Biosynthesis articles within Nature Chemistry

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  • In Your Element |

    John Steele and Stephen Wallace discuss recent advances in the chemical and biotechnological synthesis of the prolific platform chemical adipic acid.

    • John F. C. Steele
    •  & Stephen Wallace

  • Article |

    Ribosomally synthesized and post-translationally modified peptides (RiPPs) can have vast structural diversity and biological functions enabled by disparate post-translational modifications (PTMs). However, unconventional PTMs derived from non-RiPP biosynthesis are rarely reported. Now a class of lipopeptides featuring a distinct fatty-acyl-modified N terminus and the responsible RiPP/fatty-acid hybrid biosynthetic machinery have been characterized.

    • Hengqian Ren
    • , Chunshuai Huang
    •  & Huimin Zhao

  • Article |

    Methods for transition-metal-catalysed enantioselective C(sp3)–S bond construction are underdeveloped. Now, by taking advantage of the biomimetic radical homolytic substitution manifold, the copper-catalysed enantioconvergent C(sp3)–S cross-coupling of racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles has been realized. This reaction provides access to an array of α-chiral alkyl organosulfur compounds.

    • Yu Tian
    • , Xi-Tao Li
    •  & Xin-Yuan Liu

  • Article |

    Celastrol is a potent anti-obesity agent found in the root of Tripterygium wilfordii, but its medicinal application is compromised by limited availability. Now, by combining plant biochemistry with metabolic engineering and chemistry, the biosynthetic pathway of celastrol has been elucidated and has afforded its scalable production in yeast.

    • Yong Zhao
    • , Nikolaj L. Hansen
    •  & Sotirios C. Kampranis

  • 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

  • News & Views |

    2+2-cycloaddition reactions have long been considered key transformations in the biosynthesis of cyclobutane-containing natural products, but enzymes for these reactions have not yet been identified. Now, a 2+2 cyclase has been discovered, characterized and bioengineered to catalyse cycloadditions with different selectivity.

    • Bo Zhang
    •  & Hui Ming Ge

  • Article |

    Cycloaddition reactions are among the most useful reactions in chemical synthesis, but biosynthetic enzymes with 2 + 2 cyclase activity have yet to be observed. Now it is shown that a β-barrel-fold protein catalyses competitive 2 + 2 and 4 + 2 cycloaddition reactions. This protein can be engineered to preferentially produce the exo-2 + 2, exo-4 + 2 or endo-4 + 2 product.

    • Hongbo Wang
    • , Yike Zou
    •  & K. N. Houk

  • Article
    | Open Access

    Macrocyclic peptides can be genetically encoded and synthesized in cells; however, the programmable diversity is limited. Now, macrocycles containing two non-canonical amino acids have been genetically encoded and synthesized in codon-reassigned Syn61Δ3 cells. Incorporating diverse hydroxy acids in Syn61Δ3 cells enables the synthesis of non-natural depsipeptides containing either one or two ester bonds.

    • Martin Spinck
    • , Carlos Piedrafita
    •  & Jason W. Chin

  • 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 |

    In silico chemical prediction of a polyketide synthase gene cluster in the bacterium Gynuella sunshinyii has led to the discovery of a class of natural products called janustatins. The absolute configuration of the stereocentres in these compounds was determined by a combination of techniques including DFT calculations and 2D NMR experiments—and finally confirmed by total synthesis. Janustatins were found to cause delayed, synchronized cell death at subnanomolar concentrations.

    • Reiko Ueoka
    • , Philipp Sondermann
    •  & Jörn Piel

  • Article |

    The biosynthesis of fuscimiditide, a ribosomally synthesized post-translationally modified peptide, has now been reported. Heterologous expression and analysis of fuscimiditide showed it contained two side-chain–side-chain ester linkages and an aspartimide in its backbone. The aspartimide moiety is unexpectedly stable, suggesting this structure is the intended natural product.

    • Hader E. Elashal
    • , Joseph D. Koos
    •  & A. James Link

  • Article
    | Open Access

    Burkholderia pseudomallei is a species of bacteria that poses a global health threat and, more generally, bacteria of the Burkholderia pseudomallei group cause severe diseases that are recalcitrant to treatment with antibiotics. Now, it has been shown how these infamous pathogens repurpose the widespread enzyme BurG to produce a reactive cyclopropanol head group found in the virulence-promoting malleicyprol toxins. Interrupting the synthesis of the cyclopropanol warhead is a potential route for developing antivirulence treatments.

    • Felix Trottmann
    • , Keishi Ishida
    •  & Christian Hertweck

  • Article |

    The introduction of fluorine into a drug molecule can alter the biological responses to it, including modulating bioavailability, pharmacokinetics and selectivity. Now, a hybrid polyketide/fatty acid synthase multienzyme has been designed to incorporate fluorinated precursors during polyketide biosynthesis in an approach that provides new chemoenzymatic access to fluorinated natural compounds.

