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| Open AccessBile salt hydrolase catalyses formation of amine-conjugated bile acids
We find that bile salt hydrolase N-acyltransferase activity can form bacterial bile acid amidates that are positively correlated with the colonization of gut bacteria that assist in the regulation of the bile acid metabolic network.
- Bipin Rimal
- , Stephanie L. Collins
- & Andrew D. Patterson
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Bile salt hydrolase acyltransferase activity expands bile acid diversity
Acyltransferase activity of the enzyme bile salt hydrolase is identified and shown to mediate microbial bile acid conjugation, diversifying the bile acid pool and expanding their role in gut physiology.
- Douglas V. Guzior
- , Maxwell Okros
- & Robert A. Quinn
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Article |
A light-driven enzymatic enantioselective radical acylation
Enzyme-bound ketyl radicals derived from thiamine diphosphate are selectively generated through single-electron oxidation by a photoexcited organic dye and shown to lead to enantioselective radical acylation reactions.
- Yuanyuan Xu
- , Hongwei Chen
- & Xiaoqiang Huang
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Article
| Open AccessPlant carbonic anhydrase-like enzymes in neuroactive alkaloid biosynthesis
We show how neuroactive alkaloids from clubmosses are biosynthesized, which reveals an unexpected role for carbonic anhydrase-like enzymes in alkaloid scaffold formation.
- Ryan S. Nett
- , Yaereen Dho
- & Elizabeth S. Sattely
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Matters Arising |
DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition
- Eikan Mishima
- , Toshitaka Nakamura
- & Marcus Conrad
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Article
| Open AccessPhase separation of FSP1 promotes ferroptosis
An inhibitor of the ferroptosis-suppressing FSP1 induces phase separation of FSP1, thereby impairing its function and reducing tumour growth.
- Toshitaka Nakamura
- , Clara Hipp
- & Marcus Conrad
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Article
| Open AccessGenome expansion by a CRISPR trimmer-integrase
CRISPR systems lacking Cas4 can use fused or recruited exonucleases for faithful acquisition of new CRISPR immune sequences.
- Joy Y. Wang
- , Owen T. Tuck
- & Jennifer A. Doudna
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Article
| Open AccessDe novo design of luciferases using deep learning
A deep-learning-based strategy is used to design artificial luciferases that catalyse the oxidative chemiluminescence of diphenylterazine with high substrate specificity and catalytic efficiency.
- Andy Hsien-Wei Yeh
- , Christoffer Norn
- & David Baker
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Structural basis of regulated m7G tRNA modification by METTL1–WDR4
Structures of the human METTL1–WDR4 complex are revealed, providing molecular insights into substrate recognition, modification and catalytic regulation by the N7-methylguanosine methyltransferase complex.
- Jiazhi Li
- , Longfei Wang
- & Richard I. Gregory
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Article
| Open AccessStructural basis of tankyrase activation by polymerization
Structural insights into the poly-ADP-ribosyltransferase tankyrase reveal its filamentous architecture and illustrate how assembly controls catalytic and non-catalytic functions.
- Nisha Pillay
- , Laura Mariotti
- & Sebastian Guettler
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Article
| Open AccessStructural basis for directional chitin biosynthesis
Using cryo-electron microscopy, the directional multiple step mechanism of chitin biosynthesis is revealed.
- Wei Chen
- , Peng Cao
- & Qing Yang
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Plant receptor-like protein activation by a microbial glycoside hydrolase
A structural analysis focusing on plant immunity reveals how LRR-containing receptor-like proteins recognize pathogenic ligands and consequently become activated, with the data suggesting that these proteins target pathogens through two different mechanisms.
- Yue Sun
- , Yan Wang
- & Jijie Chai
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Biosynthesis of selenium-containing small molecules in diverse microorganisms
Using genome mining, a dedicated pathway for the production of selenosugars and selenoneine is uncovered, thereby expanding the use of biological selenium.
