Glycopeptide antibiotic biosynthesis: Enzymatic assembly of the dedicated amino acid monomer (
            <i>S</i>
            )-3,5-dihydroxyphenylglycine

Chen, Huawei; Tseng, Claire; Hubbard, Brian K.; Walsh, Christopher T.

doi:10.1073/pnas.221582098

Cited by 102 publications

(125 citation statements)

References 29 publications

(49 reference statements)

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“…VemA–F are homologues of Ken2–7, which have been proposed to catalyse the formation of the 3,5‐dihydroxybenzoic acid starter unit utilised by a type I modular PKS for the assembly of kendomycin in Streptomyces violaceoruber 20. VemA has 60–70 % identity to DpgA, a type III PKS that has been shown to catalyse the conversion of four malonyl‐CoA molecules to (3,5‐dihydroxyphenyl)acetyl‐CoA 21. VemB and VemD are homologues of DpgB and DpgD, respectively, which have been shown to increase the efficiency of the DpgA‐catalysed reaction 21.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Unusual Biaryl Polyketides by Activation of a SilentStreptomyces venezuelaeBiosynthetic Gene Cluster

et al. 2016

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Comparative transcriptional profiling of a ΔbldM mutant of Streptomyces venezuelae with its unmodified progenitor revealed that the expression of a cryptic biosynthetic gene cluster containing both type I and type III polyketide synthase genes is activated in the mutant. The 29.5 kb gene cluster, which was predicted to encode an unusual biaryl metabolite, which we named venemycin, and potentially halogenated derivatives, contains 16 genes including one—vemR—that encodes a transcriptional activator of the large ATP‐binding LuxR‐like (LAL) family. Constitutive expression of vemR in the ΔbldM mutant led to the production of sufficient venemycin for structural characterisation, confirming its unusual biaryl structure. Co‐expression of the venemycin biosynthetic gene cluster and vemR in the heterologous host Streptomyces coelicolor also resulted in venemycin production. Although the gene cluster encodes two halogenases and a flavin reductase, constitutive expression of all three genes led to the accumulation only of a monohalogenated venemycin derivative, both in the native producer and the heterologous host. A competition experiment in which equimolar quantities of sodium chloride and sodium bromide were fed to the venemycin‐producing strains resulted in the preferential incorporation of bromine, thus suggesting that bromide is the preferred substrate for one or both halogenases.

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Section: Resultsmentioning

confidence: 99%

Discovery of Unusual Biaryl Polyketides by Activation of a SilentStreptomyces venezuelaeBiosynthetic Gene Cluster

et al. 2016

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“…This indicates that the three gene products DpgB-D are required to convert the reaction product of DpgA into the amino acid Dpg. Enzymatic assays with the protein expressed in S. lividans showed that DpgA uses malonyl-CoA as the sole substrate to synthesize DPA-CoA (31,32).…”

Section: Bacterial Type III Pkssmentioning

confidence: 99%

Type III polyketide synthases in natural product biosynthesis

et al. 2012

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SummaryPolyketides represent an important class of biologically active and structurally diverse compounds in nature. They are synthesized from acyl-coenzyme A substrates by polyketide synthases (PKSs). PKSs are classified into three groups: types I, II, and III. This article introduces recent studies on type III PKSs identified from plants, bacteria, and fungi, and describes the catalytic functions of these enzymes in detail. Plant type III PKSs have been widely studied, as exemplified by chalcone synthase, which plays an important role in the synthesis of plant metabolites. Bacterial type III PKSs fall into five groups, many of which were identified from Streptomyces, a genus that has been well known for its production of bioactive molecules and genetic alterability. Although it was believed that type III PKSs exist exclusively in plants and bacteria, recent fungal genome sequencing projects and biochemical studies revealed the presence of type III PKSs in filamentous fungi, which provides a new chance to study fungal secondary metabolism and synthesize ''unnatural'' natural products. Type III PKSs have been used for the biosynthesis of novel molecules through precursordirected and structure-based mutagenesis approaches.2012 IUBMB IUBMB Life, 64(4): [285][286][287][288][289][290][291][292][293][294][295] 2012

