Natural product synthesis articles within Nature Communications

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  • Article
    | Open Access

    The Ganoderma meroterpenoids are a growing class of natural products with a wide range of biological activities. Here, the authors report the enantioselective total synthesis of the Ganoderma meroterpenoid (‒)-lucidumone, featuring a copper-catalyzed enantioselective silicon-tethered intramolecular Diels-Alder cycloaddition to assemble the bicyclo[2.2.2]octane framework and a domino deprotection/Prins reaction/cycloetherification/oxidation sequence to generate concurrenly the tetrahydrofuran and the fused indanone skeleton.

    • Xian-Zhang Liao
    • , Ran Wang
    •  & Guang Li

  • Article
    | Open Access

    Polyketide macrolides are of interest for drug discovery but their inherent structural and stereochemical complexity hinders the exploration of related regions of chemical space more broadly. Here, the authors designed in silico and synthesized a library of tetrahydrofuran-containing polyketide macrolides, and screened them against a panel of biological assays, identifying biologically active library members.

    • Darryl M. Wilson
    • , Daniel J. Driedger
    •  & Robert A. Britton

  • Article
    | Open Access

    Paclitaxel is an important anticancer drug whose biosynthetic pathway reconstruction is hindered by the propensity of heterologously expressed pathway cytochromes P450, including taxadiene 5α-hydroxylase (T5αH), to form multiple products. Here, the authors tune the promoter strength for T5αH expression in Nicotiana plants to increase the levels of paclitaxel precursor taxadien-5α-ol by three-fold and reconstitute the six step early biosynthetic pathway of paclitaxel.

    • Jack Chun-Ting Liu
    • , Ricardo De La Peña
    •  & Elizabeth S. Sattely

  • Article
    | Open Access

    Nature generates the stereoisomeric yohimbine alkaloids using bioavailable monoterpene secolaganin as the building block. Here, the authors reset the stage by the development of a bioinspired coupling, in which the pentacyclic skeleton is constructed through enantioselective kinetic resolution of an achiral, easily accessible synthetic surrogate.

    • Meiyi Tang
    • , Haigen Lu
    •  & Liansuo Zu

  • Article
    | Open Access

    Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects but total synthesis procedures are often limited by the scale. Here, the authors present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol.

    • Peihao Chen
    • , Jing Wang
    •  & Xiangbing Qi

  • Article
    | Open Access

    Minor changes to complex structures can exert major influences on synthesis strategy and functional properties but synthetic difficulties can obstruct the exploration of natural product function. Here the authors explore two parallel series of picrotoxinin analogs and identify leads with selectivity between mammalian and insect ion channels.

    • Guanghu Tong
    • , Samantha Griffin
    •  & Ryan A. Shenvi

  • Article
    | Open Access

    Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.

    • Carolin Thomas
    • , Reto Erni
    •  & Michael Ristow

  • Article
    | Open Access

    Type II polyketide synthases (PKSs) normally synthesize polycyclic aromatic compounds, but the potential for the synthesis of further diverse skeletons remains under investigated. Here, the authors report the discovery of the type II PKS machinery for the biosynthesis of a five-membered nonaromatic skeleton contained in the nonproteinogenic amino acid cispentacin and the plant toxin coronatine.

    • Genki Hibi
    • , Taro Shiraishi
    •  & Tomohisa Kuzuyama

  • Article
    | Open Access

    Alkylphosphonates are used as chargeneutral replacements for naturally-occurring phosphodiester backbones in nucleotides but the choice of alkyl moieties that can be attached to phosphorus atoms in these compounds is limited to methyl groups or primary/secondary alkyls. Here, the authors demonstrate the tertiary alkylation of the phosphorus atoms of phosphites bearing two 2’-deoxynuclosides using a carbocation generated via a light-driven radical-polar crossover mechanism

    • Kenji Ota
    • , Kazunori Nagao
    •  & Hirohisa Ohmiya

  • Article
    | Open Access

    Quaternary amino acids are important building blocks and precursors of medicinal compounds. Here, the authors describe a copper-catalyzed regiodivergent electrochemical core structure-oriented crossdehydrogenative coupling reaction of Schiff bases and commercially available hydroquinones to obtain three classes of chiral quaternary amino acid derivatives

    • Tian Xie
    • , Jianming Huang
    •  & Chang Guo

  • Article
    | Open Access

    MonCI, a flavin-dependent monooxygenase, transforms all three C = C groups in the polyene substrate into epoxides during monensin A biosynthesis. Here, the authors present the structural basis for this enzyme’s regio- and stereoselective epoxidation activity.

    • Qian Wang
    • , Ning Liu
    •  & Chu-Young Kim

  • Article
    | Open Access

    Diazo compounds, such as kinamycin, are rare bioactive natural products whose assembly has been extensively studied, but the formation of the diazo group is elusive. Here, the authors report O-methyltransferase-like protein, AlpH, which is responsible for the l-glutamylhydrazine incorporation in kinamycin biosynthesis.

