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| Open AccessTandem-biocatalysis reactors constructed by topological evolution of CaCO3 particles into hollow metal hydroxide spheres
Hollow inorganic spheres (HISs) hold potential in various technological areas including biocatalysis and biomedicine, but the harsh synthetic conditions have precluded the use of HISs in biological fields. Here, the authors report a biocompatible strategy for synthesizing metal hydroxide HISs that can function as tandem-biocatalytic reactors.
- Sang Yeong Han
- , Nayoung Kim
- & Insung S. Choi
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Article
| Open AccessLactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis
Currently the structure and biological function of Lactate Dehydrogenase D (LDHD) are unclear. Here the authors report the structure of LDHD bound with various ligands and show that LDHD is a general dehydrogenase for D-2-hydroxyacids with small to moderate-size hydrophobic moieties and investigate loss-of-function mutations that play an important role in D-lactic acidosis.
- Shan Jin
- , Xingchen Chen
- & Jianping Ding
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Article
| Open AccessStructural basis for the unique molecular properties of broad-range phospholipase C from Listeria monocytogenes
The bacterium Listeria monocytogenes possesses two major virulence factors, broad-range phospholipase C (LmPC-PLC) and the pore-forming toxin listeriolysin O (LLO). Here, authors perform structural and biochemical analysis of LmPC-PLC and show that unique structural features enable self-regulation of its enzymatic activity and positive synergy with the pore-forming toxin listeriolysin O.
- Nejc Petrišič
- , Maksimiljan Adamek
- & Marjetka Podobnik
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Article
| Open AccessMolecular mechanism of decision-making in glycosaminoglycan biosynthesis
Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.
- Douglas Sammon
- , Anja Krueger
- & Erhard Hohenester
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Article
| Open AccessStructure of full-length cobalamin-dependent methionine synthase and cofactor loading captured in crystallo
Methionine synthase (MS) harnesses B12 and flexibility to catalyze three different reactions on one protein. The full-length structure of MS yields insights into a protein that epitomizes controlled dynamics to dictate chemical outcome.
- Johnny Mendoza
- , Meredith Purchal
- & Markos Koutmos
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Article
| Open AccessTriepoxide formation by a flavin-dependent monooxygenase in monensin biosynthesis
MonCI, a flavin-dependent monooxygenase, transforms all three C = C groups in the polyene substrate into epoxides during monensin A biosynthesis. Here, the authors present the structural basis for this enzyme’s regio- and stereoselective epoxidation activity.
- Qian Wang
- , Ning Liu
- & Chu-Young Kim
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Article
| Open AccessAcetylation-dependent coupling between G6PD activity and apoptotic signaling
Lysine acetylation is highly prevalent in metabolic enzymes. Here, the authors highlight the diverse roles of acetylation and show that G6PD acetylation can activate/deactivate G6PD, and promote G6PD ubiquitylation and phosphorylation, its interaction with p53, and p53-dependent pro-apoptotic events.
- Fang Wu
- , Natali H. Muskat
- & Eyal Arbely
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Article
| Open AccessAutoantibody binding and unique enzyme-substrate intermediate conformation of human transglutaminase 3
Dermatitis herpetiformis, a skin manifestation of the gluten-sensitive condition celiac disease, is hallmarked by autoantibody production to transglutaminase 3. Here, the authors present the 3D-structures of an autoantibody bound to transglutaminase 3 with an inhibitor mimicking a gluten-peptide substrate.
- Julie Elisabeth Heggelund
- , Saykat Das
- & Ludvig M. Sollid
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Article
| Open AccessComputational remodeling of an enzyme conformational landscape for altered substrate selectivity
The ability to rationally remodel enzyme conformational landscapes to modify catalytic properties is limited. Here, the authors, using a computational procedure, redesign the conformational landscape of an aminotransferase to stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate.
- Antony D. St-Jacques
- , Joshua M. Rodriguez
- & Roberto A. Chica
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Article
| Open AccessCharacterization and structure-based protein engineering of a regiospecific saponin acetyltransferase from Astragalus membranaceus
Currently little is known about the acetylation on sugar moieties. Here the authors report a saponin acetyltransferase from Astragalus membranaceus, AmAT7-3, and utilise crystal structures and QM/MM computation to elucidate the catalytic mechanism: they generate mutants for specific site acetylation.
