Cloning and characterization of Streptomyces galilaeus aclacinomycins polyketide synthase (PKS) cluster

Räty, Kaj; Kantola, Jaana; Hautala, Anne; Hakala, Juha; Ylihonko, Kristiina; Mäntsälä, Pekka

doi:10.1016/s0378-1119(02)00699-6

Cited by 65 publications

(52 citation statements)

References 26 publications

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“…Examples include enterocin, which is primed by benzoate (13), benastatin, which is primed with hexanoate (14), the R1128 antibiotics, which are primed by a range of short-chain carboxylic acids (15), oxytetracycline, which is primed by malonamate (16), and daunorubicin, which is primed by propionate (17,18). This priming is catalyzed by initiation PKS modules, which vary depending on the priming unit.…”

Section: Resultsmentioning

confidence: 99%

Evolution of polyketide synthases in bacteria

Ridley

Lee

Khosla

2008

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

171

157

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The emergence of resistant strains of human pathogens to current antibiotics, along with the demonstrated ability of polyketides as antimicrobial agents, provides strong motivation for understanding how polyketide antibiotics have evolved and diversified in nature. Insights into how bacterial polyketide synthases (PKSs) acquire new metabolic capabilities can guide future laboratory efforts in generating the next generation of polyketide antibiotics. Here, we examine phylogenetic and structural evidence to glean answers to two general questions regarding PKS evolution. How did the exceptionally diverse chemistry of present-day PKSs evolve? And what are the take-home messages for the biosynthetic engineer?biosynthesis ͉ metabolism ͉ engineering P olyketides are a large family of medicinally important natural products, which are formed through the condensation of acylthioester units such as malonyl-CoA and methylmalonyl-CoA to yield metabolites with diverse structures and biological activities. Broadly speaking, there are three separate types of polyketide synthases (PKSs) recognized in bacteria. Multimodular PKSs consist of one or more large multidomain polypeptides where the growing polyketide chain is sequentially passed from one active site to the next. Depending on the nature of their constituent catalytic domains, these megasynthases generate chemical variety and complexity in a stepwise fashion (reviewed in ref. 1). In contrast, iterative PKSs are comprised of a single set of catalysts that assemble a polyketide of controlled chain length through repetitive use of active sites (reviewed in ref.2). In both cases, the nascent polyketide product is frequently acted on by further tailoring enzymes to generate the antibiotic. A third type of PKS (called type III PKSs) is fundamentally different in that the growing polyketide chain is never directly attached to a protein (reviewed in ref.3). This article focuses on the evolution of only the first two PKS classes.Bacteria, in particular Actinomycetes and Cyanobacteria, are prolific sources of polyketides, many of which possess antibiotic activity. Erythromycin, tetracycline, and amphotericin B are three well known examples of antimicrobial warfare agents from this group of bacteria that have been found useful for treating human diseases. Polyketides have also been discovered that play other roles in the environment other than to defeat microbial competitors. One such polyketide, mycolactone, is a pathogenesis-enabling immunosuppressant produced by the bacterium Mycobacterium ulcerans. This human pathogen is the causative agent of Buruli ulcer, but M. ulcerans mycolactone-negative mutants are avirulent. Addition of mycolactone to the mycolactone-negative mutants (chemical complementation) restores virulence (4). Other polyketides have been discovered that support a symbiotic relationship. One such compound, rhizoxin, is produced by a Burkholderia sp. symbiont of the fungus Rhizopus sp. Without the symbiont, the fungus cannot make the polyketide that functions to inh...

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Section: Resultsmentioning

confidence: 99%

Evolution of polyketide synthases in bacteria

Ridley

Lee

Khosla

2008

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

171

157

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“…Our previous investigations on the biosynthesis pathways of the anthracycline antibiotics nogalamycin (17,24) and aclacinomycins (14) (Fig. 1) combined with the genes from the silent angucycline gene cluster presented us an opportunity to study the interface of these two classes of aromatic polyketides and to assess the extent to which these pathways are compatible.…”

mentioning

confidence: 99%

Engineering Anthracycline Biosynthesis toward Angucyclines

Metsä‐Ketelä

Palmu

Kunnari

et al. 2003

Antimicrob Agents Chemother

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The biosynthesis pathways of two anthracyclines, nogalamycin and aclacinomycin, were directed toward angucyclines by using an angucycline-specific cyclase, pgaF, isolated from a silent antibiotic biosynthesis gene cluster. Addition of pgaF to a gene cassette that harbored the early biosynthesis genes of nogalamycin resulted in the production of two known angucyclinone metabolites, rabelomycin and its precursor, UWM6. Substrate flexibility of pgaF was demonstrated by replacement of the nogalamycin minimal polyketide synthase genes in the gene cassette with the equivalent aclacinomycin genes together with aknE2 and aknF, which specify the unusual propionate starter unit in aclacinomycin biosynthesis. This modification led to the production of a novel angucyclinone, MM2002, in which the expected ethyl side chain was incorporated into the fourth ring.

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“…Coclustered with the deoxysugar biosynthesis gene locus were genes predicted for aglycone biosynthesis comprising an aromatic type II polyketide synthase (PKS). Further analysis of the gene set revealed its similarity to the aclacinomycin gene cluster from Streptomyces galileus (41,42). This enabled the classification of the target compound as a glycosylated anthracycline polyketide.…”

Section: A Ms-glycogenetic Code Connecting Microbial Gnp Chemotypes Andmentioning

confidence: 96%

Glycogenomics as a mass spectrometry-guided genome-mining method for microbial glycosylated molecules

Kersten

Ziemert

Gonzalez³

et al. 2013

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

103

107

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Glycosyl groups are an essential mediator of molecular interactions in cells and on cellular surfaces. There are very few methods that directly relate sugar-containing molecules to their biosynthetic machineries. Here, we introduce glycogenomics as an experimentguided genome-mining approach for fast characterization of glycosylated natural products (GNPs) and their biosynthetic pathways from genome-sequenced microbes by targeting glycosyl groups in microbial metabolomes. Microbial GNPs consist of aglycone and glycosyl structure groups in which the sugar unit(s) are often critical for the GNP's bioactivity, e.g., by promoting binding to a target biomolecule. GNPs are a structurally diverse class of molecules with important pharmaceutical and agrochemical applications. Herein, O-and N-glycosyl groups are characterized in their sugar monomers by tandem mass spectrometry (MS) and matched to corresponding glycosylation genes in secondary metabolic pathways by a MS-glycogenetic code. The associated aglycone biosynthetic genes of the GNP genotype then classify the natural product to further guide structure elucidation. We highlight the glycogenomic strategy by the characterization of several bioactive glycosylated molecules and their gene clusters, including the anticancer agent cinerubin B from Streptomyces sp. SPB74 and an antibiotic, arenimycin B, from Salinispora arenicola CNB-527.secondary metabolite | drug discovery | microbial genomics | deoxysugar | polyketide

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Cloning and characterization of Streptomyces galilaeus aclacinomycins polyketide synthase (PKS) cluster

Cited by 65 publications

References 26 publications

Evolution of polyketide synthases in bacteria

Evolution of polyketide synthases in bacteria

Engineering Anthracycline Biosynthesis toward Angucyclines

Glycogenomics as a mass spectrometry-guided genome-mining method for microbial glycosylated molecules

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