Identification and characterization of the biosynthetic gene cluster of polyoxypeptin A, a potent apoptosis inducer

BackgroundPolyoxypeptin A was isolated from a culture broth of Streptomyces sp. MK498-98 F14, which has a potent apoptosis-inducing activity towards human pancreatic carcinoma AsPC-1 cells. Structurally, polyoxypeptin A is composed of a C15 acyl side chain and a nineteen-membered cyclodepsipeptide core that consists of six unusual nonproteinogenic amino acid residues (N-hydroxyvaline, 3-hydroxy-3-methylproline, 5-hydroxypiperazic acid, N-hydroxyalanine, piperazic acid, and 3-hydroxyleucine) at high oxidation states.ResultsA gene cluster containing 37 open reading frames (ORFs) has been sequenced and analyzed for the biosynthesis of polyoxypeptin A. We constructed 12 specific gene inactivation mutants, most of which abolished the production of polyoxypeptin A and only ΔplyM mutant accumulated a dehydroxylated analogue polyoxypeptin B. Based on bioinformatics analysis and genetic data, we proposed the biosynthetic pathway of polyoxypeptin A and biosynthetic models of six unusual amino acid building blocks and a PKS extender unit.ConclusionsThe identified gene cluster and proposed pathway for the biosynthesis of polyoxypeptin A will pave a way to understand the biosynthetic mechanism of the azinothricin family natural products and provide opportunities to apply combinatorial biosynthesis strategy to create more useful compounds.

• Publication year

  2014

• Venue

  BMC Microbiology

• Publication date

  2014-02-08

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1186/1471-2180-14-30PMID 24506891PMCID 3943440
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2014cited by this paper
• The Antimicrobial Compound Xantholysin Defines a New Group of Pseudomonas Cyclic Lipopeptides

  2013cited by this paper
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  2013cited by this paper
• Structure and biosynthesis of scabichelin, a novel tris-hydroxamate siderophore produced by the plant pathogen Streptomyces scabies 87.22.

  2013cited by this paper
• EcdGHK are three tailoring iron oxygenases for amino acid building blocks of the echinocandin scaffold.

  2013cited by this paper
• Biosynthesis of Piperazic Acid via N5‐Hydroxy‐Ornithine in Kutzneria spp. 744

  2012cited by this paper
• The structures of type I polyketide synthases.

  2012cited by this paper
• Tailoring enzymes acting on carrier protein-tethered substrates in natural product biosynthesis.

  2012cited by this paper
• Mining the Cinnabaramide Biosynthetic Pathway to Generate Novel Proteasome Inhibitors

  2011cited by this paper
• A branched extender unit shared between two orthogonal polyketide pathways in an endophyte.

  2011cited by this paper
• Biosynthesis of himastatin: assembly line and characterization of three cytochrome P450 enzymes involved in the post-tailoring oxidative steps.

  2011cited by this paper
• Identification and characterization of the pyridomycin biosynthetic gene cluster of Streptomyces pyridomyceticus NRRL B-2517.

  2011cited by this paper
• Structure and biosynthesis of the marine streptomycete ansamycin ansalactam A and its distinctive branched chain polyketide extender unit.

  2011cited by this paper
• Piperazic acid-containing natural products: isolation, biological relevance and total synthesis.

  2011cited by this paper
• Cloning, sequencing and characterization of the biosynthetic gene cluster of sanglifehrin A, a potent cyclophilin inhibitor.

  2011cited by this paper
• Unusual carbon fixation gives rise to diverse polyketide extender units.

  2011cited by this paper
• Biosynthesis of thuggacins in myxobacteria: comparative cluster analysis reveals basis for natural product structural diversity.

  2010cited by this paper
• Cloning of Separate Meilingmycin Biosynthesis Gene Clusters by Use of Acyltransferase-Ketoreductase Didomain PCR Amplification

  2010cited by this paper
• Carboxylation mechanism and stereochemistry of crotonyl-CoA carboxylase/reductase, a carboxylating enoyl-thioester reductase

  2009cited by this paper
• Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-l-methionine

  2009cited by this paper
• Structural enzymology of polyketide synthases.

  2009cited by this paper
• Structure and Functional Analysis of RifR, the Type II Thioesterase from the Rifamycin Biosynthetic Pathway*

  2009cited by this paper
• Structural basis for the selectivity of the external thioesterase of the surfactin synthetase

  2008cited by this paper
• Delta-amino group hydroxylation of L-ornithine during coelichelin biosynthesis.

  2008cited by this paper
• Piperazimycins: cytotoxic hexadepsipeptides from a marine-derived bacterium of the genus Streptomyces.

  2007cited by this paper
• Cloning and characterization of the biosynthetic gene cluster for kutznerides

  2007cited by this paper
• Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: The ethylmalonyl-CoA pathway

  2007cited by this paper
• The type I fatty acid and polyketide synthases: a tale of two megasynthases.