- Chase M. Kayrouz
- , Jonathan Huang
- & Mohammad R. Seyedsayamdost
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Structure of dynein–dynactin on microtubules shows tandem adaptor binding
The structure of the complete dynein–dynactin complex and its interaction with microtubules and cargo adaptors are visualized using cryo-electron microscopy.
- Sami Chaaban
- & Andrew P. Carter
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Article
| Open AccessCryo-EM structure of an active bacterial TIR–STING filament complex
Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined.
- Benjamin R. Morehouse
- , Matthew C. J. Yip
- & Philip J. Kranzusch
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Membrane-anchored HDCR nanowires drive hydrogen-powered CO2 fixation
The cryo-electron microscopy structure of the filamentous hydrogen-dependent CO2 reductase (HDCR) enzyme from Thermoanaerobacter kivui, together with enzymatic analysis and in situ cryo-electron tomography, provides insight into the high catalytic activity of HDCR.
- Helge M. Dietrich
- , Ricardo D. Righetto
- & Jan M. Schuller
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Structure of Tetrahymena telomerase-bound CST with polymerase α-primase
Cryo-electron microscopy structures of Tetrahymena thermophila telomerase-bound Ctc1–Stn1–Ten1 and DNA polymerase α–primase provide insights into the molecular mechanisms underlying telomere replication and maintenance.
- Yao He
- , He Song
- & Juli Feigon
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Article
| Open AccessStructural basis for SHOC2 modulation of RAS signalling
Cryo-electron microscopy structure, molecular dynamics and biochemical analyses of the SHOC2–PP1C–MRAS complex demonstrate the dependence of the complex formation on RAS–GTP and identify the determinants of RAS isoform preference for SHOC2–PP1C and specificity of the complex for RAF dephosphorylation.
- Nicholas P. D. Liau
- , Matthew C. Johnson
- & Jawahar Sudhamsu
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An exercise-inducible metabolite that suppresses feeding and obesity
A newly identified exercise-induced signalling metabolite—an amidated conjugate of lactate and phenylalanine—can reduce food intake and improve blood glucose homeostasis.
- Veronica L. Li
- , Yang He
- & Jonathan Z. Long
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Article
| Open AccessOrganocatalytic stereoselective cyanosilylation of small ketones
The development of confined organocatalysts for the enantioselective cyanosilylation of small, unbiased substrates, including 2-butanone, is shown to lead to catalysts that are as selective as enzymes, with excellent levels of control.
- Hui Zhou
- , Yu Zhou
- & Benjamin List
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Article
| Open AccessPhage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity
A study using a biochemical screen of 57 phages in two bacterial species identifies and characterizes proteins enabling phages to evade CBASS and Pycsar immune systems, and describes the mechanisms involved.
- Samuel J. Hobbs
- , Tanita Wein
- & Philip J. Kranzusch
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Multifunctional biocatalyst for conjugate reduction and reductive amination
A biocatalytic enzyme originating from bacteria, EneIRED, facilitates amine-activated conjugate alkene reduction followed by reductive amination, efficiently preparing chiral amine diastereomers, which are commonly used in pharmaceuticals and agrochemicals.
- Thomas W. Thorpe
- , James R. Marshall
- & Nicholas J. Turner
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Discovery of a Ni2+-dependent guanidine hydrolase in bacteria
A bacterial enzyme is characterized and demonstrated to have Ni2+-dependent activity and high specificity for free guanidine enabling the bacteria to use guanidine as the sole nitrogen source for growth.
- D. Funck
- , M. Sinn
- & J. S. Hartig
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Structure determination of high-energy states in a dynamic protein ensemble
Combining NMR spectroscopy-derived pseudocontact shifts (PCSs) with Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion enables protein structure determination of lowly populated high-energy states that are essential for macromolecular function.
- John B. Stiller
- , Renee Otten
- & Dorothee Kern
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| Open AccessMechanism-based traps enable protease and hydrolase substrate discovery
Light-activated trapping is used in a mechanism-based assay to capture and identify substrates of protein hydrolases.
