Natural products

  • Article
    | Open Access

    Microbial DNA glycosylases associated with the biosynthesis of DNA-damaging antibiotics have evolved self-resistance for their cognate natural products. Here, the authors provide evidence that cellular self-resistance is enabled by reduced affinity of the glycosylases for the excision products of the corresponding DNA lesions.

    • Elwood A. Mullins
    • , Jonathan Dorival
    •  & Brandt F. Eichman
  • 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

    Borosins are ribosomally encoded and posttranslationally modified peptide (RiPP) natural products featuring amide-backbone α-N-methylation. Here, the authors report the discovery and characterization of type IV borosin ‘split’ pathways encoding distinct, separate α-N-methyltransferases and precursor peptide substrates.

    • Fredarla S. Miller
    • , Kathryn K. Crone
    •  & Michael F. Freeman
  • Article
    | Open Access

    The only known animal polyketide-nonribosomal peptides, the nemamides, are biosynthesized by two megasynthetases in the canal-associated neurons (CANs) of C. elegans. Here, the authors map the biosynthetic roles of individual megasynthetase domains and identify additional enzymes in the CANs required for nemamide biosynthesis.

    • Likui Feng
    • , Matthew T. Gordon
    •  & Rebecca A. Butcher
  • Article
    | Open Access

    An efficient chassis for heterologous expression of biosynthetic gene clusters (BGCs) from Gram-negative bacteria is still unavailable. Here, the authors report rational construction of genome-reduced Burkholderials chassis to facilitate production of a class of new compounds by expressing BGC from Chitinimonas koreensis.

    • Jiaqi Liu
    • , Haibo Zhou
    •  & Xiaoying Bian
  • Article
    | Open Access

    Aurantinins are polyketides with unusual connectivities and broad antibacterial activity. Here the authors show the biosynthesis of aurantinins, which proceeds via an on-line methyl esterification at the terminus that enables the iterative chain elongations prior to condensation and cyclization.

    • Pengwei Li
    • , Meng Chen
    •  & Yihua Chen
  • 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
  • Review Article
    | Open Access

    Natural products are an important source of bioactive compounds and have versatile applications in different fields, but their discovery is challenging. Here, the authors review the recent developments in genome mining for discovery of natural products, focusing on compounds from unconventional microorganisms and microbiomes.

    • Kirstin Scherlach
    •  & Christian Hertweck
  • Article
    | Open Access

    Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy.

    • Srijita Bhowmik
    • , Juraj Galeta
    •  & Dalibor Sames
  • Article
    | Open Access

    A large number of mass spectra from different samples have been collected, and to identify small molecules from these spectra, database searches are needed, which is challenging. Here, the authors report molDiscovery, a mass spectral database search method that uses an algorithm to generate mass spectrometry fragmentations and learns a probabilistic model to match small molecules with their mass spectra.

    • Liu Cao
    • , Mustafa Guler
    •  & Hosein Mohimani
  • 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
  • Article
    | Open Access

    Current genome mining methods predict many putative non-ribosomal peptides (NRPs) from their corresponding biosynthetic gene clusters, but it remains unclear which of those exist in nature and how to identify their post-assembly modifications. Here, the authors develop NRPminer, a modification-tolerant tool for the discovery of NRPs from large genomic and mass spectrometry datasets, and use it to find 180 NRPs from different environments.

    • Bahar Behsaz
    • , Edna Bode
    •  & Hosein Mohimani
  • Article
    | Open Access

    Caerulomycins and collismycins are two types of 2,2’-bipyridine natural products that are biosynthesized via a hybrid NRPS-PKS pathway, but the details of their biosynthesis were unknown. Here, the authors elucidate their biosynthetic pathways, validate the generality of 2,2’-bipyridine formation, and clarify the process for 2,2’-bipyridine furcation.

    • Bo Pang
    • , Rijing Liao
    •  & Wen Liu
  • Article
    | Open Access

    Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.

    • Zizheng Zou
    • , Xiyuan Hu
    •  & Zhiyong Luo
  • Article
    | Open Access

    Engineering efforts have focused on acyltransferase (AT) domains of modular polyketide synthases (PKSs) to site-selectively modify the resulting polyketides, but critical AT residues involved in substrate selection have not been fully elucidated. Here, the authors use molecular dynamics to pinpoint mutations that impact AT domain selectivity and exchange structural motifs to obtain chimeric PKS modules with expanded substrate specificity.

    • Edward Kalkreuter
    • , Kyle S. Bingham
    •  & Gavin J. Williams
  • Article
    | Open Access

    Rubromycin family of natural products belongs to aromatic polyketides with diverse bioactivities, but details of their biosynthesis are limited. Here, the authors report the complete in vitro reconstitution of enzymatic formation of the spiroketal moiety of rubromycin polyketides, driven by flavin-dependent enzymes, and characterize reaction intermediates.