  2007cited by this paper
• Lydiamycins A-D: cyclodepsipetides with antimycobacterial properties.

  2006cited by this paper
• Novel Cyclophilin-binding Compounds Isolated from Streptomyces sp . A 92-308110 II . Structure Elucidation , Stereochemistry and Physico-chemical Properties

  2006cited by this paper
• Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms.

  2006influential reference
• Kettapeptin: Isolation, Structure Elucidation and Activity of a New Hexadepsipeptide Antibiotic from a Terrestrial Streptomyces sp.

  2006cited by this paper
• Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs)

  2005cited by this paper
• NRPS-PKS: a knowledge-based resource for analysis of NRPS/PKS megasynthases

  2004cited by this paper
• Studies on the synthesis of (2S,3R)-3-hydroxy-3-methylproline via C2-N bond formation.

  2003cited by this paper
• Computational approach for prediction of domain organization and substrate specificity of modular polyketide synthases.

  2003cited by this paper
• Regeneration of misprimed nonribosomal peptide synthetases by type II thioesterases

  2002cited by this paper
• Isolation of a novel cyclic hexadepsipeptide pipalamycin from Streptomyces as an apoptosis-inducing agent.

  2002cited by this paper
• SAM (dependent) I AM: the S-adenosylmethionine-dependent methyltransferase fold.

  2002cited by this paper
• Biosynthesis of the lipophilic side chain in the cyclic hexadepsipeptide antibiotic IC101.

  2002cited by this paper
• Conversion of L-proline to pyrrolyl-2-carboxyl-S-PCP during undecylprodigiosin and pyoluteorin biosynthesis.

  2002cited by this paper
• Biosynthesis of polyoxypeptin A: novel amino acid 3-hydroxy-3-methylproline derived from isoleucine

  2001cited by this paper
• Predictive, structure-based model of amino acid recognition by nonribosomal peptide synthetase adenylation domains.

  2000cited by this paper
• Chloptosin, an apoptosis-inducing dimeric cyclohexapeptide produced by Streptomyces.

  2000cited by this paper
• Practical Streptomyces Genetics: A Laboratory Manual

  2000influential reference
• Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110. I. Taxonomy, fermentation, isolation and biological activity.

  1999cited by this paper
• Polyoxypeptins A and B Produced by Streptomyces: Apoptosis-Inducing Cyclic Depsipeptides Containing the Novel Amino Acid (2S,3R)-3-Hydroxy-3-methylproline.

  1999cited by this paper
• FramePlot: a new implementation of the frame analysis for predicting protein-coding regions in bacterial DNA with a high G + C content.

  1999cited by this paper
• Screening for inducers of apoptosis in apoptosis-resistant human carcinoma cells.

  1999cited by this paper
• Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110. II. Structure elucidation, stereochemistry and physico-chemical properties.

  1999cited by this paper
• The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases.

  1999cited by this paper
• Diperamycin, a new antimicrobial antibiotic produced by Streptomyces griseoaurantiacus MK393-AF2. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

  1998cited by this paper
• Polyoxypeptin isolated from Streptomyces: A bioactive cyclic depsipeptide containing the novel amino acid 3-hydroxy-3-methylproline

  1998cited by this paper
• GE3, a novel hexadepsipeptide antitumor antibiotic produced by Streptomyces sp. II. Structure determination.

  1998cited by this paper
• Multifunctional Peptide Synthetases.

  1997cited by this paper
• GE3, a novel hexadepsipeptide antitumor antibiotic, produced by Streptomyces sp. I. Taxonomy, production, isolation, physico-chemical properties, and biological activities.

  1997cited by this paper
• Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

  1997cited by this paper
• Quinoxapeptins: novel chromodepsipeptide inhibitors of HIV-1 and HIV-2 reverse transcriptase. I. The producing organism and biological activity.

  1996cited by this paper
• Aurantimycins, new depsipeptide antibiotics from Streptomyces aurantiacus IMET 43917. Production, isolation, structure elucidation, and biological activity.

  1995cited by this paper
• Anti-inflammatory effects and specificity of L-156,602: comparison of effects on concanavalin A and zymosan-induced footpad edema, and contact sensitivity response.

  1995cited by this paper
• L-156,602, a C5a antagonist with a novel cyclic hexadepsipeptide structure from Streptomyces sp. MA6348. Fermentation, isolation and structure determination.

  1991cited by this paper
• L-156,602, a C5a antagonist with a novel cyclic hexadepsipeptide structure from Streptomyces sp. MA6348. Fermentation, isolation and structure determination.

  1991cited by this paper
• A new depsipeptide antibiotic, variapeptin.

  1990cited by this paper
• A new depsipeptide antibiotic, citropeptin.

  1990cited by this paper
• A83586C, a new depsipeptide antibiotic.

  1988cited by this paper
• Sequence-specific binding of luzopeptin to DNA.

