Natural products articles within Nature Chemistry

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  • Article
    | Open Access

    Natural products discovery remains an ongoing challenge. Now, halide depletion offers a complementary approach to discover natural products whose biosynthesis requires halides, including products of cryptic halogenation. Halide depletion reveals that nostochlorosides, the products of an orphan biosynthetic gene cluster in Nostoc punctiforme, are polymerized by a halide-displacing etherifying enzyme.

    • Nathaniel R. Glasser
    • , Dongtao Cui
    •  & Emily P. Balskus

  • Article |

    Two glycosylated enzymes, EupfF and PycR1, have now been characterized and shown to independently catalyse the tandem intermolecular [4 + 2] cycloaddition in the biosynthesis of bistropolone-sesquiterpenes. Through analysis of enzyme–substrate co-crystal structures, together with computational and mutational studies, the origins of their catalytic activity and stereoselectivity were elucidated.

    • Jiawang Liu
    • , Jiayan Lu
    •  & Youcai Hu

  • Article |

    Enteropeptins are peptide natural products produced by the gut microbe Enterococcus cecorum. Now, the structure, biosynthesis and function of enteropeptins have been determined. After ribosomal biosynthesis, enteropeptins are post-translationally modified in three reactions carried out by a radical S-adenosylmethionine enzyme, an Mn2+-dependent arginase, and an Fe–S-containing methyltransferase, respectively, to form the N-methylornithine-containing peptide natural products.

    • Kenzie A. Clark
    • , Brett C. Covington
    •  & Mohammad R. Seyedsayamdost

  • Article |

    The total synthesis and complete stereochemical assignment of the cyclic peptide natural product SR-A3—which has potential as a cancer therapeutic—has now been reported. Single-molecule biophysical and cellular experiments reveal a crucial, stereospecific role for a side-chain hydroxyl in SR-A3, which confers enhanced target residence time and efficacy in a mouse tumour model.

    • Hao-Yuan Wang
    • , Haojun Yang
    •  & Jack Taunton

  • Article
    | Open Access

    Entomopathogenic nematodes carrying Xenorhabdus and Photorhabdus bacteria prey on insect larvae in the soil. Now, a comprehensive analysis of the bacterial genome has revealed ubiquitous and unique families of biosynthetic gene clusters. Evaluation of the bioactivity of the natural products expressed by the most prevalent cluster families explains the functional basis of bacterial natural products involved in bacteria–nematode–insect interactions.

    • Yi-Ming Shi
    • , Merle Hirschmann
    •  & Helge B. Bode

  • Thesis |

    Michelle Francl reminds #ChemistsWhoCook to look at the chemistry behind the cooking.

    • Michelle Francl

  • Article |

    O-methyl nitronate is a rare functional group in natural products. Now, the biosynthetic pathway to O-methyl nitronate, which involves O-methylation of a peptidyl carrier protein (PCP)-tethered nitronate, has been revealed. In some bacteria, the same PCP-tethered nitronate is shown to be oxidized by nitronate monooxygenases to provide nitrite and a PCP-tethered glyoxylate.

    • Hai-Yan He
    •  & Katherine S. Ryan

  • Article |

    A series of enzymes that catalyse the formation of strained peptide cyclophanes through a stereospecific C(sp2)–C(sp3) bond have been identified. Crosslinking occurs on three-residue motifs that include tryptophan or phenylalanine to form indole- or phenyl-bridged cyclophanes. These enzymes are widely distributed in nature and represent promising tools for peptide biotechnology.

    • Thi Quynh Ngoc Nguyen
    • , Yi Wei Tooh
    •  & Brandon I. Morinaka

  • Article |

    The biosynthesis of goadvionins—hybrid lipopeptide antibiotics—is not fully understood. An unusual acyltransferase, GdvG, has now been identified and shown to catalyse a condensation reaction between an acyl-carrier-protein-tethered very-long-chain fatty acid and an eight-residue ribosomally synthesized and post-translationally modified peptide. The position of functional groups in the very-long acyl chain have been determined by tandem mass spectrometry.

    • Ryosuke Kozakai
    • , Takuto Ono
    •  & Hiroyasu Onaka

  • Article |

    The invariable core of a type II polyketide synthase has been characterized using X-ray crystallography, simulations, mutagenesis experiments and functional assays. The characterization of the ternary acyl carrier protein complexes provides a mechanistic understanding of the reactivity and could inform future engineering of this complex biosynthetic machinery.

