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| Open AccessDe novo synthesized Min proteins drive oscillatory liposome deformation and regulate FtsA-FtsZ cytoskeletal patterns
The Min biochemical network regulates bacterial cell division and is a prototypical example of self-organizing molecular systems. Here authors synthesize Min proteins from their genes inside liposomes and observe dynamic protein patterns and liposome shape deformation.
- Elisa Godino
- , Jonás Noguera López
- & Christophe Danelon
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Article
| Open AccessMolecular mechanism of azoxy bond formation for azoxymycins biosynthesis
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
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Article
| Open AccessStructure of a bound peptide phosphonate reveals the mechanism of nocardicin bifunctional thioesterase epimerase-hydrolase half-reactions
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
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Article
| Open AccessThe predominance of nucleotidyl activation in bacterial phosphonate biosynthesis
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
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Article
| Open AccessPhysiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin
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
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Article
| Open AccessKistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics
Kistamicin is a structurally divergent glycopeptide antibiotic (GPA) that contains a unique 15-membered A-O-B ring. Here, the authors obtained a crystal structure of the kistamicin OxyA/X-domain complex and analysed the cyclisation cascade leading to the formation of the A-O-B ring.
- Anja Greule
- , Thierry Izoré
- & Max J. Cryle
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Article
| Open AccessDifferences in S/G ratio in natural poplar variants do not predict catalytic depolymerization monomer yields
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
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Article
| Open AccessReconstitution of the lipid-linked oligosaccharide pathway for assembly of high-mannose N-glycans
Attachment of the oligosaccharide Man9GlcNAc2 is required for glycoprotein folding and secretion but synthesizing this compound for structural and functional studies has remained challenging. Here, the authors achieve efficient Man9GlcNAc2 synthesis by reconstituting its biosynthetic pathway in vitro.
- Sheng-Tao Li
- , Tian-Tian Lu
- & Xiao-Dong Gao
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Article
| Open AccessEfficient biosynthesis of heterodimeric C3-aryl pyrroloindoline alkaloids
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
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Article
| Open AccessGenome mining of cyclodipeptide synthases unravels unusual tRNA-dependent diketopiperazine-terpene biosynthetic machinery
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
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Article
| Open AccessInsights into a dual function amide oxidase/macrocyclase from lankacidin biosynthesis
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
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Article
| Open AccessStrobilurin biosynthesis in Basidiomycete fungi
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
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Article
| Open AccessDiscovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining
Microbial genomes encode enzymes for biosynthesis of many uncharacterized peptides. Here, the authors screen over 7,300 bacterial genomes for potential biosynthesis of cationic non-ribosomal peptides, and identify two novel peptides with activities against antibiotic-resistant Gram-negative pathogens.
- Yong-Xin Li
- , Zheng Zhong
- & Pei-Yuan Qian
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Correspondence
| Open AccessReply to ‘C–C bond cleavage in biosynthesis of 4-alkyl-l-proline precursors of lincomycin and anthramycin cannot precede C-methylation’
- Guannan Zhong
- , Hua Chen
- & Wen Liu
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Correspondence
| Open AccessC-C bond cleavage in biosynthesis of 4-alkyl-L-proline precursors of lincomycin and anthramycin cannot precede C-methylation
- Zdenek Kamenik
- , Radek Gazak
- & Jiri Janata
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Article
| Open AccessProbing the coordination and function of Fe4S4 modules in nitrogenase assembly protein NifB
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
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Article
| Open AccessEnzymatic one-step ring contraction for quinolone biosynthesis
Viridicatin is a fungal alkaloid. Here, the authors identify and characterize the cyclopenase that catalyzes the last step of its biosynthesis in Aspergillus nidulans, the conversion of cyclopenin to viridicatin, and find that the reaction proceeds via an unusual elimination mechanism.
- Shinji Kishimoto
- , Kodai Hara
- & Kenji Watanabe
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Article
| Open AccessA radical S-adenosyl-L-methionine enzyme and a methyltransferase catalyze cyclopropane formation in natural product biosynthesis
The biosynthesis of the antitumour antibiotic CC-1065 includes formation of a cyclopropane. Here, the authors identify the two enzymes that work together to catalyze this reaction, a radical S-adenosyl-l-methionine enzyme and a methyltransferase, and propose a mechanism for the cyclopropanation.
- Wen-Bing Jin
- , Sheng Wu
- & Gong-Li Tang
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Article
| Open AccessSingle-pot glycoprotein biosynthesis using a cell-free transcription-translation system enriched with glycosylation machinery
The ability to produce homogeneous glycoproteins is expected to advance fundamental understanding in glycoscience, but current in vivo-based production systems have several limitations. Here, the authors develop an E. coli extract-based one-pot system for customized production of N-linked glycoproteins.