  1988cited by this paper
• Microbial products. VIII. Azinothricin, a novel hexadepsipeptide antibiotic.

  1986cited by this paper
• A Broad Host Range Mobilization System for In Vivo Genetic Engineering: Transposon Mutagenesis in Gram Negative Bacteria

  1983cited by this paper
• Antrimycin, a new peptide antibiotic.

  1981cited by this paper

• Molecular landscape analysis of azinothricin-type natural products enables the identification of kettapeptin from Streptomyces durmitorensis

  2025cites this paper
• Taxonomic and biosynthetic diversity of the marine actinomycete Salinispora across spatial scales

  2025cites this paper
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  2025cites this paper
• Evidence supporting the first secondary chromosome in actinobacteria as a hallmark of the Embleya genus

  2025cites this paper
• Selective Synthesis of Cyclopeptides with a 2-Oxindole or 3a-Hydroxy-hexahydropyrrolo-[2,3-b]indole Structure by Cytochrome P450 Enzymes.

  2025cites this paper
• Unearthing a Cryptic Biosynthetic Gene Cluster for the Piperazic Acid-Bearing Depsipeptide Diperamycin in the Ant-Dweller Streptomyces sp. CS113

  2024cites this paper
• Origin and characterization of cyclodepsipeptides: Comprehensive structural approaches with focus on mass spectrometry analysis of alkali‐cationized molecular species

  2024cites this paper
• Proline Analogues.

  2024cites this paper
• Actinomycetota bioprospecting from ore-forming environments

  2024cites this paper
• Analyzing and engineering of the biosynthetic pathway of mollemycin A for enhancing its production

  2024cites this paper
• Recent advances on cyclodepsipeptides: biologically active compounds for drug research

  2023cites this paper
• Potentiality of Actinomycetia Prevalent in Selected Forest Ecosystems in Assam, India to Combat Multi-Drug-Resistant Microbial Pathogens

  2023cites this paper
• Directed evolution of piperazic acid incorporation by a nonribosomal peptide synthetase

  2023cites this paper
• Argenteolides A and B, Glycosylated Polyketide-Peptide Hybrid Macrolides from an Actinomycete Streptomyces argenteolus.

  2022cites this paper
• Insights into the biosynthesis of icumazole unveiling a distinctive family of crotonyl-CoA carboxylase/reductase

  2022cites this paper
• Free Piperazic Acid as a Precursor to Nonribosomal Peptides.

  2022cites this paper
• Genome-Mining-Guided Discovery and Characterization of the PKS-NRPS-Hybrid Polyoxyperuin Produced by a Marine-Derived Streptomycete.

  2022cites this paper
• Nocardia noduli sp. nov., a novel actinobacterium with biotechnological potential

  2022cites this paper
• Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller Streptomyces lunaelactis MM109T

  2022cites this paper
• Structural diversity, biosynthesis, and biological functions of lipopeptides from Streptomyces.

  2022cites this paper
• Modular Chemoenzymatic Synthesis of GE81112 B1 and Related Analogues Enables Elucidation of Its Key Pharmacophores.

  2021cites this paper
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  2021cites this paper
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  2021cites this paper
• Microbial symbionts of insects as a source of new antimicrobials: a review

  2021cites this paper
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  2021cites this paper
• Chlorinated metabolites from Streptomyces sp. highlight the role of biosynthetic mosaics and superclusters in the evolution of chemical diversity.

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• Enzymatic Cβ-H Functionalization of l-Arg and l-Leu in Nonribosomally Derived Peptidyl Natural Products: A Tale of Two Oxidoreductases.

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• Micromonospora tarapacensis sp. nov., a bacterium isolated from a hypersaline lake.

  2021cites this paper
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  2020cites this paper
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  2020cites this paper
• Hybrid Peptide–Polyketide Natural Product Biosynthesis

  2020cites this paper
• Biosynthesis of depsipeptides, or Depsi: The peptides with varied generations

  2020cites this paper
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  2020cites this paper
• Concise Chemoenzymatic Total Synthesis of GE81112 B1 and Simplified Analogs Enable Elucidation of Its Key Pharmaco-phores

  2019cites this paper
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  2019cites this paper
• Efficient Chemoenzymatic Synthesis of (2S,3R)-3-Hydroxy-3-Methylproline, a Key Fragment in Polyoxypeptin A and FR225659.

  2019cites this paper
• A new phthalazinone derivative and a new isoflavonoid glycoside from lichen-associated Amycolatopsis sp.

  2019cites this paper
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  2019cites this paper
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  2019cites this paper
• Biosynthetic Pathways to Nonproteinogenic α-Amino Acids.

  2019cites this paper
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  2019cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2017cites this paper
• Heteroatom-Heteroatom Bond Formation in Natural Product Biosynthesis.

  2017cites this paper
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  2016cites this paper
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  2016cites this paper