Biosynthesis of the Antitumor Agent Chartreusin Involves the Oxidative Rearrangement of an Anthracyclic Polyketide

Xu, Zhongli; Jakobi, Kathrin; Welzel, Katrin; Hertweck, Christian

doi:10.1016/j.chembiol.2005.04.017

Cited by 85 publications

(94 citation statements)

References 55 publications

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“…The other sequences present in the KS and CLF trees are not located in well supported clades, leaving some doubt as to their placement, and therefore we will not discuss the incongruent clades between the various trees for these other sequences relative to each other. Two C-9 KRs were identified in the chartreusin gene cluster (35). One of these, ChaE, falls within the isochromanequinone clade.…”

Section: Resultsmentioning

confidence: 99%

Evolution of polyketide synthases in bacteria

Ridley

Lee

Khosla

2008

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

169

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.

169

157

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“…In the sequenced Streptomyces avermitilis genome (24), there is an orthologue with sequence identity over 80% to each of these NsdA-like proteins and NsdA itself. Streptomyces chartreusis, producing a potent antitumor agent chartreusin, contains an NsdA homologue ChaR2 (27% identity), whose gene is inside the chartreusin gene cluster (49). Blast searching indicated that besides Streptomyces, several other actinomycetes (i.e., cellulolytic Thermobifida fusca, GenBank accession number NC_007333; symbiotic nitrogen-fixing Frankia sp.…”

Section: Vol 188 2006 Negative Gene Affecting Streptomyces Differenmentioning

confidence: 99%

Identification of a Gene Negatively Affecting Antibiotic Production and Morphological Differentiation inStreptomyces coelicolorA3(2)

Xin

Guo

et al. 2006

J Bacteriol

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“…The analyzed GNPs were selected based on the availability of MS n data in the METLIN database (26) (daunomycin, staurosporine, oleandomycin, vancomycin, tylosin, avermectin B1a, nystatin, aclacinomycin A, novobiocin, erythromycin A), the literature [spinosyn A (27), megalomicin (28), chartreusin (29), neocarzinostatin (30), lankamycin (31), Sch40832 (32), lomaiviticin C (33)], or generated for this study (phenalinolactone, amphotericin B, chalcomycin), and the availability of nucleotide sequences associated with biosynthetic gene clusters (Datasets S3 and S4). Eighteen of 20 analyzed GNPs could be connected successfully with their biosynthetic gene cluster by the MS-glycogenetic code ( Table 1).…”

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

confidence: 99%

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.

102

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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Biosynthesis of the Antitumor Agent Chartreusin Involves the Oxidative Rearrangement of an Anthracyclic Polyketide

Cited by 85 publications

References 55 publications

Evolution of polyketide synthases in bacteria

Evolution of polyketide synthases in bacteria

Identification of a Gene Negatively Affecting Antibiotic Production and Morphological Differentiation inStreptomyces coelicolorA3(2)

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

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