Biosynthesis

  • 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

    Glycomics can uncover important molecular changes but measured glycans are highly interconnected and incompatible with common statistical methods, introducing pitfalls during analysis. Here, the authors develop an approach to identify glycan dependencies across samples to facilitate comparative glycomics.

    • Bokan Bao
    • , Benjamin P. Kellman
    •  & Nathan E. Lewis
  • 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

    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
  • 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

    Substrate channeling can improve biosynthetic efficiency and has been implicated in the reactions of fusicoccadiene synthase. Here, the authors analyze this bifunctional enzyme complex by cryoEM, cross-linking MS and integrative modeling, providing structural insights into how substrate channeling is achieved.

    • Jacque L. Faylo
    • , Trevor van Eeuwen
    •  & David W. Christianson
  • 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

    Non-ribosomal peptide synthetases (NRPSs) are multi-modular enzymes assembling complex natural products. Here, the structures of a Thermobifida fusca NRPS condensation domain bound to the substrate-bearing peptidyl carrier protein (PCP) domain provide insight into the mechanisms of substrate selectivity and engagement within the catalytic pocket.

    • Thierry Izoré
    • , Y. T. Candace Ho
    •  & Max J. Cryle
  • Article
    | Open Access

    Streptoseomycin is a potent antibiotic that contains a pentacyclic 5/14/10/6/6 ring system. Here, the authors report the enzymatic and non-enzymatic steps of the downstream modification of streptoseomycin biosynthesis and show a [6 + 4]-cycloaddition adduct as an unexpected biosynthetic intermediate.

    • Kai Biao Wang
    • , Wen Wang
    •  & Hui Ming Ge
  • 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

    Microbial symbionts can help their hosts metabolise diverse diets. A study on herbivorous turtle ants identifies the cuticular components which are nitrogen-enriched by gut bacteria, highlighting the role of symbionts in insect evolution.

    • Christophe Duplais
    • , Vincent Sarou-Kanian
    •  & Corrie S. Moreau
  • Article
    | Open Access

    Azoles are five-membered heterocycles found in peptidic natural products and synthetic peptiodomimetics. Here the authors demonstrate a posttranslational chemical modification method for in vitro ribosomal synthesis of peptides with exotic azole groups at specific positions.

    • Haruka Tsutsumi
    • , Tomohiro Kuroda
    •  & Hiroaki Suga
  • 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

    Short-chain primary amines (SCPAs) are industrially important compounds that are commonly produced under harsh synthetic conditions. Here, the authors report a combination of retrobiosynthesis and precursor selection step for design of biosynthetic pathways leading to production of SCPAs, using valine decarboxylase-expressing Escherichia coli strains.

    • Dong In Kim
    • , Tong Un Chae
    •  & Sang Yup Lee
  • Article
    | Open Access

    A fundamental function of living systems is regenerating essential components. Here the authors design an artificial cell using a minimal transcription-translation system in microfluidic reactors for sustained regeneration of multiple essential proteins.

    • Barbora Lavickova
    • , Nadanai Laohakunakorn
    •  & Sebastian J. Maerkl
  • Article
    | Open Access

    Heme biosynthesis depends on iron-sulfur (Fe-S) cluster biogenesis but the molecular connection between these pathways is not fully understood. Here, the authors show that the heme biosynthesis enzyme ALAD contains an Fe-S cluster, disruption of which reduces ALAD activity and heme production in human cells.

    • Gang Liu
    • , Debangsu Sil
    •  & Tracey Ann Rouault
  • 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

    Biosynthesis of biotin precursor, pimelate moiety, is elucidated in Escherichia coli and Bacillus subtilis, but not understood in alphaproteobacteria. Here, the authors show that BioZ, a 3-ketoacyl-ACP synthase, catalayses pimeloyl-thioester synthesis in alphaproteobacteria using malonyl-ACP and glutaryl-CoA that is derived from lysine degradation.

    • Yuanyuan Hu
    •  & John E. Cronan
  • Article
    | Open Access

    The extreme oxygen sensitive character of hydrogenases is a longstanding issue for hydrogen production in bacteria. Here, the authors build carboxysome shells in E. coli and incorporate catalytically active hydrogenases and functional partners within the empty shell for the production of hydrogen.

    • Tianpei Li
    • , Qiuyao Jiang
    •  & Lu-Ning Liu
  • Article
    | Open Access

    Aliphatic α,ω-dicarboxylic acids (DCAs) are widely used chemicals that are synthesised by multistage chemical oxidations. Here, the authors report an artificially designed biocatalytic cascade for the oxidation of cycloalkanes or cycloalkanols to DCAs in the form of microbial consortia, composed of three Escherichia coli cell modules.

    • Fei Wang
    • , Jing Zhao
    •  & Aitao Li
  • 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

    Controlled membrane synthesis in liposomes is a prerequisite for synthetic systems emulating the fundamental properties of living cells. Here authors present that a de novo synthesized metabolic pathway converts precursors into a variety of lipids, including the constituents of the parental liposome.

    • Duco Blanken
    • , David Foschepoth
    •  & Christophe Danelon
  • Article
    | Open Access

    Several different genetic strategies have been reported for the modification of polyketide synthases but the highly repetitive modular structure makes this difficult. Here the authors report on an adapted Cas9 reaction and Gibson assembly to edit a target region of the polyketide synthases gene in vitro.

