Biosynthesis articles within Nature Communications

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  • Article
    | Open Access

    Diels-Alderases (DAs), enzymes catalyzing [4 + 2] cycloaddition reactions, are of high interest, but insights into their evolution are lacking. Here, the authors investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites, suggesting they evolved from an ancestor functioning as a flavin adenine dinucleotide-dependent oxidocyclase.

    • Qi Ding
    • , Nianxin Guo
    •  & Xiaoguang Lei

  • 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

    Here the authors use NMR, SAXS and MD simulations to characterise the structure of proteusin peptides, which are atypically long RiPP substrates. They show a small, unstructured region in the proteusin leader is sufficient for its interaction with a halogenase that brominates the terminal tryptophan residue.

    • Nguyet A. Nguyen
    • , F. N. U. Vidya
    •  & Vinayak Agarwal

  • Article
    | Open Access

    Hemiacetal compounds are valuable building blocks in synthetic chemistry, but difficult to obtain by enzymatic synthesis. Here, the authors use reaction engineering of an immobilized unspecific peroxygenase from Agrocybe aegerita for selective C-H bond oxyfunctionalisation of environmentally significant cyclic ethers to chiral cyclic hemiacetals.

    • Xiaofeng Han
    • , Fuqiang Chen
    •  & Wuyuan Zhang

  • Article
    | Open Access

    Much is still unknown of the evolution of animal metabolic enzymes. This study describes a new enzyme family bridging the production of polyketides and membrane lipids. This expands the known biochemical repertoire of animals for making ecologically and biomedically important natural products.

    • Zhenjian Lin
    • , Feng Li
    •  & Eric W. Schmidt

  • Article
    | Open Access

    Given the importance of the chiral α-benzyl cyclic carbonyl motif in pharmaceutically active compounds, various transformations have been developed to access chiral compounds containing this motif but they often include harsh reaction conditions. Here the authors develop a one-pot concurrent chemoenzymatic cascade reaction and demonstrate the synthesis of α-benzylcyclic ketones with high enantioselectivity.

    • Yunting Liu
    • , Teng Ma
    •  & Yanjun Jiang

  • 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

    Glycopeptide antibiotics (GPAs) are microbial natural products synthesized by multiple enzymes, including a nonribosomal peptide synthetase for assembly of the peptide core. Here, the authors use computational techniques to infer a gene set for biosynthesis of an ancestral GPA, produce the peptide in a microbial host, and provide insights into the evolution of key enzymatic domains.

    • Mathias H. Hansen
    • , Martina Adamek
    •  & Nadine Ziemert

  • Article
    | Open Access

    Apiosides are plant bioactive natural products containing apiose, but the details of the key apiosylation reaction in their biosynthesis are missing. Here, the authors identify the apiosyltransferase GuApiGT that could efficiently catalyze 2″-O-apiosylation of flavonoid glycosides, solve its crystal structure and obtain mutants with altered sugar selectivity.

    • Hao-Tian Wang
    • , Zi-Long Wang
    •  & Min Ye

  • Article
    | Open Access

    Nonribosomal peptides have diverse bioactivities and can possess unusual moieties at their C-terminus, such as polyamines. In this study, the authors identify a class of dodecapeptides glidonins that feature diverse N-terminal modifications and a uniform putrescine moiety at the C-terminus, elucidate their biosynthesis, and introduce the putrescine into the C-terminus of other nonribosomal peptides.

    • Hanna Chen
    • , Lin Zhong
    •  & Xiaoying Bian

  • 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

    Polymerizations in living systems can effectively regulate cell functions and behaviors, but their uses have been hindered by the existence of complicated intracorporal interferences, the needs of high concentration of monomers and extra stimulates. Here, the authors address these issues by developing a nanocompartment-confined strategy to achieve broad-spectrum polymerizations in living systems.