    • Britta Frensch
    • , Thorsten Lechtenberg
    •  & Robin Teufel
  • Article
    | Open Access

    Trans-acyltransferase polyketide synthases are multimodular enzymes that synthesise diverse polyketides. Here, the authors present an algorithm for the global study of their diversity, showing exchange of conserved consecutive modules as a driver of diversification, and guiding the discovery of polyketides.

    • Eric J. N. Helfrich
    • , Reiko Ueoka
    •  & Marnix H. Medema
  • Article
    | Open Access

    Furanocembranoid-like natural products with the alkene-substituted furan scaffold display a range of biological activities, but are difficult to access. Here, the authors report a modular biomimetic strategy to synthesise diverse alkene-substituted furan-containing macrolactams via palladium-catalysed unactivated Csp3-H olefination.

    • Jiping Hao
    • , Xueying Guo
    •  & Weibo Yang
  • Article
    | Open Access

    Biosynthesis of the statin precursor lovastatin depends on the LovB–LovC megasynthase complex. Here, the authors present cryoEM structures of LovB–LovC and core LovB, providing structural insights into the catalytic cycle underlying lovastatin production.

    • Jialiang Wang
    • , Jingdan Liang
    •  & Zhijun Wang
  • Article
    | Open Access

    Nonribosomal lipopeptides contain an acyl chain important for bioactivity, but its incorporation into the peptidyl backbone, mediated by the starter condensation (Cs) domain of nonribosomal peptide synthases, is not fully understood. Here, the authors show that acyl chains of different lengths can be obtained by engineering Cs domains and identify residues that determine the selectivity for acyl chains.

    • Lin Zhong
    • , Xiaotong Diao
    •  & Xiaoying Bian
  • Article
    | Open Access

    FR900359 (FR) is a Gq protein inhibitor depsipeptide isolated from an uncultivable plant endosymbiont and synthesized by non-ribosomal peptide synthetases. Here, the authors discover a cultivable bacterial FR producer and show that FrsA thioesterase domain catalyses intermolecular transesterification of the FR side chain to the depsipeptide core during biosynthesis, improving Gq inhibition properties.

    • Cornelia Hermes
    • , René Richarz
    •  & Max Crüsemann
  • Article
    | Open Access

    Bacterial heterodimeric tryptophan-containing diketopiperazines (HTDKPs) are bioactive natural products that are difficult to access chemically. Here, the authors identify a family of three related HTDKP-forming cytochrome P450s and engineer key amino acid residues to produce distinct diketopiperazines frameworks.

    • Chenghai Sun
    • , Zhenyao Luo
    •  & Xudong Qu
  • Article
    | Open Access

    Large-scale sequencing efforts have uncovered a large number of secondary metabolic pathways, but the chemicals they synthesise remain unknown. Here the authors present PRISM 4, which predicts the chemical structures encoded by microbial genome sequences, including all classes of bacterial antibiotics in clinical use.

    • Michael A. Skinnider
    • , Chad W. Johnston
    •  & Nathan A. Magarvey
  • Article
    | Open Access

    Oxepinamides are a class of fungal oxepins with biological activities. Here, the authors elucidate the biosynthetic pathway of oxepinamide F from Aspergillus ustus and show that it involves enyme-catalysed oxepin ring formation, hydroxylation-induced double bond migration, epimerization and methylation.

    • Liujuan Zheng
    • , Haowen Wang
    •  & Shu-Ming Li
  • Article
    | Open Access

    Biosynthetic gene clusters (BGCs) make small molecules with fitness-enhancing activities that drive BGC evolution. Here, the authors show that synthetic biology can leverage bioactivity to achieve continuous evolution of an antibiotic BGC in the lab and improve antibiotic production in a new host.

    • Chad W. Johnston
    • , Ahmed H. Badran
    •  & James J. Collins
  • Article
    | Open Access

    Plants synthesize more than 3000 tetrahydroisoquinoline (THIQ) alkaloids, but only a few of them have been produced by engineered microbes and titers are very low. Here, the authors increase (S)-reticuline titer to 4.6 g/L and repurpose the yeast Ehrlich pathway to synthesize a diverse array of THIQ scaffolds.

    • Michael E. Pyne
    • , Kaspar Kevvai
    •  & Vincent J. J. Martin
  • Article
    | Open Access

    Complex polyketides are usually produced by microbes, whereas the origin of polyketides found in animals remained unknown. This study shows that sacoglossan animals, such as sea slugs, employ fatty acid synthase-like proteins to produce microbe-like polyketides.

    • Joshua P. Torres
    • , Zhenjian Lin
    •  & Eric W. Schmidt
  • Article
    | Open Access

    Lactazole A is a thiopeptide from Streptomyces lactacystinaeus, encoded by a compact 9.8 kb biosynthetic gene cluster. Here, the authors show a platform for in vitro biosynthesis of lactazole A via a combination of a flexible in vitro translation system with recombinantly produced lactazole biosynthetic enzymes.