    • Kei Kudo
    • , Takuya Hashimoto
    •  & Kazuo Shin-ya
  • 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

    Mutation of the C-terminal extension of 5′-aminolevulinate synthase 2 (ALAS2) is the molecular cause for X-linked protoporphyria, but the underlying mechanism is unclear. Based on crystal structures and MD simulations of ALAS2, the authors here show how the C-terminal extension regulates ALAS2 activity.

    • Henry J. Bailey
    • , Gustavo A. Bezerra
    •  & Wyatt W. Yue
  • 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

    The formation of C-C bonds in fatty acid and polyketide biosynthesis depends on β-ketoacyl-acyl carrier protein (ACP) synthases (KSs). Here, the authors present structures of E.coli KSs bound to substrate mimetic bearing ACPs, providing insights into the catalytic mechanism underlying C-C bond forming reactions.

    • Jeffrey T. Mindrebo
    • , Ashay Patel
    •  & Michael D. Burkart
  • 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

    Azoxy bonds are frequently found in liquid crystals, chemical intermediates, dyes, agrochemicals and pharmaceuticals. Here, the authors investigated azoxy bond formation by the non-heme diiron N-oxygenase AzoC in azoxymycin biosynthesis and show that the nitroso group plays a key part in it.

    • Yuan-Yang Guo
    • , Zhen-Hua Li
    •  & Yong-Quan Li
  • Article
    | Open Access

    NocTE is a nonribosomal peptide synthetase thioesterase that completes the biosynthesis of pro-nocardicin G, the precursor for nocardicin β-lactam antibiotics. Here the authors provide mechanistic insights into NocTE by determining its crystal structures in the ligand-free form and covalently linked to a fluorophosphonate substrate mimic.

    • Ketan D. Patel
    • , Felipe B. d’Andrea
    •  & Andrew M. Gulick
  • Article
    | Open Access

    Phosphonate modifications can be present on microbial cell surfaces. Here the authors perform bioinformatics analyses and observe a widespread occurrence of nucleotidyltransferase-encoding genes in bacterial phosphonate biosynthesis and functionally characterize two of the identified phosphonate specific cytidylyltransferases (PntCs) and determine the crystal structure of T. denticola PntC.

    • Kyle Rice
    • , Kissa Batul
    •  & Geoff P. Horsman
  • Article
    | Open Access

    The mechanism of iron-sulfur (Fe-S) cluster biosynthesis is not fully understood. Here, the authors develop a physiologically relevant in vitro model of Fe-S cluster assembly, allowing them to elucidate the sequence of Fe-S cluster synthesis along with the respective roles of ferredoxin-2 and frataxin.

    • Sylvain Gervason
    • , Djabir Larkem
    •  & Benoit D’Autréaux
  • Article
    | Open Access

    The ratio of syringyl (S) and guaiacyl (G) units in lignin has been regarded as a major factor in determining the maximum monomer yield. Here, the authors challenge this common conception using reductive catalytic fractionation in flow-through reactors as an analytical tool to depolymerize lignin in poplar with naturally varying S/G ratios.

    • Eric M. Anderson
    • , Michael L. Stone
    •  & Yuriy Román-Leshkov
  • Article
    | Open Access

    The hexahydropyrrolo[2, 3-b]indole (HPI) framework is found in many natural products. Here, the authors discover a P450 enzyme and develop a whole-cell biocatalysis system that produces the HPI naseseazine C (NAS-C) and 30 NAS-C analogs, several of which show neuroprotective properties.

    • Wenya Tian
    • , Chenghai Sun
    •  & Xudong Qu
  • Article
    | Open Access

    Diketopiperazine derivatives are bioactive molecules with scaffold formed by the condensation of two amino acids. Here, Yao et al. mine the genomes of Streptomyces strains and identify new biosynthetic machinery for drimentines biosynthesis, which includes cyclodipeptide synthase, prenyltransferase, and terpene cyclase.

    • Tingting Yao
    • , Jing Liu
    •  & Wenli Li
  • Article
    | Open Access

    The monoamine oxidase family member LkcE is an enzyme from the lankacidin polyketide biosynthetic pathway, where it catalyzes an amide oxidation followed by an intramolecular Mannich reaction, yielding the polyketide macrocycle. Here the authors characterize LkcE and present several of its crystal structures, which explains the unusual dual activity of LkcE.

    • Jonathan Dorival
    • , Fanny Risser
    •  & Kira J. Weissman
  • Article
    | Open Access

    Strobilurins are fungal metabolites that inspired the creation of β-methoxyacrylate agricultural fungicides. Here, Nofiani et al. identify the strobilurin biosynthesis gene cluster, encoding a polyketide synthase as well as an FAD-dependent oxygenase for an oxidative rearrangement leading to β-methoxyacrylate formation.

    • Risa Nofiani
    • , Kate de Mattos-Shipley
    •  & Russell J. Cox
  • Article
    | Open Access

    NifB is a key enzyme in the biosynthesis pathway of the nitrogenase FeMo cofactor. Here, the authors investigate the maturation of its iron-sulfur clusters by EPR and biochemical analyses, showing how individual precursor clusters participate in the formation of the final iron-sulfur cluster.

    • Lee A. Rettberg
    • , Jarett Wilcoxen
    •  & Yilin Hu