christopher M.; Crump, Matthew P.; Cox, Russell J.; Simpson, Thomas J.; Willis, Christine L.

doi:10.1021/ja501731p

Cited by 42 publications

(69 citation statements)

References 23 publications

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“…MupU, the TmlU homolog in mupirocin biosynthesis, loads the fatty acyl carboxylate in pseudomonic acid B onto a stand alone acyl carrier protein (ACP) MacpE for additional tailoring. [22] However, thiomarinol biosynthesis lacks a MacpE-like standalone ACP. Instead, an additional ACP and ketosynthase domain appear to have been incorporated into the large PKS subunits, possibly replacing MacpE and MupU, respectively.…”

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confidence: 99%

Enzymatic Basis of “Hybridity” in Thiomarinol Biosynthesis

et al. 2015

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Thiomarinol is a naturally occurring double-headed antibiotic that is highly potent against methicillin-resistant Staphylococcus aureus. Its structure comprises two antimicrobial sub-components, marinolic acid and holothin, linked by an amide bond. TmlU was thought to be the sole enzyme responsible for this amide bond formation. Contrary to this idea, we show that TmlU acts as a CoA ligase that activates marinolic acid as its thioester before it is processed by the acetyltransferase HolE to catalyze the amidation. TmlU prefers complex acyl acids as substrates, whereas HolE is relatively promiscuous, accepting a range of acyl-CoA and amine substrates. Our results provide detailed biochemical information on thiomarinol biosynthesis, and evolutionary insight regarding how the marinolic acid and holothin pathways converge to generate this potent hybrid antibiotic. This work also demonstrates the potential of TmlU/HolE enzymes as engineering tools to generate new “hybrid” molecules.

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confidence: 99%

Enzymatic Basis of “Hybridity” in Thiomarinol Biosynthesis

et al. 2015

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“…7,8 Consequently, mupirocin-H 1, is a novel metabolite belongs to the family of mupirocin and it is resulted mutation of the β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) synthase encoding mup H gene in Pseudomonas fluorescens and providing in vivo evidence for the roles of mup H and cognate genes found in several "AT-less" and other bacterial PKS gene clusters responsible for the biosynthesis of diverse metabolites containing acetate/propionate derived side chains, as well as possess anti bacterial activity akin mupirocin. 3,9,10 Moreover, Mupirocin-H consisting of six stereogenic centers and one trans-olefinic bond, the structure of mupirocin-H was determined by extensive analysis spectroscopic data and has been confirmed by recent total syntheses. [10][11][12][13][14][15] The amenable biological importance and fascinating structure of the mupirocin-H attracted the attention of chemists for the total synthesis.…”

Section: Introductionmentioning

confidence: 75%

“…1 It is a mixture of pseudomonic acids produced by Pseudomonas fluorescens, a soil isolate reported to possess antibacterial activity as early as 1887, 2,3 while the mixture of pseudomonic acids was found to be the active component in the 1960s, 4 the major constituent was characterized later and named pseudomonic acid A (mupirocin). 5,6 It is prescribed for treating skin infections such as cuts, burn wounds, candidiasis and impetigo.…”

Section: Introductionmentioning

confidence: 99%

Attempts towards the synthesis of mupirocin-H

Bommagani¹,

Prashanth²,

Sharma³

2017

Arkivoc

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The stereoselective synthesis of segments C1-C6 (3), C7-C12 (4) of mupirocin-H has been achieved. The synthetic procedure for the C1-C6 segment includes the zinc mediated allyl Grignard reaction with Rglyceraldehyde, Swern oxidation/Witting olefination reactions and followed by Sharpless asymmetric epoxidation. The C7-C12 segment was synthesized using again Sharpless asymmetric epoxidation on mono PMB protected 2-butene-1,4-diol, followed by regioselective opening of this epoxide with trimethyl aluminium. Both segments C1-C6 (3) and C7-C12 (4) possesses the five new stereogenic centers along with trans-olefin, but in various attempts condensation of 3 and 4 segments to give C-C bond forming parent segment (2) not affirmed, hence this work constitutes the synthesis of fragments C1-C6 (3) and C7-C12 (4) of mupirocin-H.

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“…Recently, a complete biosynthetic pathway for mupirocin production has been revealed in P. fluorescens strain NCIMB 10586. Systematic inactivation of polyketide synthase (PKS) and tailoring genes for mupirocin production in P. fluorescens has shown that its production proceeds via major (10,11-epoxide) and minor (10,11-alkene) parallel pathways (Gao et al 2014). Moreover, selected mutations have led the researchers to identify novel intermediates in the biosynthesis of mupirocin and thiomarinol antibiotics.…”

Section: Advances In Identification and Characterization Of Secondarymentioning

confidence: 99%

A decade of understanding secondary metabolism in Pseudomonas spp. for sustainable agriculture and pharmaceutical applications

Shahid

Malik

Mehnaz

2018

Environmental Sustainability

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Pseudomonas spp. have been widely studied for their plant growth promoting and antimicrobial metabolites. The genus got attention due to the production of array of secondary metabolites involved in the suppression of phytopathogens and ability to stimulate plant growth by means of nitrogen-fixation, production of hydrolytic enzymes, regulatory hormones, and solubilization of inorganic minerals. In recent years, research was focused towards identification of biosynthesis pathways and genes involved in the production of secondary metabolites that led to the discovery of novel metabolites including many new phenazine derivatives, quorum-sensing signals, rhizoxin analogues, cyclic lipopeptides, and a new class of alkylsubstituted aromatic acids. Identification of these biosynthetic pathways provided insights for their successful application in agriculture and for environmental sustainability. In addition, many genomic and metabolomic databases such as; METLIN, KEGG, GNPS, CFM-ID, MassBank, and MetaboLights, allowed exploring intricate metabolic pathways and significant genes involved in the biosynthesis of compounds. Several softwares, genome-mining tools and new techniques, such as MALDI-IMS and MALDI-FTICR MS were developed to facilitate the characterization of new metabolites. Additionally, use of MALDI-imaging techniques facilitated real-time visualization of complex microbial communities and their relationship with pathogens. Secondary metabolites of Pseudomonas spp. were also demonstrated for their apoptotic, anti-mitotic, nematocidal, herbicidal, anthelmintic, insecticidal, and phytotoxic effects. Total biosynthesis of metabolic derivatives and genetic engineering enabled to develop strains with improved yield of targeted bio-products. Availability and access to published genomic sequences and comparative bioinformatics tools helped in identification of strain-specific traits and development of multifunctional inocula. This review highlights significant advances in identification of Pseudomonas secondary metabolites for their successful agricultural and pharmaceutical applications.

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Biosynthesis of Mupirocin by Pseudomonas fluorescens NCIMB 10586 Involves Parallel Pathways

Cited by 42 publications

References 23 publications

Enzymatic Basis of “Hybridity” in Thiomarinol Biosynthesis

Enzymatic Basis of “Hybridity” in Thiomarinol Biosynthesis

Attempts towards the synthesis of mupirocin-H

A decade of understanding secondary metabolism in Pseudomonas spp. for sustainable agriculture and pharmaceutical applications

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