- Thapakorn Jaroentomeechai
- , Jessica C. Stark
- & Matthew P. DeLisa
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Article
| Open AccessNovofumigatonin biosynthesis involves a non-heme iron-dependent endoperoxide isomerase for orthoester formation
Novofumigatonin is a meroterpenoid found in the fungus Aspergillus novofumigatus. Here, the authors elucidate the biosynthetic pathway of novofumigatonin and show that the endoperoxidase NvfI and the endoperoxide isomerase NvfE are involved in it.
- Yudai Matsuda
- , Tongxuan Bai
- & Thomas O. Larsen
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Article
| Open AccessDeciphering the late steps of rifamycin biosynthesis
The enzymes Rif15 and Rif16 are involved in the late steps of the biosynthesis of rifamycins, a group of antibiotics. Here, the authors characterized these two proteins and found that they catalyse unusual biochemical reactions.
- Feifei Qi
- , Chao Lei
- & Shengying Li
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Article
| Open AccessMolecular basis of dimer formation during the biosynthesis of benzofluorene-containing atypical angucyclines
Benzofluorene-containing angucyclines, bacterial natural compounds with potential use as therapeutics/antibiotics, occur as dimers. Here, the authors elucidated the dimerization mechanism which turned out to work spontaneously, without enzymatic catalysis.
- Chunshuai Huang
- , Chunfang Yang
- & Changsheng Zhang
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Article
| Open AccessThree previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A
Xenovulene A is a fungal compound that has the potential to be used as an antidepressant. Here, the authors unravel the pathway leading to its formation in fungi and discover a new class of enzymes, which accounts for some unusual chemistry in the synthesis of xenovulene.
- Raissa Schor
- , Carsten Schotte
- & Russell J. Cox
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Article
| Open AccessBiosynthetic pathway for furanosteroid demethoxyviridin and identification of an unusual pregnane side-chain cleavage
Demethoxyviridin is a fungal steroid that inhibits a phosphatidylinositol 3-kinase, an enzyme contributing to tumor progression. Here, the authors elucidate the biosynthetic route that leads to the formation of demethoxyviridin in fungi.
- Gao-Qian Wang
- , Guo-Dong Chen
- & Hao Gao
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Article
| Open AccessA distributive peptide cyclase processes multiple microviridin core peptides within a single polypeptide substrate
Microviridins belong to the family of ribosomally synthesized and post-translationally modified peptides (RiPPs). Here, the authors discover a microviridin-synthesizing enzyme in a cyanobacterium that modifies multiple core peptides from a single substrate in a distributive and unstrictly directional manner, an unusual biosynthetic logic for RiPPs.
- Yi Zhang
- , Kunhua Li
- & Yousong Ding
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Article
| Open AccessTwo distinct domains contribute to the substrate acyl chain length selectivity of plant acyl-ACP thioesterase
The substrate specificity of acyl-ACP thioesterase (TE) plays a crucial role in determining the product profile of type II fatty acid synthase. Utilizing two FatB-type acyl-ACP TEs, the authors here define determinants of substrate specificity and create synthetic enzymes with distinct catalytic traits.
- Fuyuan Jing
- , Le Zhao
- & Basil J. Nikolau
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Article
| Open AccessIdentification of a Golgi GPI-N-acetylgalactosamine transferase with tandem transmembrane regions in the catalytic domain
Mammalian GPI membrane anchors are modified by GalNAc to confer structural diversity but the biosynthetic pathway is poorly understood. Here, the authors identify and characterize the Golgi-resident GPI-GalNAc transferase PGAP4, providing insights into the initial step of GPI-GalNAc biosynthesis.
- Tetsuya Hirata
- , Sushil K. Mishra
- & Taroh Kinoshita
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Article
| Open AccessWarhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors
Metalloproteinase inhibitors are leads for drug development, but their biosynthetic pathways are often unknown. Here the authors show that the acyl branched warhead of actinonin and matlystatins derives from an ethylmalonyl-CoA-like pathway and the structural diversity of matlystatins is due to the activity of a decarboxylase-dehydrogenase enzyme.
- Franziska Leipoldt
- , Javier Santos-Aberturas
- & Leonard Kaysser
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Article
| Open AccessGyrI-like proteins catalyze cyclopropanoid hydrolysis to confer cellular protection
GyrI-like proteins are small-molecule binding proteins that are widely distributed in prokaryotes and eukaryotes, with functions that are poorly characterized. Here, the authors identify GyrI-like proteins as cyclopropanoid cyclopropyl hydrolases that can confer resistance to cytotoxic cyclopropanoid compounds.