    • Yun Chen
    • , Mengxuan Zuo
    •  & Yanli Zhao

  • 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

    Developing a biocompatible polymerization system applicable for the synthesis of intrinsically non-natural polymers is a key step towards intracellular engineering of living organism. Here the authors report tyrosine residues-mediated radical photopolymerizations for intracellular synthesis of non-natural macromolecules

    • Mei Zhu
    • , Shengliang Wang
    •  & Xin Huang

  • Article
    | Open Access

    Natural proteins exhibit rich structural diversity based on the folds of an invariably linear chain. Here the authors design a single-domain GFP catenane as the counterpart of conventional linear GFP with enhanced thermal resilience and to provide a robust scaffold for making fusion protein catenanes.

    • Zhiyu Qu
    • , Jing Fang
    •  & Wen-Bin Zhang

  • 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

    Prussian blue has been used as a photothermal agent for cancer therapy. Here the authors describe the production of Prussian blue nanoparticles from S. oneidensis MR-1 bacteria and show that a Prussian blue-based mitochondria-targeting nanoplatform potentiates response to immune checkpoint blockade.

    • Dongdong Wang
    • , Jiawei Liu
    •  & Yanli Zhao

  • Article
    | Open Access

    Production of highly modified sterols, such as cholesterol, is essential to eukaryotic physiology but has not been yet reported for bacteria. Here, Lee et al. show that a marine myxobacterium produces cholesterol, and provide evidence for further downstream modifications in this and other bacterial species.

    • Alysha K. Lee
    • , Jeremy H. Wei
    •  & Paula V. Welander

  • Article
    | Open Access

    Multi-enzymatic cascades benefit from precise nanometric organization but achieving this using available scaffolds is challenging. Here the authors present strategy for organizing multienzymatic systems using a protein scaffold based on TRAP domains, and demonstrate improved catalytic output.

    • Alba Ledesma-Fernandez
    • , Susana Velasco-Lozano
    •  & Aitziber L. Cortajarena

  • 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

    ATP citrate lyase (ACLY) is the main nucleocytosolic source of acetyl-CoA and the enzyme contains citrate synthase homology (CSH) and acyl-CoA synthetase homology (ASH) domains. Here, the authors report data on an ACLY mutant that supports an allosteric role for the CSH domain in ACLY catalysis.

    • Xuepeng Wei
    • , Kollin Schultz
    •  & Ronen Marmorstein

  • Review Article
    | Open Access

    Naturally evolved genomes tend to be unnecessarily large and redundant, and are not optimised for biotechnological or research applications. In this review, the authors explore genome minimization and re-functionalisation approaches, and discuss their potential for industrial applications.

    • Xin Xu
    • , Felix Meier
    •  & Thomas C. Williams

  • 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

    Biological nitrogen fixation is achieved by nitrogenase, but the mechanism remains enigmatic. Here, the authors report high resolution single particle cryoEM structures of homocitrate-compromised MoFe-proteins and unveil a new binding partner.

    • Rebeccah A. Warmack
    • , Ailiena O. Maggiolo
    •  & Douglas C. Rees

  • Article
    | Open Access

    Natural antimicrobial metabolites produced by soil microorganisms can be used as green pesticides. Here, the authors isolated a Pseudomonas mosselii strain 923 from rice rhizosphere soils and identify the compound pyrazolotriazine pseudoiodinine inhibits the growth of plant bacterial and fungal pathogens.

    • Ruihuan Yang
    • , Qing Shi
    •  & Gongyou Chen

  • 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

    Treatment of hypertension entails use of angiotensin-converting enzyme inhibitors. Here, the authors show a series of karnamicins with significant inhibitory activity and identify two unusual flavoprotein hydroxylases involved in the assembly of the fully-substituted hydroxypyridine core of karnamicins.

    • Zhiyin Yu
    • , Jian-Ping Huang
    •  & Sheng-Xiong Huang

  • Article
    | Open Access

    The identification of synthetic routes combining enzymatic and non-enzymatic reactions has been challenging and requiring expert knowledge. Here, the authors describe a computational retrosynthetic approach relying on neural network models for planning synthetic routes using both strategies.