- Shan Tang
- , Adam T. Beattie
- & Jason W. Chin
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β-NAD as a building block in natural product biosynthesis
β-Nicotinamide adenine dinucleotide is used as a building block in secondary metabolite biosynthetic pathways for a novel class of natural products.
- Lena Barra
- , Takayoshi Awakawa
- & Ikuro Abe
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A single sulfatase is required to access colonic mucin by a gut bacterium
A single sulfatase produced by a bacterium found in the human colon is essential for degradation of sulfated O-glycans in secreted mucus.
- Ana S. Luis
- , Chunsheng Jin
- & Eric C. Martens
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Mechanism for Cas4-assisted directional spacer acquisition in CRISPR–Cas
Structures of the Cas4–Cas1–Cas2 complex from Geobacter sulfurreducens show that a 3′-overhang in the protospacer adjacent motif is required for complex assembly and spacer insertion into the CRISPR array.
- Chunyi Hu
- , Cristóbal Almendros
- & Ailong Ke
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The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway
18O2 labelling is used to identify metabolites in human cells that incorporate gaseous oxygen, including 4-hydroxymandelate, an intermediate in the synthesis of the coenzyme Q10 head group.
- Robert S. Banh
- , Esther S. Kim
- & Michael E. Pacold
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Molecular basis for DarT ADP-ribosylation of a DNA base
Structural and mechanistic data of the ADP-ribosyltransferase DarT demonstrate the role of ADP-ribosylation of DNA by this enzyme in generating toxicity and regulating cellular signalling processes in bacteria.
- Marion Schuller
- , Rachel E. Butler
- & Ivan Ahel
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Discovery, characterization and engineering of ligases for amide synthesis
A family of enzymes—coronafacic acid ligases, involved in the synthesis of bacterial phytotoxins—are found to catalyse amide bond formation with a wide range of substrates.
- Michael Winn
- , Michael Rowlinson
- & Jason Micklefield
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Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine
Tissue nonspecific alkaline phosphatase (TNAP) within mitochondria hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation in thermogenic fat cells.
- Yizhi Sun
- , Janane F. Rahbani
- & Bruce M. Spiegelman
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High CO2 levels drive the TCA cycle backwards towards autotrophy
In the deltaproteobacterium Hippea maritima, the tricarboxylic acid (TCA) cycle can be reversed by high partial pressures of CO2 for the autotrophic fixation of carbon.
- Lydia Steffens
- , Eugenio Pettinato
- & Ivan A. Berg
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A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis
The dynamic and reversible S-palmitoylation of the transcription factor STAT3 enhances its activation and promotes the differentiation of TH17 cells.
- Mingming Zhang
- , Lixing Zhou
- & Hening Lin
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Bridging of DNA breaks activates PARP2–HPF1 to modify chromatin
The PARP2–HPF1 histone-modifying complex bridges two nucleosomes to align broken DNA ends for ligation, initiating conformational changes that activate PARP2 and enable DNA damage repair.
- Silvija Bilokapic
- , Marcin J. Suskiewicz
- & Mario Halic
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Structural basis for the action of the drug trametinib at KSR-bound MEK
Crystal structures of the MEK kinase bound to the scaffold protein KSR and various MEK inhibitors, including the anti-cancer drug trametinib, reveal the molecular and functional mechanisms behind MEK inhibition.
- Zaigham M. Khan
- , Alexander M. Real
- & Arvin C. Dar
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Structures of fungal and plant acetohydroxyacid synthases
Structures of the acetohydroxyacid synthase complexes of Saccharomyces cerevisiae and Arabidopsis thaliana provide insights into the biosynthesis of and feedback inhibition by branched-chain amino acids.
- Thierry Lonhienne
- , Yu Shang Low
- & Luke W. Guddat
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Envelope protein ubiquitination drives entry and pathogenesis of Zika virus
The E3 ubiquitin ligase TRIM7 polyubiquitinates the envelope protein of Zika virus, adding Lys63-linked polyubiquitin chains that interact with the TIM1 receptor of host cells to enhance virus entry and replication.