    • Alexander Rittner
    • , Mirko Joppe
    •  & Martin Grininger

  • Article |

    Natural products are produced by living organisms practising nature’s chemical transformations. Now, an unnatural product has been generated by creating hybrid biosynthetic microorganisms. These microorganisms combine an unnatural chemical transformation—catalysis by an artificial metalloenzyme containing an iridium-based, unnatural cofactor—with a natural biosynthetic pathway within the same cell.

    • Jing Huang
    • , Zhennan Liu
    •  & John F. Hartwig

  • Article |

    Located in the catalytically important belt region, the ‘ninth sulfur’ of the nitrogenase cofactor has now been shown to be inserted through coordination of sulfite by two cluster iron atoms at a vacant belt site. This is followed by in situ reduction of sulfite to sulfide, which enables the subsequent transfer and functionalization of the cofactor.

    • Kazuki Tanifuji
    • , Andrew J. Jasniewski
    •  & Markus W. Ribbe

  • Article |

    The molybdenum cofactor (Moco) is found in the active site of numerous enzymes, but the mechanism of molybdate insertion is not clear. Now, the mechanism of the final maturation step, in which adenylated molybdopterin and molybdate are the substrates, has been revealed. X-ray crystallography of an Mo-insertase identified adenylated Moco as an unexpected intermediate in this reaction sequence.

    • Corinna Probst
    • , Jing Yang
    •  & Tobias Kruse

  • 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

  • News & Views |

    Mimicking biosynthetic pathways can provide access to medicinally important natural products, but generating the reactive species used by nature can often be difficult. Now, a photoredox-based strategy has been developed to access a reactive radical intermediate postulated to be involved in complex lignan biosynthesis.

    • Danny Q. Thach
    •  & Thomas J. Maimone

  • 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 |

    Class II terpene cyclases convert simple linear substrates into complex polycyclic compounds, which typically requires multiple protein domains. Now, a single-domain class II cyclase, a cyanobacterial merosterolic acid synthase, has been identified and characterized. High-resolution X-ray crystal structures provide detailed insights into how a minimalistic enzyme accomplishes this complex cyclization process.

    • Philipp Moosmann
    • , Felix Ecker
    •  & Jörn Piel

  • 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 |

    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

  • 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 |

    The complete biosynthesis of the fungal indole alkaloid malbrancheamide, which culminates in an intramolecular [4+2] hetero-Diels–Alder cyclization to produce the bicyclo[2.2.2]diazaoctane scaffold, has now been discovered. Chemical synthesis and protein structural analysis were used to provide mechanistic insight into this enzyme-dependent diastereo- and enantioselective cycloaddition.

    • Qingyun Dan
    • , Sean A. Newmister
    •  & Robert M. Williams

  • Article |

    Polytheonamides are potently cytotoxic hypermodified ribosomal peptides that are produced by an uncultivated bacterium. Now, a bioinformatic mining strategy has enabled the development of a bacterial production host that can be cultivated in a laboratory. The host generates polytheonamide-like compounds within 2 days, and can efficiently introduce multiple d-amino acids, asparagine N-methylations and C-methyl groups into various peptides.

    • Agneya Bhushan
    • , Peter J. Egli
    •  & Jörn Piel

  • Article |

    LepI is an S-adenosylmethionine-dependent pericyclase that catalyses the dehydration, hetero-Diels–Alder reaction and retro-Claisen rearrangement reactions that occur in the formation of the 2-pyridone natural product leporin C. Now, the mechanistic details that underpin this range of catalytic reactions have been uncovered from the crystal structures of LepI and LepI in complex with ligands.

    • Yujuan Cai
    • , Yang Hai
    •  & Yi Tang

  • 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

  • Thesis |

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

    • Bruce C. Gibb

  • News & Views |

    A new pyrrolysyl-tRNA synthetase/PyltRNA (PylRS/PyltRNA) pair that is mutually orthogonal to existing PylRS/PyltRNA pairs has now been discovered and optimized. This system could enable the site-specific incorporation of a greater number of distinct non-canonical amino acids into a protein.

    • William S. C. Ngai
    •  & Peng R. Chen

  • Article |

    The M-cluster in the active site of nitrogenase is derived from an 8Fe core assembled via coupling and rearrangement of two [Fe4S4] clusters concomitant with the insertion of an interstitial carbon and a ninth sulfur. Now, by combining synthetic [Fe4S4] clusters and assembly with a protein template, it has been shown that sulfite gives rise to the ninth sulfur that is inserted into the nitrogenase cofactor after the radical SAM-dependent carbide insertion and cofactor core rearrangement.

    • Kazuki Tanifuji
    • , Chi Chung Lee
    •  & Markus W. Ribbe

  • News & Views |

    Ribosomes have now been shown to accept certain initiator tRNAs acylated with aromatic foldamer–dipeptides thereby enabling the translation of a peptide or protein with a short aromatic foldamer at the N-terminus. Some foldamer–peptide hybrids could be cyclized to generate macrocycles that present conformationally restricted peptide loops.