    • Alois Bräuer
    • , Qiuqin Zhou
    •  & Michael Groll

  • Article |

    A naturally occurring stand-alone and intermolecular Diels–Alderase, MaDA, has been identified from Morus alba cell cultures. MaDA is a FAD-dependent enzyme, which catalyses the intermolecular [4+2] cycloaddition via a concerted but asynchronous pericyclic pathway between morachalcone A and a diene generated from moracin C. Characterization revealed that MaDA possesses good substrate promiscuity towards both dienes and dienophiles.

    • Lei Gao
    • , Cong Su
    •  & Xiaoguang Lei

  • Perspective |

    The structures of biologically active natural products have long served as inspiration in drug discovery. This Perspective outlines design principles and connectivity patterns for the de novo combination of natural product-derived fragments. The resulting ‘pseudo-natural products’ retain biological relevance yet exhibit structures and bioactivities not found in the natural products and their derivatives.

    • George Karageorgis
    • , Daniel J. Foley
    •  & Herbert Waldmann

  • News & Views |

    The biosynthetic pathway that produces the structurally uncharacterized gut bacterial genotoxin colibactin can produce unstable, macrocyclic products; however, the extent to which these structures contribute to colibactin’s biological activities is not yet fully understood. Now, two recent studies have provided new insights and reached distinct conclusions regarding their potential mechanisms of action and relevance for genotoxicity.

    • Erik S. Carlson
    •  & Emily P. Balskus

  • Article |

    Enacyloxin IIa is an antibiotic, assembled by a modular polyketide synthase, with promising activity against the Gram-negative bacterium Acinetobacter baumannii. Now, it has been shown that the enacyloxin IIa polyketide chain is released via transfer to a separately encoded carrier protein by a non-elongating ketosynthase domain, followed by condensation with 3,4-dihydroxycyclohexane carboxylic acid by a non-ribosomal peptide synthetase condensation domain.

    • Joleen Masschelein
    • , Paulina K. Sydor
    •  & Gregory L. Challis

  • Article |

    The antibiotic enacyloxin IIa is assembled by a modular polyketide synthase, and released from it by condensation of the enacyloxin acyl chain with 3,4-dihydroxycyclohexane carboxylic acid. A multipronged approach shows the structural basis for recognition between the peptidyl carrier protein domain that bears the acyl chain and the non-ribosomal peptide synthetase condensation domain that ligates it with the carboxylic acid.

    • Simone Kosol
    • , Angelo Gallo
    •  & Józef R. Lewandowski

  • Article |

    Precolibactin 886 is a complex microbiome-derived metabolite implicated in colorectal cancer and produced by the clb gene cluster. A chemical synthesis and analysis of precolibactin 886 is reported which shows that its biosynthetic precursor degrades to other known clb metabolites. The data also provide insights into the structures and reactivity of advanced clb products.

    • Alan R. Healy
    • , Kevin M. Wernke
    •  & Seth B. Herzon

  • Article |

    Colibactin is produced by human enterobacteria and assumed to be a gut bacterial genotoxin. Now, colibactin-645 has been identified as a macrocyclic colibactin metabolite that contains a C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety and induces DNA double-strand breaks in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism.

    • Zhong-Rui Li
    • , Jie Li
    •  & Pei-Yuan Qian

  • Article |

    Non-ribosomal peptide synthetases have now been modified and de novo non-ribosomal peptide synthetases constructed using new assembly points within condensation domains. This approach enabled the production of new-to-nature peptides, including some carrying synthetic amino acids, as well as the generation of peptide libraries.

    • Kenan A. J. Bozhüyük
    • , Annabell Linck
    •  & Helge B. Bode

  • News & Views |

    Natural products often provide lead scaffolds for the development of therapeutics, but complexity of their synthesis can limit the discovery of improved analogues. Pharmacophore-directed retrosynthesis aims to accelerate the building of a structure–activity relationship profile of a natural product, aiming to identifying a simplified lead.

    • Jason R. Hudlicky
    •  & Gary A. Sulikowski

  • Article |

    Pharmacophore-directed retrosynthesis targets a potential pharmacophore from early on in a natural product synthesis and incremental increases in the complexity of this minimal structure enable a SAR profile to develop over the course of the campaign. The method is applied to gracilin A, finding simplified derivatives displaying potent immunosuppressive effects or selective neuroprotective effects in cell-based assays.

    • Mikail E. Abbasov
    • , Rebeca Alvariño
    •  & Daniel Romo

  • Thesis |

    Bruce Gibb focuses on fatty acids and wonders whether we’ll all be eating cyanobacteria before too long.