- Maria I. Giraldo
- , Hongjie Xia
- & Ricardo Rajsbaum
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Structure of replicating SARS-CoV-2 polymerase
A cryo-electron microscopy structure of the RNA-dependent RNA polymerase of SARS-CoV-2 sheds light on coronavirus replication and enables the analysis of the inhibitory mechanisms of candidate antiviral drugs.
- Hauke S. Hillen
- , Goran Kokic
- & Patrick Cramer
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Structure and mechanism of human diacylglycerol O-acyltransferase 1
The structure of human diacylglycerol O-acyltransferase 1, a membrane protein that synthesizes triacylglycerides, is solved with cryo-electron microscopy, providing insight into its function and mechanism of enzymatic activity.
- Lie Wang
- , Hongwu Qian
- & Ming Zhou
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Structural basis for catalysis and substrate specificity of human ACAT1
The structure of human ACAT1, which catalyses the transfer of an acyl group from acyl-coenzyme A to cholesterol to form cholesteryl ester, is resolved by cryo-electron microscopy.
- Hongwu Qian
- , Xin Zhao
- & Nieng Yan
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Structure of nevanimibe-bound tetrameric human ACAT1
The structure of human ACAT1 in complex with the inhibitor nevanimibe is resolved by cryo-electron microscopy.
- Tao Long
- , Yingyuan Sun
- & Xiaochun Li
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The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis
Phosphorylation of INSIG1 and INSIG2 by PCK1 leads to a reduction in the binding of sterols, the activation of SREBP1 and SREBP2 and the downstream transcription of lipogenesis-associated genes that promote tumour growth.
- Daqian Xu
- , Zheng Wang
- & Zhimin Lu
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An anti-CRISPR viral ring nuclease subverts type III CRISPR immunity
Bacteria and archaea use cyclic oligoadenylate molecules as part of the CRISPR system for antiviral defence; here, a family of viral enzymes that rapidly degrades cyclic oligoadenylates is identified and biochemically and structurally described.
- Januka S. Athukoralage
- , Stephen A. McMahon
- & Malcolm F. White
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Marine Proteobacteria metabolize glycolate via the β-hydroxyaspartate cycle
Marine Proteobacteria use the β-hydroxyaspartate cycle to assimilate glycolate, which is secreted by algae on a petagram scale, providing evidence of a previously undescribed trophic interaction between autotrophic phytoplankton and heterotrophic bacterioplankton.
- Lennart Schada von Borzyskowski
- , Francesca Severi
- & Tobias J. Erb
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Structural insights into the mechanism of human soluble guanylate cyclase
Cryo-electron microscopy structures of human soluble guanylate cyclase in inactive and activated states shed light on the activation mechanism of this enzyme by nitric oxide.
- Yunlu Kang
- , Rui Liu
- & Lei Chen
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Letter |
Lysine harvesting is an antioxidant strategy and triggers underground polyamine metabolism
The harvest of large quantities of lysine by yeast and other microbes triggers a reprogramming of redox metabolism, in which NADPH is channelled into glutathione metabolism to reduce levels of reactive oxygen species and increase tolerance to oxidative stress.
- Viridiana Olin-Sandoval
- , Jason Shu Lim Yu
- & Markus Ralser
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Letter |
Design and evolution of an enzyme with a non-canonical organocatalytic mechanism
A hydrolytic enzyme with a non-canonical organocatalytic mechanism was generated by introducing Nδ-methylhistidine into a designed active site using engineered translation components, allowing optimization of enzyme performance using laboratory evolution.
- Ashleigh J. Burke
- , Sarah L. Lovelock
- & Anthony P. Green
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Transposon molecular domestication and the evolution of the RAG recombinase
Identification of the changes that converted a transposase to a recombinase sheds light on the evolution of the vertebrate adaptive immune system.
- Yuhang Zhang
- , Tat Cheung Cheng
- & David G. Schatz