    • Yuchun Zhao
    • , Xiangyang Liu
    •  & Ming Jiang

  • Article
    | Open Access

    Diterpene synthase VenA catalyses the synthesis of venezuelaene A with a unique 5-5-6-7 tetracyclic skeleton from geranylgeranyl pyrophosphate. Here, the authors report crystal structures of apo- and holo-VenA, provide mechanistic insights into its substrate selectivity and promiscuity, and engineer VenA into a sesterterpene synthase.

    • Zhong Li
    • , Lilan Zhang
    •  & Shengying Li

  • Article
    | Open Access

    The fungal dioxygenase AsqJ catalyses the conversion of benzo[1,4]diazepine-2,5-diones into quinolone antibiotics, and can also catalyse the production of quinazolinones. Here, the authors perform comprehensive substrate promiscuity mapping of AsqJ revealing its large tolerance towards various substrates, giving biocatalytic access to a plethora of biomedically valuable heterocyclic frameworks.

    • Manuel Einsiedler
    •  & Tobias A. M. Gulder

  • Article
    | Open Access

    Cyclic peptides are important bioactive compounds and drugs, synthesised by enzymatic side-chain macrocyclization of ribosomal peptides, which rarely involves histidine residues. Here, the authors report the discovery and biosynthesis of tricyclic lanthipeptide noursin, constrained by a tri amino acid labionin crosslink and histidine-to-butyrine crosslink, which is important for copper binding of noursin.

    • Yuqing Li
    • , Yeying Ma
    •  & Huan Wang

  • Article
    | Open Access

    Diketopiperazine (DKP) natural products have diverse structures and biological functions. Here, the authors elucidate the biosynthetic pathway for indole alkaloid DKP nocardioazine B which includes DKP stereoisomerization by an unusual aspartate/glutamate racemase homolog and N- and C-methylation by a dual function methyltransferase.

    • Garrett Deletti
    • , Sajan D. Green
    •  & Amy L. Lane

  • Article
    | Open Access

    Eribulin is an anticancer drug and the most structurally complex non-peptidic drug made by chemical synthesis. Here, the authors report a streamlined synthesis of eribulin that creates new opportunities for drug discovery and development.

    • Anissa Kaghad
    • , Dimitrios Panagopoulos
    •  & Robert Britton

  • Article
    | Open Access

    RiPP discovery has expanded the scope of post-translational modification chemistry, but genome mining of RiPP classes remains an unsolved challenge. Here, the authors employed bioinformatics and synthetic biology approaches to discover and characterize an unknown class of RiPPs, defined by an unusual amino-modified C-terminus.

    • Hengqian Ren
    • , Shravan R. Dommaraju
    •  & Huimin Zhao

  • Article
    | Open Access

    Biosynthesis of complex polyketides by polyketide synthases often relies on trans-acting enzymes to modify the intermediates. Here, the authors elucidate how β-methylation enzymes identify their substrates. The recognition is imperfect, resulting in a doubly β-methylated virginiamycin derivative.

    • Sabrina Collin
    • , Russell J. Cox
    •  & Arnaud Gruez

  • Article
    | Open Access

    Intermodular recognition in polyketide synthase (PKS) is a key prerequisite for catalysis and assembly-line engineering. Here, the authors present a specific domain interaction between modules and an evolution-oriented strategy for PKS engineering derived from the enoylreduction module of azalomycin F.

    • Guifa Zhai
    • , Yan Zhu
    •  & Yuhui Sun

  • Article
    | Open Access

    A diterpenoid biosynthetic gene cluster (BGC) has been identified in a few species in the Lamiaceae (mint) family, but its origin and evolution remain unclear. Here, the authors report assembly of genomes of three species within the family and reveal the dynamic evolutionary trajectory of the BGC.

    • Abigail E. Bryson
    • , Emily R. Lanier
    •  & Björn Hamberger

  • Article
    | Open Access

    MraY is a membrane enzyme required for bacterial cell wall synthesis. Here, the authors modify sphaerimicins as antibacterials targeting it via structure-based design and synthesis through two key reactions, showing a platform for further development of MraY inhibitors as antibacterials.

    • Takeshi Nakaya
    • , Miyuki Yabe
    •  & Satoshi Ichikawa

  • Article
    | Open Access

    The biosynthetic pathway of type II ganoderic acids (GAs) in Ganoderma lucidum, a traditional medicinal mushroom, is unknown. Here, the authors assemble the genome of type II GAs accumulating accession, identify CYPs involving in type II GAs biosynthesis, and achieve their production in engineered baker’s yeast.

    • Wei Yuan
    • , Chenjian Jiang
    •  & Han Xiao

  • Article
    | Open Access

    Syntheses of quinine have fascinated organic chemists for over a hundred years. Here, the authors developed an organocatalyst-mediated pot-economical enantioselective total synthesis using five reaction vessels.