- Linlin Wang
- , Zhihui Jiang
- & Xue Qiao
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Article
| Open AccessStructure of the peroxisomal Pex1/Pex6 ATPase complex bound to a substrate
The AAA ATPase Pex1/Pex6 fuels the enzyme import across the peroxisomal membrane. Defects in either ATPase in humans result in severe disorders and early death. Here, the authors provide a detailed cryo-EM structures of the complex in the process of translocating an endogenous substate.
- Maximilian Rüttermann
- , Michelle Koci
- & Christos Gatsogiannis
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Article
| Open AccessMolecular basis for bacterial N-glycosylation by a soluble HMW1C-like N-glycosyltransferase
NGTs glycosylate asparagine residues in proteins, crucial for bacterial adhesion and pathogenicity. Here, the authors provide insights via crystallography and simulations, showing acceptor asparagine uses imidic form for catalysis and UDP-glucose phosphate group acts as general base.
- Beatriz Piniello
- , Javier Macías-León
- & Ramon Hurtado-Guerrero
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Article
| Open AccessStructural insights into functional properties of the oxidized form of cytochrome c oxidase
Using resonance Raman spectroscopy and serial femtosecond X-ray crystallography, the authors show the heme a3 iron and CuB in the resting oxidized form of Cytochrome c Oxidase are coordinated by a hydroxide ion and a water molecule, respectively.
- Izumi Ishigami
- , Raymond G. Sierra
- & Denis L. Rousseau
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Article
| Open AccessClass III hybrid cluster protein homodimeric architecture shows evolutionary relationship with Ni, Fe-carbon monoxide dehydrogenases
Here, the authors present an X-ray crystal structure of a class III hybrid cluster protein (HCP), structurally similar to Ni, Fe-carbon monoxide dehydrogenases (CODHs), enabling conclusions to be drawn regarding the structural evolution of HCP/CODH superfamily.
- Takashi Fujishiro
- & Kyosei Takaoka
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Article
| Open AccessThe H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease
SARS-CoV-2 main protease adapts a disulfide bonded inactive state to escape oxidative stress. Here, the authors report a crystal structure of an inactive conformation of the enzyme achieved through a H163A mutation, and the mechanistic details of conformational changes using atomistic simulations.
- Norman Tran
- , Sathish Dasari
- & Aravindhan Ganesan
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Article
| Open AccessMolecular architecture and electron transfer pathway of the Stn family transhydrogenase
Acetogenic bacteria deploy electron-bifurcating transhydrogenase for electron carrier adjustments in the ancient Wood-Ljungdahl pathway. Here, the authors report a cryo-EM structure of the Stn class transhydrogenase from the Sporomusa ovata and dissect its electron transfer pathway.
- Anuj Kumar
- , Florian Kremp
- & Jan M. Schuller
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Article
| Open AccessTailored photoenzymatic systems for selective reduction of aliphatic and aromatic nitro compounds fueled by light
The selective enzymatic reduction of nitroaliphatic and nitroaromatic compounds is challenging. Here, the authors report selective (sun)light-driven photoenzymatic reduction of a wide variety of nitro compounds to aliphatic amines and amino-, azoxy- and azo-aromatics using flavin-dependent nitroreductases and chlorophyll as photocatalyst
- Alejandro Prats Luján
- , Mohammad Faizan Bhat
- & Gerrit J. Poelarends
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Article
| Open AccessProgrammable RNA detection with CRISPR-Cas12a
Cas12a is widely used in diagnostic platforms. Here the authors show that Cas12a can be programmed to directly detect RNA substrates, this is due to the 3’-end of the crRNA tolerating both RNA and DNA substrates: they use this to report a method, SAHARA, to detect RNA sequences.
- Santosh R. Rananaware
- , Emma K. Vesco
- & Piyush K. Jain
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Article
| Open AccessO-methyltransferase-like enzyme catalyzed diazo installation in polyketide biosynthesis
Diazo compounds, such as kinamycin, are rare bioactive natural products whose assembly has been extensively studied, but the formation of the diazo group is elusive. Here, the authors report O-methyltransferase-like protein, AlpH, which is responsible for the l-glutamylhydrazine incorporation in kinamycin biosynthesis.