    • Itai Levin
    • , Mengjie Liu
    •  & Connor W. Coley

  • Article
    | Open Access

    4(3H)-quinazolinone is the core scaffold in more than 200 natural alkaloids and numerous drugs. Here, the authors show an alternative assembly machinery for 4(3H)-quinazolinone mainly includes a two-module NRPS catalysing tripeptide formation, unusual N-3 original sources and an α-KGD catalysing the C-N bond oxidative cleavage of a tripeptide to form a dipeptide.

    • Xi-Wei Chen
    • , Li Rao
    •  & Yi Zou

  • Article
    | Open Access

    Ribosomes have evolved to polymerize L-α-amino acids into proteins comprising a peptide backbone. Here, a pyridazinone backbone is formed using ribosomes in vitro, producing a variety of sequence-defined alternating block-copolymers.

    • Joongoo Lee
    • , Jaime N. Coronado
    •  & Michael C. Jewett

  • Article
    | Open Access

    Establishing methods to access the chemical space that lies beyond canonical terpenoid biosynthesis will increase the applications of isoprenoids. Here, the authors reconstruct the modular structure of terpene biosynthesis on 16-carbon backbones by engineered yeast and synthesize 28 different unique terpenes.

    • Codruta Ignea
    • , Morten H. Raadam
    •  & Sotirios C. Kampranis

  • Article
    | Open Access

    The chemical diversity of peptides from ribosomal origin is a growing field of research. Here, the authors report the discovery, genomic and biosynthetic investigations of kintamdin, a ribosomally synthesized and post-translationally modified peptides featuring a beta-enamino acid and a bis-thioether macrocyclic motif.

    • Shan Wang
    • , Sixing Lin
    •  & Hai Deng

  • Article
    | Open Access

    Epoxide ring opening reactions are important in both biological processes and synthetic applications. Here, the authors show that flavin cofactors can catalyze reductive and oxidative epoxide ring opening reactions and propose the underlying mechanisms.

    • Bidhan Chandra De
    • , Wenjun Zhang
    •  & Changsheng Zhang

  • Article
    | Open Access

    The genomes of filamentous fungi, such as Aspergillus, include many biosynthetic gene clusters of unknown function. Here, the authors show that copper starvation induces expression of an enzyme that generates a valine-derived isocyanide participating in two different pathways, for biosynthesis of acylated sugar alcohols and modified ergot alkaloids.

    • Tae Hyung Won
    • , Jin Woo Bok
    •  & Frank C. Schroeder

  • Article
    | Open Access

    Macrocyclization is an important process in bioactive natural product synthesis. Here, the authors report on the study of a macrocyclic ring constructing enzyme in the biosynthesis of alchivemycin A and using gene deletion, biochemical assays and isotope labelling show the enzyme catalyses tandem dehydration and Michael-type addition.

    • Hong Jie Zhu
    • , Bo Zhang
    •  & Hui Ming Ge

  • Article
    | Open Access

    Haloacid dehalogenase-like phosphatases are widespread across all domains of life and play a crucial role in the regulation of levels of sugar phosphate metabolites in cells. The authors report on the structure-guided engineering of phosphatases for dedicated substrate specificity for the conversion of sucrose and starch into fructose and mannose.

    • Chaoyu Tian
    • , Jiangang Yang
    •  & Yanhe Ma

  • Article
    | Open Access

    Reprogramming biosynthetic assembly-lines is a topic of interest for antibiotics. Here, the authors explore the evolutionary biosynthesis of anti-tubercular wollamides, show gene duplication and neo-functionalisation results in bifurcation allowing for testing of new structures with the ability to recover old structures by gene loss.

    • Thomas J. Booth
    • , Kenan A. J. Bozhüyük
    •  & Barrie Wilkinson

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