    • Bruce C. Gibb

  • Article |

    New natural-product-inspired molecules are often limited by their only partial coverage of biologically relevant chemical space. Combining fragments of natural products has now been shown to yield pseudo natural products, which — while still being inspired by natural products — populate previously unexplored areas of chemical space and have novel biological activities.

    • George Karageorgis
    • , Elena S. Reckzeh
    •  & Herbert Waldmann

  • Thesis |

    Bruce C. Gibb discusses the biochemistry behind the sensory experiences associated with eating chillies and the lesser-known tingle-inducing ‘sanshools’.

    • Bruce C. Gibb

  • Article |

    Peptides derived from non-ribosomal peptide synthetases (NRPS) are an important class of pharmaceutically relevant drugs. However, no general rules for the modification of NRPS or the generation of artificial NRPS are known. Now, a new strategy for the modification of NRPS has been developed that uses defined exchange units that are fused at specific positions connecting the condensation and adenylation domains.

    • Kenan A. J. Bozhüyük
    • , Florian Fleischhacker
    •  & Helge B. Bode

  • Article |

    The anthraquinone and enediyne halves of the antitumor antibiotic dynemicin A were previously thought to be assembled by two separate polyketide synthases (PKS). Now, a single polyketide synthase has been proposed to be responsible for their production, and a working model for their biosynthesis from a common octaketide intermediate has been suggested.

    • Douglas R. Cohen
    •  & Craig A. Townsend

  • Article |

    Nature has evolved a variety of different mechanisms to generate chemical diversity; however, the reactions responsible for generating such diverse chemical libraries are often not clear. Now, the mechanisms employed by entomopathogenic bacteria for the biosynthesis of a large family of bioactive peptides have been identified. These include substrate promiscuity, enzyme cross-talk and enzyme stoichiometry.

    • Xiaofeng Cai
    • , Sarah Nowak
    •  & Helge. B. Bode

  • Article |

    Anti-proliferative compounds that display enhanced toxicity in a low-oxygen (hypoxic) environment may be used to eradicate aggressive and therapy-resistant cancer cells. Now, a promising lead structure has been identified in the BE-43547-class of depsipeptide natural products.

    • Nikolaj L. Villadsen
    • , Kristian M. Jacobsen
    •  & Thomas B. Poulsen

  • Review Article |

    Natural products are a prime source of innovative molecular fragments and privileged scaffolds for drug discovery and chemical biology. Advanced machine-learning approaches can help analyse and design synthetically accessible, natural-product-derived, compound libraries and provide insight into the high selectivity of such compounds.

    • Tiago Rodrigues
    • , Daniel Reker
    •  & Gisbert Schneider

  • Article |

    Analysis of the structure of the highly complex yet racemic secondary metabolite epicolactone suggests that it may arise biosynthetically from a cascade similar to that which produces purpurogallin. This led to a synthesis of epicolactone in only eight steps using an intricate reaction cascade.

    • Pascal Ellerbrock
    • , Nicolas Armanino
    •  & Dirk Trauner

  • Article |

    The complexity and diversity of natural product structures make them an ideal starting point for the creation of chemical libraries. Now it is shown that a semi-synthetic process can combine heterologous expression of a multipotent biosynthetic intermediate with multiple non-enzymatic steps to produce libraries of pseudo-natural products.

    • Teigo Asai
    • , Kento Tsukada
    •  & Yoshiteru Oshima

  • Article |

    Marmycin A is an anthraquinone natural product with antiproliferative properties. Now the chemical synthesis of marmycin A—through a Diels–Alder cycloaddition, an Ullmann aromatic amination and a Friedel–Crafts cyclization—has enabled a study of its biological activity. Fluorescence microscopy reveals that marmycin A accumulates in lysosomes and promotes cell death independently of genome targeting.

    • Tatiana Cañeque
    • , Filipe Gomes
    •  & Raphaël Rodriguez

  • Article |

    A chemical synthesis of (–)-jiadifenolide, a small molecule neurotrophin, has been achieved in eight steps. The route relies on a stereoselective coupling of two simple butenolides to build the entire skeleton in a single step and produce one gram of the target for broad distribution to the biomedical community.

    • Hai-Hua Lu
    • , Michael D. Martinez
    •  & Ryan A. Shenvi

  • News & Views |

    Symbiotic bacteria synthesize many specialized small molecules; however, establishing the role these chemicals play in human health and disease has been difficult. Now, the chemical structure and mechanism of the Escherichia coli product colibactin provides insight into the link between this secondary metabolite and colorectal cancer.

    • Eric W. Schmidt

  • Article |

    Structural elucidation of a peptide natural product has revealed an unprecedented post-translational modification involving formation of a carbon–carbon bond between the side-chains of lysine and tryptophan. This motif defines a new family of cyclic peptides. Biochemical studies reveal that this C-C bond is generated by a radical SAM enzyme, and delineate its catalytic mechanism.