- Hua Yuan
- , Jinru Zhang
- & Gong-Li Tang
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Article
| Open AccessA three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate
The biosynthetic pathway of preakuammicine, a monoterpene precursor of the anti-cancer agent vinblastine, has remained largely unexplored. Here, the authors provide transcriptomic and biochemical data to identify two enzymes that, in tandem, convert strictosidine to akuammicine, the stable shunt product of preakuammicine.
- Evangelos C. Tatsis
- , Inês Carqueijeiro
- & Sarah E. O’Connor
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Article
| Open Access4-alkyl-L-(Dehydro)proline biosynthesis in actinobacteria involves N-terminal nucleophile-hydrolase activity of γ-glutamyltranspeptidase homolog for C-C bond cleavage
γ-Glutamyltranspeptidases in gram-positive bacteria are not involved in glutathione metabolism, as their counterparts in eukaryotes and gram-negative bacteria. Here, the authors show that in Actinobacteria they catalyse the unusual cleavage of a C–C bond for the biosynthesis of non-proteinogenic amino acids.
- Guannan Zhong
- , Qunfei Zhao
- & Wen Liu
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Article
| Open AccessAn L-threonine transaldolase is required for L-threo-β-hydroxy-α-amino acid assembly during obafluorin biosynthesis
Obafluorin is a β-lactone antibiotic produced byPseudomonas fluorescens. Here the authors present the biosynthetic gene cluster and biosynthetic pathway of obafluorin, which is characterized by a central transaldolase step catalysed by a rare L-threonine transaldolase.
- Thomas A. Scott
- , Daniel Heine
- & Barrie Wilkinson
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Article
| Open AccessCryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification
The biosynthesis of xiamycin, an antimicrobial bacterial indolosesquiterpenoid, involves an unusual cyclization cascade. Here, the authors characterise the XiaF enzyme, which resembles xenobiont-degrading enzymes and is responsible for a hidden indole hydroxylation step that triggers the cyclization reaction.
- Susann Kugel
- , Martin Baunach
- & Christian Hertweck
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Article
| Open AccessDecoding and reprogramming fungal iterative nonribosomal peptide synthetases
Nonribosomal peptides are important bioactive molecules that are synthetized by enzymes containing several catalytic domains. Here the authors describe the catalytic mechanism of fungal nonribosomal peptide synthetases and present an approach to modify these enzymes to produce specific nonribosomal peptides.
- Dayu Yu
- , Fuchao Xu
- & Jixun Zhan
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Article
| Open AccessGlobal metabolic rewiring for improved CO2 fixation and chemical production in cyanobacteria
Cyanobacteria are promising biofactories to reduce atmospheric CO2 and convert it into chemicals. Here the authors engineer Synechococcus elongatus carbon metabolism to increase 2,3-butanediol production from glucose and CO2under light and dark conditions.
- Masahiro Kanno
- , Austin L. Carroll
- & Shota Atsumi
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Article
| Open AccessDissection of goadsporin biosynthesis by in vitro reconstitution leading to designer analogues expressed in vivo
Goadsporin is an antibacterial peptide highly customized by multiple post-translational modifying enzymes. Here, the authors dissect its biosynthetic pathway byin vitro reconstitution and use their insights to produce goadsporin analogues in vitro and in vivo.
- Taro Ozaki
- , Kona Yamashita
- & Hiroyasu Onaka
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Article
| Open AccessA crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units
Polyketides are typically assembled from a starter unit and malonyl- and/or methylmalonyl-CoA-derived extender units, but the macrolide antibiotics stambomycins incorporate non-standard alkylmalonyl-CoA extender units. Here, the authors describe the biosynthetic pathway responsible for this unusual synthesis.
- Lauren Ray
- , Timothy R. Valentic
- & Gregory L. Challis
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Article
| Open AccessNon-enzymatic pyridine ring formation in the biosynthesis of the rubrolone tropolone alkaloids
The biosynthesis of pyridine rings is still poorly understood. Here the authors propose a biosynthetic pathway for pyridine-containing rubrolones, which is characterized by a non-enzymatic condensation and cyclization of the pyridine moiety.
- Yijun Yan
- , Jing Yang
- & Sheng-Xiong Huang
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Article
| Open AccessEngineering biosynthesis of the anticancer alkaloid noscapine in yeast
Noscapine is a potential anticancer drug that is traditionally isolated from the opium poppy Papaver somniferum. Here, Li and Smolke reconstitute the noscapine gene cluster in Saccharomyces cerevisiae, to achieve the microbial production of noscapine and related pathway intermediates, and provide new insights into the biosynthesis of noscapine.