    • Alexander A. Vinogradov
    • , Morito Shimomura
    •  & Hiroyasu Onaka
  • Article
    | Open Access

    O-alkylation of carboxylates by alkyl halides has only been observed transiently in enzymatic processes. Here, the authors show a carboxylate alkylating enzyme, BrtB, that catalyzes C-O bond formation between free fatty acids and secondary alkyl chlorides.

    • João P. A. Reis
    • , Sandra A. C. Figueiredo
    •  & Pedro N. Leão
  • Article
    | Open Access

    Small molecules in the rhizosphere regulate interactions between plants and other organisms. Here the authors show that an ascaroside pheromone secreted by plant-parasitic nematodes is converted by host plant peroxisomal β-oxidation into shorter side-chained ascarosides that repel nematodes.

    • Murli Manohar
    • , Francisco Tenjo-Castano
    •  & Frank C. Schroeder
  • Article
    | Open Access

    Soil microorganisms are a rich source of bioactive molecules. Here, the authors present a targeted sequencing workflow that reconstructs the clustered organization of biosynthetic domains in metagenomic libraries from amplicon data, thus guiding the discovery of novel metabolites from rare members of the soil microbiome.

    • Vincent Libis
    • , Niv Antonovsky
    •  & Sean F. Brady
  • Article
    | Open Access

    Tropane alkaloids (TAs) are a group of phytochemicals that are used to treat neurological disorders. Here, the authors engineer baker’s yeast to produce tropine, a key intermediate in the biosynthetic pathway of TAs, and cinnamoyltropine, a non-canonical TA, from simple carbon and nitrogen sources.

    • Prashanth Srinivasan
    •  & Christina D. Smolke
  • Article
    | Open Access

    The antimicrobial β-lactone obafluorin is produced by a Nonribosomal Peptide Synthetase (NRPS). Here the authors present the crystal structure of the obafluorin NRPS and develop a reconstitution assay that allows them to analyse product formation from obafluorin NRPS mutants and alternate substrates.

    • Dale F. Kreitler
    • , Erin M. Gemmell
    •  & Andrew M. Gulick
  • Article
    | Open Access

    C19 hydroxylation is a unique feature of some bioactive steroids. Here, the authors developed a direct C19 hydroxylation approach to scalably access 19-OH-cortexolone in the host T. cucumeris and then converted the product into various pharmaceutically useful products via chemical synthesis.

    • Junlin Wang
    • , Yanan Zhang
    •  & Qianghui Zhou
  • Article
    | Open Access

    Mother Nature is a valuable resource for the discovery of drug and agricultural chemicals. Here, the authors show that 7-deoxy-sedoheptulose produced by a cyanobacterium is an antimicrobial and herbicidal compound that acts through inhibition of 3-dehydroquniate synthase in the shikimate pathway.

    • Klaus Brilisauer
    • , Johanna Rapp
    •  & Karl Forchhammer
  • Article
    | Open Access

    Rhabdopeptides are synthesized by non-ribosomal peptide synthetases (NRPSs) and the multiple NRPS subunits interact through docking domains (DD). Here the authors provide insights into DD interaction patterns and present the structures of three N-terminal docking domains (NDD) and a NDD-CDD complex and derive a set of recognition rules for DD interactions.

    • Carolin Hacker
    • , Xiaofeng Cai
    •  & Jens Wöhnert
  • Article
    | Open Access

    New natural products can be identified via mass spectrometry by excluding all known ones from the analysis, a process called dereplication. Here, the authors extend a previously published dereplication algorithm to different classes of secondary metabolites.

    • Hosein Mohimani
    • , Alexey Gurevich
    •  & Pavel A. Pevzner
  • Article
    | Open Access

    The bacterial diterpene synthase CotB2 catalyses the cyclisation of geranylgeranyl diphosphate to cyclooctat-9-en7-ol. Here the authors present various CotB2 structures including a trapped abrupt reaction product that were used for molecular dynamic simulations and allowed them to model all intermediates along the reaction cascade.

    • Ronja Driller
    • , Sophie Janke
    •  & Bernhard Loll
  • Article
    | Open Access

    The phytohormone JA-Ile can promote plant resistance against herbivores and fungal pathogens but also inhibits growth, limiting its potential use in agriculture. Here, the authors design a stereoisomer of JA-Ile analog and demonstrate that it can promote defense while having minimal impact on growth.

    • Yousuke Takaoka
    • , Mana Iwahashi
    •  & Minoru Ueda
  • Article
    | Open Access

    Burkholderia bacteria protect the offspring of Lagria beetles against pathogens. Here, Flórez et al. identify an antifungal polyketide that is likely encoded by a horizontally acquired gene cluster on the genome of a dominant, uncultured Burkholderia symbiont of Lagria villosa.

    • Laura V. Flórez
    • , Kirstin Scherlach
    •  & Martin Kaltenpoth