    • Kelsey R. Schramma
    • , Leah B. Bushin
    •  & Mohammad R. Seyedsayamdost

  • Article |

    Genotoxic small molecules from the bacterial colibactin pathway — a gut-associated non-ribosomal peptide synthetase–polyketide synthase hybrid gene cluster linked to colorectal cancer — have remained elusive due to their instability. Now, one of these, the colibactin warhead, an unprecedented substituted spirobicyclic structure, has been characterized and shown to crosslink duplex DNA in vitro.

    • Maria I. Vizcaino
    •  & Jason M. Crawford

  • Article |

    A minimal cell — one that has all the minimum requirements for life — is still a complex entity comprising informational, compartment-forming and metabolic subsystems. Here it is shown that, contrary to previous assumptions, a common prebiotically plausible chemistry can give rise to building blocks for all the subsystems.

    • Bhavesh H. Patel
    • , Claudia Percivalle
    •  & John D. Sutherland

  • Article |

    Natural products provide a rich source of leads for drug discovery. Now, a computational method is available that can be used to identify the macromolecular targets of these compounds. Much like medicinal chemists' reasoning, the software infers target information by comparing the substructures with those of drugs and other natural products with known targets.

    • Daniel Reker
    • , Anna M. Perna
    •  & Gisbert Schneider

  • Article |

    Adjuvants are used to increase the immune response to molecular vaccines. A minimal synthetic variant of the saponin natural product QS-21 has been developed as a potent, non-toxic adjuvant, enabling dissection of structural requirements in the triterpene domain and in vivo biodistribution studies to probe mechanisms of action.

    • Alberto Fernández-Tejada
    • , Eric K. Chea
    •  & David Y. Gin

  • News & Views |

    The lomaiviticins are exceedingly potent antibiotic agents, but the mechanism responsible for this activity has so far been unclear. Now, efficient generation of double-strand breaks in DNA by lomaiviticin A has been linked to the remarkable cytotoxicity of these diazobenzofluorene-containg natural products.

    • Kent S. Gates

  • Article |

    (−)-Lomaiviticin A inhibits the growth of cancer cells at nanomolar to picomolar concentrations; however, the basis for this potent cytotoxicity is not known. This natural product has now been shown to induce production of DNA double-strand breaks at nanomolar concentrations. Evidence demonstrates that strand cleavage proceeds via reactive carbon-centred free radical intermediates.

    • Laureen C. Colis
    • , Christina M. Woo
    •  & Seth B. Herzon

  • News & Views |

    High selectivity is essential in the enzymatic biosynthesis of complex natural products. Now, the discovery of multiple sequential bifurcations on the reaction path towards the formation of a diterpenoid shows how dynamics affect selectivity, and suggests how enzymes may steer reactions towards a specific product.

    • Charles E. Hornsby
    •  & Robert S. Paton

  • Article |

    A terpene-forming carbocation reaction is described for which a single transition-state structure leads to the formation of many isomeric products via pathways that feature multiple sequential bifurcations. Dynamic effects are shown to contribute to the selectivity of the reaction, with consequences for how enzymes control the biosynthesis of complex natural products.

    • Young Joo Hong
    •  & Dean J. Tantillo

  • News & Views |

    Fluorine imparts many drugs with beneficial properties, however, the synthesis of fluorinated complex natural products is challenging. Biosynthetic strategies and recent experimental precedents have paved the way for bioengineered fluorinated polyketides.

    • Peter A. Jordan
    •  & Bradley S. Moore

  • Article |

    Emulating the biogenesis of natural products, a synthetic strategy is described in which an achiral multipotent intermediate reacts through three distinct [4 + 2] cyclizations and two types of redox-mediated annulation. This results in divergent access to natural product-like scaffolds in 6–9 steps. The efficiency of this approach is highlighted in the total syntheses of three natural products.

    • Haruki Mizoguchi
    • , Hideaki Oikawa
    •  & Hiroki Oguri

  • Article |

    The trioxacarcins are polyoxygenated natural products that potently inhibit the growth of cultured human cancer cells. Here, the syntheses of trioxacarcin A, DC-45-A1 and structural analogues are described — the majority of which were found to be active in antiproliferative assays. A convergent, component-based route comprising sequential stereoselective glycosylation reactions allows assembly of these analogues in 11 steps or fewer.

    • Thomas Magauer
    • , Daniel J. Smaltz
    •  & Andrew G. Myers

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