- Yuchun Zhao
- , Xiangyang Liu
- & Ming Jiang
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Article
| Open AccessElectrostatic interactions guide substrate recognition of the prokaryotic ubiquitin-like protein ligase PafA
Pupylation is the bacterial equivalent of ubiquitination. Here, the authors show selective binding of the Pup ligase PafA to substrates is driven by tertiary structure features rather than linear motifs and is achieved by a small number of electrostatic interactions, enabling quick adaption to new substrates.
- Matthias F. Block
- , Cyrille L. Delley
- & Eilika Weber-Ban
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Article
| Open AccessA synthetic cell-free 36-enzyme reaction system for vitamin B12 production
Adenosylcobalamin (AdoCbl) is an essential vitamin whose production is limited to bacterial fermentation. Here, the authors report an alternative method for the synthesis of AdoCbl based on a cell-free reaction system integrating more than 30 biocatalytic reactions to produce AdoCbl from 5-aminolevulinic acid.
- Qian Kang
- , Huan Fang
- & Dawei Zhang
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Article
| Open AccessCrystal structure and functional implications of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases
Here, the authors present structural and functional characterization of bacterial CD-NTases that synthesize cyclic dipyrimidines for phage resistance, revealing a (R/Q)xW motif dictating pyrimidine selection which suggests a sequential pathway for synthesizing 2’3’-cyclic di-UMP.
- Chia-Shin Yang
- , Tzu-Ping Ko
- & Yeh Chen
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Article
| Open AccessDeSUMOylation of a Verticillium dahliae enolase facilitates virulence by derepressing the expression of the effector VdSCP8
Verticillium dahliae, a soil-borne fungal pathogen, causes vascular wilt in a wide variety of economically important crops. This study reveals a sophisticated pathogenic mechanism of VdUlpB-deSUMOylated enolase to facilate fungal virulence by derepressing the expression of the effector VdSCP8.
- Xue-Ming Wu
- , Bo-Sen Zhang
- & Hui-Shan Guo
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Article
| Open AccessHigh resolution cryo-EM and crystallographic snapshots of the actinobacterial two-in-one 2-oxoglutarate dehydrogenase
The 2-oxoglutarate dehydrogenase complex (ODH) is a textbook example of multienzymatic machinery. Here, the authors report the structural and regulatory properties of the Actinobacterial enzyme OdhA, a fusion of two ODH components acting in a supercomplex with pyruvate dehydrogenase.
- Lu Yang
- , Tristan Wagner
- & Marco Bellinzoni
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Article
| Open AccessStructure and regulation of full-length human leucine-rich repeat kinase 1
Leucine-rich repeat kinase 1 (LRRK1) and its counterpart LRRK2 play crucial roles in regulating fundamental cellular processes. Here, the authors use cryo-EM to characterize the LRRK1 monomer and dimer, revealing interfaces that regulate kinase activity and structural differences to LRRK2.
- Riley D. Metcalfe
- , Juliana A. Martinez Fiesco
- & Ping Zhang
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Article
| Open AccessAuranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes
Decreased activity of the E1 ubiquitin-activating enzyme UBA1 can contribute to aging and diseases like Alzheimer’s and VEXAS syndrome. Here, the authors found that auranofin, a rheumatoid arthritis drug, can significantly boost UBA1 activity.
- Wenjing Yan
- , Yongwang Zhong
- & Shengyun Fang
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Article
| Open AccessCatalytic site flexibility facilitates the substrate and catalytic promiscuity of Vibrio dual lipase/transferase
Vibrio dual lipases/transferases are virulence-related enzymes, with both substrate and catalytic promiscuity. Wang et al reveal their prominent structural flexibility, proposing a catalytic site tuning mechanism underlying enzyme promiscuity.
- Chongyang Wang
- , Changshui Liu
- & Qingjun Ma
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Article
| Open AccessProteomics and constraint-based modelling reveal enzyme kinetic properties of Chlamydomonas reinhardtii on a genome scale
Closing a major gap in photosynthetic metabolic modelling, the authors provide over 500 estimates of in vivo enzyme catalytic rate in C. reinhardtii, which considerably improves predictions on how enzyme mass is allocated to different pathways.
- Marius Arend
- , David Zimmer
- & Zoran Nikoloski
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Article
| Open AccessStructure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism
MslH, encoded in the MS-271 biosynthetic gene cluster, catalyzes the epimerization at the Cα center of the MslA C-terminal Trp21, however, the detailed catalytic process was unknown. Here, the authors report MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold.