- Yanran Li
- & Christina D. Smolke
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Article
| Open AccessProduction of fatty acid-derived oleochemicals and biofuels by synthetic yeast cell factories
While yeast is an attractive alternative to bacteria for the production of biofuels it currently has low production yields. Here, the authors systematically engineer Saccharomyces cerevisiae for high-level production of fatty acids, alkanes and fatty alcohols, which are important fuel precursors.
- Yongjin J. Zhou
- , Nicolaas A. Buijs
- & Jens Nielsen
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Article
| Open AccessOrthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides
Bicyclic peptides can inhibit biological targets hard to address with small molecules. Here, the authors combine two orthogonal ring-closing reactions to produce bicyclic peptides with improved bioactivity thereby providing a strategy that can greatly improve the structural diversity of such peptides.
- Philipp M. Cromm
- , Sebastian Schaubach
- & Herbert Waldmann
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Article
| Open AccessA squalene synthase-like enzyme initiates production of tetraterpenoid hydrocarbons in Botryococcus braunii Race L
The green microalga Botryococcus braunii is a promising biofuel producer due to its ability to produce large amounts of hydrocarbon oils that can be converted into fuels. Here the authors implicate lycopaoctaene synthase, a squalene synthases-like enzyme, in the first step towards the biosynthesis of the C40 tetraterpenoid hydrocarbon lycopadiene.
- Hem R. Thapa
- , Mandar T. Naik
- & Timothy P. Devarenne
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Article
| Open AccessDiscovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway
Pathogenic microbes can often attach to surfaces and form biofilms that display increased antibiotic resistance. Here, the authors characterize the biosynthesis of a new class of natural products, the cahuitamycins, that inhibit formation of biofilms by the pathogenic bacterium Acinetobacter baumannii.
- Sung Ryeol Park
- , Ashootosh Tripathi
- & David H. Sherman
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Article
| Open AccessTotal biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli
Opiates—the gold standard for pain relief—are currently produced by extraction from opium poppies. Here the authors show that bacteria can serve as an efficient and flexible platform for the production of opiates by demonstrating the total synthesis of Thebaine and hydrocodone from stepwise fermentation in E. coli.
- Akira Nakagawa
- , Eitaro Matsumura
- & Hiromichi Minami
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Article
| Open AccessIntegrative genomic mining for enzyme function to enable engineering of a non-natural biosynthetic pathway
The modification of enzymes to generate desired compounds by non-natural pathways is a useful route for the production of commodity chemicals. Here, the authors show two approaches—genome mining and computational enzyme design—to generate higher alcohols from sugar.
- Wai Shun Mak
- , Stephen Tran
- & Justin B. Siegel
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Article
| Open AccessBiosynthesis of the mycotoxin tenuazonic acid by a fungal NRPS–PKS hybrid enzyme
Tenuazonic acid is a mycotoxin produced by various plant pathogenic fungi but its biosynthetic gene is unknown to date. Here, the authors identify the tenuazonic acid biosynthetic gene encoding a protein with a unique KS domain that conducts cyclization step for tenuazonic acid release in Magnaporthe oryzae.
- Choong-Soo Yun
- , Takayuki Motoyama
- & Hiroyuki Osada
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Article
| Open AccessA biosynthetic model of cytochrome c oxidase as an electrocatalyst for oxygen reduction
An artificial functional mimic of cytochrome coxidase is a long term research goal for the development of oxygen reduction electrocatalysts. Here, the authors use site directed mutants of myoglobin to develop an electrocatalyst for reducing oxygen to water under ambient conditions.
- Sohini Mukherjee
- , Arnab Mukherjee
- & Abhishek Dey
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Article
| Open AccessA novel thiol-reductase activity of Arabidopsis YUC6 confers drought tolerance independently of auxin biosynthesis
YUC6 is a flavin monooxygenase required for the synthesis of the plant hormone auxin. Chaet al. discover that in Arabidopsis, this enzyme also plays a role in combatting oxidative stress independently of auxin biosynthesis, by acting as a thiol-reductase.
- Joon-Yung Cha
- , Woe-Yeon Kim
- & Dae-Jin Yun
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Article
| Open AccessRefining the pathway of carbide insertion into the nitrogenase M-cluster
Carbide insertion plays a pivotal role in the biosynthesis of M-cluster, the cofactor of nitrogenase. Here the authors further define the pathway for interstitial carbide atom insertion, showing that the SAM-derived methyl group is transferred to a FeS precursor sulfur before hydrogen abstraction via an SN2-type reaction.
- Jared A. Wiig
- , Yilin Hu
- & Markus W. Ribbe