    • Alanna Schepartz

  • Article |

    The extent to which peptide synthesis by the ribosome can tolerate the inclusion of non-peptidic components is not clear. Yet such hybrids would expand the range of ribosomally synthesized structures. Now it has been shown that tRNAs acylated by aromatic foldamers can initiate the ribosomal synthesis of non-cyclic and cyclic foldamer–peptide hybrid molecules. The oligo-aryl segments contain folding information that can control peptide conformation in the hybrids.

    • Joseph M. Rogers
    • , Sunbum Kwon
    •  & Ivan Huc

  • News & Views |

    Rational engineering of biosynthetic assembly lines for production of new compounds is an attractive prospect, yet it presents many challenges. Learning from biology, some of the rules for expanding the chemical diversity of non-ribosomal peptides have been uncovered in two recent studies.

    • Binuraj R. K. Menon
    •  & Matthew Jenner

  • 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 |

    Nonribosomal peptide synthetases (NRPSs) produce vital natural products but have proven recalcitrant to biosynthetic engineering. Now, a combination of yeast surface display and fluorescence-activated cell sorting (FACS) has been used to reprogram an L-Phe-incorporating module for β-Phe. The resulting module is highly selective and functions efficiently in NRPS pathways.

    • David L. Niquille
    • , Douglas A. Hansen
    •  & Donald Hilvert

  • Article |

    Bacterial naphthoquinone meroterpenoid natural products defy biosynthetic logic via classical biochemical paradigms. Now, an enzyme promoted α-hydroxyketone rearrangement catalysed by vanadium-dependent haloperoxidases reveals a conserved biosynthetic reaction in this molecular class that further has inspired a concise biomimetic synthesis of naphthomevalin, a prominent member of the napyradiomycin meroterpenes.

    • Zachary D. Miles
    • , Stefan Diethelm
    •  & Bradley S. Moore

  • Article |

    The biomimetic syntheses of bipleiophylline, one of the most complex monoterpene indole alkaloids, and voacalgine A, its biosynthetic precursor, have been achieved from pleiocarpamine starting material. The development of a divergent oxidative coupling for the formation of the benzofuro[2,3-b]indolenine and isochromano[3,4-b]indolenine moieties was key to this accomplishment.

    • David Lachkar
    • , Natacha Denizot
    •  & Guillaume Vincent

  • Article |

    Polytheonamides are giant peptide toxins produced by the uncultivated sponge bacterium Entotheonella factor. The biosynthesis of polytheonamides involves up to 50 post-translational modifications. Now, heterologous expression in Escherichia coli and Rhizobium hosts have shown that a minimalistic, iterative enzyme set introduces this exceptional molecular complexity via epimerizations, C-/N-methylations, hydroxylations, dehydration and proteolytic maturation.

    • Michael F. Freeman
    • , Maximilian J. Helf
    •  & Jörn Piel

  • News & Views |

    A concise synthesis of the fungal natural product epicolactone suggests that this highly stereochemically complex yet racemic natural product may come from a cascade reaction between two polyhydroxylated arenes.

    • Jaron A. M. Mercer
    •  & Noah Z. Burns

  • Article |

    A method for high-throughput analysis of whole-cell biocatalysts for industrial biotechnology has been developed. The process relies on a combination of specifically tailored bacterial sensor cells that are incubated with biocatalyst variants within nanolitre-sized compartments. The product is secreted by the whole-cell biocatalysts and taken up by the sensor cells, which initiates a sequence of reactions that finish with the synthesis of green fluorescent protein.

    • Andreas Meyer
    • , René Pellaux
    •  & Martin Held

  • 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

  • News & Views |

    Mutated enzymes are useful tools for the investigation of the biosynthetic routes to natural products. Now, they are used in a new approach to carry functionalized substrates through the synthesis and produce simplified or modified unnatural compounds with useful properties.

    • Niclas Pryk
    •  & Frank Schulz

  • News & Views |

    Enhancing the structural diversity of peptide natural products relies on synthetic modifications that are typically not chemo- or regioselective. A nonribosomal peptide synthetase has now been engineered to incorporate a non-natural amino acid containing a reactive bio-orthogonal handle.

    • Jaclyn M. Winter
    •  & Yi Tang

  • Article |

    Reduction of 5-hydroxymethylcytosine (hmC) levels in DNA often occurs in cancers. Using isotope tracing experiments, this epigenetic DNA modification, which was thought to be an intermediate of demethylation, is now shown to be stable. A delay in the generation of hmC on newly synthesized DNA is responsible for the reduction of hmC levels in cancers.

    • Martin Bachman
    • , Santiago Uribe-Lewis
    •  & Shankar Balasubramanian

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