    • Takahiro Terunuma
    •  & Yujiro Hayashi

  • Article
    | Open Access

    The occurrence of isomers of the bicyclic octapeptide α-amanitin, which presents a macrolactam with a tryptathionine cross-link forming a handle, has been reported under the term of atropoisomers. Here, the authors synthesize its analogs and analyse their isomers, proposing and describing for them the term ansamer.

    • Guiyang Yao
    • , Simone Kosol
    •  & Roderich D. Süssmuth

  • Article
    | Open Access

    How triptonide is made in the medicinal plant Tripterygium wilfordii is largely unknown. Here, the authors report the identification and characterization of a suite of cytochrome P450s and show their function in catalyzing the formation of triptonide from miltriadiene in tobacco and baker’s yeast.

    • Nikolaj Lervad Hansen
    • , Louise Kjaerulff
    •  & Johan Andersen-Ranberg

  • Article
    | Open Access

    Lignans, in spite of their structural diversity, are all biosynthetically derived from coniferyl alcohol. Here, the authors describe a divergent and stereoselective chemical synthesis of three types of lignans from biomass-derived monolignols, exploiting the different reaction manifolds of highly reactive radical cation intermediate.

    • Jia-Chen Xiang
    • , Cédric Fung
    •  & Jieping Zhu

  • Article
    | Open Access

    Effective methods for accessing polycarbocycles are scarcely reported and generally involve complex, multistep transformations, thus restricting practical utility. Here, the authors construct tri-to-penta- cyclic frameworks containing at least two quaternary carbon centers via a tandem Nazarov-like cyclization / double cycloexpansion of simple 1,3-dicyclobutylidene ketone substrates.

    • Yun-Peng Wang
    • , Kun Fang
    •  & Tian Ke

  • Article
    | Open Access

    The ergot alkaloids are a class of natural products known for their pharmacologically privileged molecular structure that are used in the treatment of neurological ailments. Here the authors report on the production of the ergot (fungus)-derived therapeutic precursor, D-lysergic acid (DLA), in baker’s yeast.

    • Garrett Wong
    • , Li Rong Lim
    •  & Wen Shan Yew

  • Article
    | Open Access

    Nonribosomal peptide synthetases work with additional enzymes to synthesise secondary metabolites and therapeutics. Here, the authors explore bacillamide D synthesis and show the oxidase action is done while the intermediate is attached to the synthetase and replicate this with an oxidase bound synthetase for bioengineering applications.

    • Camille Marie Fortinez
    • , Kristjan Bloudoff
    •  & T. Martin Schmeing

  • Article
    | Open Access

    Although computational simulation-based natural product syntheses are in their initial stages of development, this concept can potentially become an indispensable resource in the field of organic synthesis. Here the authors report asymmetric total syntheses of several resveratrol dimers based on a comprehensive computational simulation of their biosynthetic pathways.

    • Masaya Nakajima
    • , Yusuke Adachi
    •  & Tetsuhiro Nemoto

  • Article
    | Open Access

    Mannosyl-queuosine (manQ) is a non-canonical RNA nucleoside present in the anticodon loop of certain tRNAs. Here, the authors use a combination of total synthesis and mass spectrometry to contradict the literature-reported structure and show that manQ features an alpha-allyl connectivity of its mannose moiety.

    • Markus Hillmeier
    • , Mirko Wagner
    •  & Thomas Carell

  • Article
    | Open Access

    Peptide secondary metabolites have a diverse range of functions. Here the authors present a method to design and screen a large library of modified peptides in E. coli against a target of interest.

    • Andrew M. King
    • , Daniel A. Anderson
    •  & Christopher A. Voigt

  • Article
    | Open Access

    Enzymes installing an intact hydropersulfide (-SSH) group into natural products have so far not been identified. Here, the authors report the characterization of an S-adenosyl methionine-dependent hydropersulfide methyltransferase (GnmP) for guangnanmycin biosynthesis, and identification of three SH domains within several NRPS-PKS assembly lines as thiocysteine lyases.

    • Song Meng
    • , Andrew D. Steele
    •  & Ben Shen

  • Article
    | Open Access

    Prenylated indole alkaloids contain spirooxindole rings with a 3R or 3S carbon stereocenter, which determines their bioactivities, but the biocatalytic mechanism controlling the 3R- or 3S-spirooxindole formation was unclear. Here, the authors report the biochemical and structural characterization of the oxygenase/semipinacolase CtdE that catalyses the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A.

    • Zhiwen Liu
    • , Fanglong Zhao
    •  & Xue Gao

  • Article
    | Open Access

    Catalytic enantioselective halocyclization of alkenes is an important bond forming tool and a key step in natural product biosynthesis, but so far no examples of the enzymatic counterpart of this reaction on simple achiral olefins have been reported. Here, the authors describe examples of engineered flavin-dependent halogenases that catalyze halolactonization of olefins with high enantioselectivity and near-native catalytic activity.

    • Dibyendu Mondal
    • , Brian F. Fisher
    •  & Jared C. Lewis

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