- Yu Nakashima
- , Atsushi Kawakami
- & Hiroyuki Morita
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Article
| Open AccessThe Ycf48 accessory factor occupies the site of the oxygen-evolving manganese cluster during photosystem II biogenesis
The Ycf48 accessory factor is important for the assembly and repair of the photosystem II (PSII) complex of oxygenic photosynthesis. Here, the authors show that Ycf48 occupies the binding site of the oxygen evolving Mn cluster early in PSII biogenesis.
- Ziyu Zhao
- , Irene Vercellino
- & Josef Komenda
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Article
| Open AccessDiscovery and rational engineering of PET hydrolase with both mesophilic and thermophilic PET hydrolase properties
Extensive research efforts have been directed towards the development of PET hydrolases with improved activity, but template enzymes used are limited. Here, the authors report a PET hydrolase from Cryptosporangium aurantiacum (CaPETase) that exhibits high thermostability and PET degradation activity at ambient temperatures and determine its crystal structure.
- Hwaseok Hong
- , Dongwoo Ki
- & Kyung-Jin Kim
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Article
| Open AccessStructural and functional fine mapping of cysteines in mammalian glutaredoxin reveal their differential oxidation susceptibility
Glutaredoxin (GLRX) is a key enzyme in redox regulation via oxidation of protein cysteines and its activity is disrupted in diverse human diseases. This study integrates molecular modeling and biochemical validation to provide insights into the mechanisms of oxidative inactivation of GLRX.
- Elizabeth M. Corteselli
- , Mona Sharafi
- & Yvonne M. W. Janssen-Heininger
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Article
| Open AccessA small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity
Here, the authors demonstrate that inhibition of PTP1B and PTPN2 in tumor cells and T-cells with a small molecule inhibitor represses the growth of immunogenic and cold tumors, and enhances response to anti-PD-1 immunotherapy without promoting immune-related toxicities.
- Shuwei Liang
- , Eric Tran
- & Tony Tiganis
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Article
| Open AccessThe Gram-positive bacterium Romboutsia ilealis harbors a polysaccharide synthase that can produce (1,3;1,4)-β-d-glucans
(1,3;1,4)-β-d-Glucans are widely distributed in many organisms, but little is known about the enzymes responsible for their synthesis outside the grasses. Here, the authors report on the presence of (1,3;1,4)-β-d-glucans in the exopolysaccharides of the Gram-positive bacterium Romboutsia ilealis and identify and characterize the (1,3;1,4)-β-d-glucan synthase RiGT2.
- Shu-Chieh Chang
- , Mu-Rong Kao
- & Yves S. Y. Hsieh
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Article
| Open AccessRAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles
In this study, the authors present structures and functional analyses for the RAD51C-XRCC3 tumor suppressor complex, providing insights into recurrent mutations in cancer and Fanconi Anemia patients that uncover distinct DNA replication fork protection, restart and reversal regions.
- Michael A. Longo
- , Sunetra Roy
- & Katharina Schlacher
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Article
| Open AccessArchitecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair
B12-dependent human methylmalonly-CoA mutase (MMUT) requires the chaperone MMAA. The authors report the crystal structure of MMUT-MMAA, which shows a MMAA-driven conformational change in MMUT involved n B12 loading and repair and helps explain the effects of disease-causing MMAA-MMUT interface mutations.
- Romila Mascarenhas
- , Markus Ruetz
- & Ruma Banerjee
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Article
| Open AccessDistinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement
In a study looking to examine the functional significance of glutamine synthetase (GS), the authors show that in Plasmodium, GS has evolved as a distinct type I enzyme with unique biochemical and structural features that complement the parasite niche.
- Sourav Ghosh
- , Rajib Kundu
- & Viswanathan Arun Nagaraj
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Article
| Open AccessDiscovery and mechanism-guided engineering of BHET hydrolases for improved PET recycling and upcycling
The degradation of PET using PETase enzymes has great potential but can face problems with incomplete degradation. Here, the authors identified two BHETases from the environment and engineered them to improve their hydrolysis efficiency for applications in dual-enzyme PET recycling and tandem chemical-enzymatic PET upcycling systems.
- Anni Li
- , Yijie Sheng
- & He Huang
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Article
| Open AccessTurnover number predictions for kinetically uncharacterized enzymes using machine and deep learning
The turnover numbers of most enzyme-catalyzed reactions are unknown. Kroll et al. developed a general model that can predict turnover numbers even for enzymes dissimilar to those used for training, outperforming existing models.