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“…The THNS from S. griseus (also known as RppA) has been shown to possess broad substrate specificity to yield a wide variety of products (20). In several strains that produce vancomycin group of natural products, a CHS-like protein performs the biosynthesis of 3,5-dihydroxyphenylglycine by using several molecules of malonyl-CoA as substrate (21)(22)(23). The precursor to the broad spectrum antimicrobial agent 2,4-diacetylphloroglucinol is produced by a CHS homologue (phlD) in many strains of fluorescent Pseudomonas sp.…”

mentioning

confidence: 99%

A New Family of Type III Polyketide Synthases in Mycobacterium tuberculosis

Saxena

Yadav²,

Mohanty

et al. 2003

Journal of Biological Chemistry

105

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The Mycobacterium tuberculosis genome has revealed a remarkable array of polyketide synthases (PKSs); however, no polyketide product has been isolated thus far. Most of the PKS genes have been implicated in the biosynthesis of complex lipids. We report here the characterization of two novel type III PKSs from M. tuberculosis that are involved in the biosynthesis of long-chain ␣-pyrones. Measurement of steady-state kinetic parameters demonstrated that the catalytic efficiency of PKS18 protein was severalfold higher for long-chain acyl-coenzyme A substrates as compared with the smallchain precursors. The specificity of PKS18 and PKS11 proteins toward long-chain aliphatic acyl-coenzyme A (C 12 to C 20 ) substrates is unprecedented in the chalcone synthase (CHS) family of condensing enzymes. Based on comparative modeling studies, we propose that these proteins might have evolved by fusing the catalytic machinery of CHS and ␤-ketoacyl synthases, the two evolutionarily related members with conserved thiolase fold. The mechanistic and structural importance of several active site residues, as predicted by our structural model, was investigated by performing site-directed mutagenesis. The functional identification of diverse catalytic activity in mycobacterial type III PKSs provide a fascinating example of metabolite divergence in CHSlike proteins.Mycobacteria are classified in the phylogeny of the Actinomycetes, along with the Streptomyces bacteria. Interestingly, these two actinomycete genera have received immense attention due to their contrasting effects on human society. Whereas Streptomyces have provided a rich source of antibiotics and other therapeutic products for human diseases, Mycobacterium tuberculosis and Mycobacterium leprae have been two of humankind's greatest scourges. Although the original phylogenic classifications of Mycobacterium and Streptomyces were based primarily on morphology, the genome sequences of these organisms have further established their common lineage (1, 2). These genome sequences have revealed several families of genes that are common between them, which include an unusually large number of gene clusters that are homologous to polyketide synthases (PKSs). 1 Although a polyketide producthas not yet been isolated from M. tuberculosis, recent studies have implicated some of its PKS genes in the biosynthesis of complex lipids (3). In this report, we have characterized two novel polyketide synthases from M. tuberculosis, which are involved in the biosynthesis of unusual long-chain ␣-pyrones.Polyketides are a diverse class of secondary metabolites that possess a broad range of biological activities (4). Despite structural diversity of these natural products, PKSs synthesize polyketides by a common chemical strategy. Initial priming by a starter molecule is followed by repetitive decarboxylative condensation of coenzyme A (CoA) analogues of simple carboxylic acids. PKS elongates the polyketide chain either by repetitively using a single active site to perform multiple condensation reaction...

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Glycopeptide antibiotic biosynthesis: Enzymatic assembly of the dedicated amino acid monomer ( S )-3,5-dihydroxyphenylglycine

Cited by 102 publications

References 29 publications

Discovery of Unusual Biaryl Polyketides by Activation of a SilentStreptomyces venezuelaeBiosynthetic Gene Cluster

Discovery of Unusual Biaryl Polyketides by Activation of a SilentStreptomyces venezuelaeBiosynthetic Gene Cluster

Type III polyketide synthases in natural product biosynthesis

A New Family of Type III Polyketide Synthases in Mycobacterium tuberculosis

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