- Alexander Kroll
- , Yvan Rousset
- & Martin J. Lercher
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| Open AccessLimited choice of natural amino acids as mimetics restricts design of protein lysine methylation studies
Protein lysine methylation plays important biological roles but its experimental characterization is limited by the lack of suitable mimetics of methylated and unmethylated lysine among the natural amino acids. Here, we summarize the consequent challenges and discuss alternative approaches for biochemical and cellular lysine methylation studies.
- Sara Weirich
- & Albert Jeltsch
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Article
| Open AccessA cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis
Digoxin is a heart medicine extracted from plants, but how plants synthesize it is largely unknown. Here Carroll et al. identify a novel enzyme for digoxin biosynthesis, paving the way to produce digoxin and other structurally similar drugs in microbes.
- Emily Carroll
- , Baradwaj Ravi Gopal
- & Zhen Q. Wang
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Article
| Open AccessThe structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase
Hypophosphatasia (HPP) is a bone disease caused by mutations in tissue non-specific alkaline phosphatase (TNAP). Here, authors solved the crystal and cryoEM structures of TNAP, shedding light on the molecular mechanisms underlying HPP.
- Yating Yu
- , Kewei Rong
- & An Qin
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Article
| Open AccessMolecular mechanism of plasmid-borne resistance to sulfonamide antibiotics
Bacterial resistance to sulfonamide antibiotics (sulfas) is mediated by acquisition of sul genes, which encode sulfa-insensitive versions of the target enzyme, dihydropteroate synthase. Here, Venkatesan et al. study Sul enzymes using biochemical, structural, mutational and functional analyses, revealing the molecular basis for Sul-mediated drug resistance.
- Meenakshi Venkatesan
- , Michael Fruci
- & Alexei Savchenko
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Article
| Open AccessDprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
Pretomanid and delamanid are pro-drugs used for the treatment of tuberculosis, but their precise mechanisms of action are unclear. Here, the authors identify an enzyme required for the synthesis of the mycobacterial cell wall as a molecular target of the activated drugs.
- Katherine A. Abrahams
- , Sarah M. Batt
- & Gurdyal S. Besra
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Article
| Open AccessAn unnatural enzyme with endonuclease activity towards small non-coding RNAs
Endonucleases play crucial roles in various biological processes but endonucleases that target small non-coding RNAs have not been reported. Here, the authors combined the metal binding non-canonical amino acid BpyAla and a high affinity binder to engineer a catalyst that degrades small non-coding RNAs.
- Noreen Ahmed
- , Nadine Ahmed
- & John Paul Pezacki
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Article
| Open AccessDiscovery of extended product structural space of the fungal dioxygenase AsqJ
The fungal dioxygenase AsqJ catalyses the conversion of benzo[1,4]diazepine-2,5-diones into quinolone antibiotics, and can also catalyse the production of quinazolinones. Here, the authors perform comprehensive substrate promiscuity mapping of AsqJ revealing its large tolerance towards various substrates, giving biocatalytic access to a plethora of biomedically valuable heterocyclic frameworks.
- Manuel Einsiedler
- & Tobias A. M. Gulder
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Article
| Open AccessStructural insight into the human SID1 transmembrane family member 2 reveals its lipid hydrolytic activity
The SID-1 family is a putative channel/transporter for transporting nucleic acids. Here, Qian et al. report the dimeric structure of human SIDT2 suggesting that it may act as a transporter but not a channel. In addition, it has a ceramidase activity.
- Dandan Qian
- , Ye Cong
- & Deshun Gong
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Article
| Open AccessA polyamine acetyltransferase regulates the motility and biofilm formation of Acinetobacter baumannii
Acinetobacter baumanii has an uncharacterized surface-associated motility which is a feature of its persistence. Here, Armalytė et al identify an acetyltransferase that affects this motility and present a functional and structural characterisation of it
- Julija Armalytė
- , Albinas Čepauskas
- & Dukas Jurėnas
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Article
| Open AccessThe structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification
Wang et al. report a structure for human MBOAT7, the enzyme responsible for remodeling acyl chains of phosphatidylinositol. The structure enabled the identification of MBOAT7 inhibitors and provides insights into substrate specificity among MBOATs.
- Kun Wang
- , Chia-Wei Lee
- & Robert V. Farese Jr