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| Open AccessProteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase
Protein ADP-ribosylation has emerged as a key post translational modification that regulates several stress responses. Here the authors characterize ARH3 as a major serine-specific mono–ADP-ribosylhydrolase and use a proteomics approach to identify the cellular targets of ARH3.
- Jeannette Abplanalp
- , Mario Leutert
- & Michael O. Hottiger
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Article
| Open AccessCharacterization of a membrane-bound C-glucosyltransferase responsible for carminic acid biosynthesis in Dactylopius coccus Costa
Carminic acid is a widely applied red colorant that is still harvested from insects because its biosynthesis is not fully understood. Here, the authors identify and characterize a membrane-bound C-glucosyltransferase catalyzing the final step during carminic acid biosynthesis.
- Rubini Kannangara
- , Lina Siukstaite
- & Birger Lindberg Møller
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Article
| Open AccessCoupling of Polo kinase activation to nuclear localization by a bifunctional NLS is required during mitotic entry
Drosophila Polo kinase is the founding member of the Polo-Like Kinase (PLK) family and a master regulator of mitosis and cytokinesis. Here the authors uncover a molecular mechanism for the spatiotemporal regulation of Polo kinase during mitotic entry through a phosphorylation event that triggers nuclear import.
- David Kachaner
- , Damien Garrido
- & Vincent Archambault
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Article
| Open AccessReassessment of chitosanase substrate specificities and classification
Chitosanases are classified according to their specificity in cleaving bonds at GlcNAc residues but the current system may be too simplistic. Here, the authors use quantitative mass spectrometry to revisit chitosanase specificity and propose additional determinants for their classification.
- Tobias Weikert
- , Anna Niehues
- & Bruno M. Moerschbacher
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Article
| Open AccessCarrageenan catabolism is encoded by a complex regulon in marine heterotrophic bacteria
Carrageenans, major cell wall polysaccharides of red macroalgae, are metabolised by marine heterotrophic bacteria through unclear mechanisms. Here, the authors identify an unusual polysaccharide-utilization locus encoding carrageenan catabolism in a marine bacterium, and characterise the complete pathway.
- Elizabeth Ficko-Blean
- , Aurélie Préchoux
- & Gurvan Michel
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Article
| Open AccessA comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
The NUDIX hydrolases are known to be involved in several cellular processes and diseases, such as cancer, but remain poorly characterized as a family. Here, the authors provide a comprehensive analysis of the structural, biochemical, and expression properties of 18 human NUDIX proteins, and begin to address their functional inter-relationships.
- Jordi Carreras-Puigvert
- , Marinka Zitnik
- & Thomas Helleday
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Article
| Open AccessCrystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features
Sirtuins are NAD+-dependent protein lysine deacylases that act as metabolic regulators and are linked to aging-related diseases. Here the authors present the Sirt4 crystal structure and show that the enzyme has dehydroxymethylglutarylation activity and is regulated by NADH.
- Martin Pannek
- , Zeljko Simic
- & Clemens Steegborn
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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 AccessINA complex liaises the F1Fo-ATP synthase membrane motor modules
The inner membrane assembly complex (INAC) interacts with components of the F1F0-ATP synthase but its function remains unclear. Here the authors show that INAC associates with two distinct complexes during F1F0-ATP synthase formation, which points towards a safeguarding role during proton-conducting channel assembly.
- Nataliia Naumenko
- , Marcel Morgenstern
- & Peter Rehling
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Article
| Open AccessStructural and electronic determinants of lytic polysaccharide monooxygenase reactivity on polysaccharide substrates
Copper-dependent lytic polysaccharide monooxygenases (LPMOs) oxidatively cleave polysaccharides. Here the authors present a structure-function characterization of fungal LPMOs, showing that a particular LPMO cleaves xylan using a mechanism that involves an alternative copper coordination geometry.
- T. J. Simmons
- , K. E. H. Frandsen
- & P. Dupree
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Article
| Open AccessNOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance
NADPH oxidase NOX4 has been linked to poor cancer survival. Here the authors show that NOX4 regulates drug resistance in renal cancer carcinoma by regulating PKM2 and that NOX4 activity is allosterically activated by reduced mitochondrial ATP levels thus coupling energy metabolism to drug resistance.
- Karthigayan Shanmugasundaram
- , Bijaya K. Nayak
- & Karen Block
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Article
| Open AccessControl of enzyme reactions by a reconfigurable DNA nanovault
DNA nanostructures can cage enzymes but currently fall short of controlling their reactions with substrates. Here, the authors enclose an enzyme inside a dynamic DNA vault, which regulates its access to substrate molecules—and thus its enzymatic activity—through a multi-lock mechanism.
- Guido Grossi
- , Mette Dalgaard Ebbesen Jepsen
- & Ebbe Sloth Andersen
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Article
| Open AccessA homologue of the Parkinson’s disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover
The Parkinson’s disease‐associated LRRK2 protein is a multidomain Roco protein with GTPase activity. Here the authors use a multidisciplinary approach to characterize the GTPase mechanism of a homologous bacterial Roco protein and give mechanistic insights into disease-causing LRRK2 mutations.
- Egon Deyaert
- , Lina Wauters
- & Wim Versées
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Article
| Open AccessMRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells
BRCA proteins have emerged as key stabilizing factors for the maintenance of replication forks following replication stress. Here the authors describe how reversed replication forks are degraded in the absence of BRCA2, and a MUS81 and POLD3-dependent mechanism of rescue following the withdrawal of genotoxic agent.
- Delphine Lemaçon
- , Jessica Jackson
- & Alessandro Vindigni
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Article
| Open AccessSingle-molecule study of oxidative enzymatic deconstruction of cellulose
Understanding the role of enzymes in biomass depolymerization is essential for the development of more efficient biorefineries. Here, the authors show by atomic force microscopy the real-time mechanism of cellulose deconstruction by lytic polysaccharide monooxygenases.
- Manuel Eibinger
- , Jürgen Sattelkow
- & Bernd Nidetzky
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Article
| Open AccessOligomerization-primed coiled-coil domain interaction with Ubc13 confers processivity to TRAF6 ubiquitin ligase activity
Ubiquitin ligase TRAF6 catalyzes assembly of free polyubiquitin chains for TAK1 activation in the IL-1R/TLR pathways, but the mechanism underlying its processivity is unclear. Here, the authors show that TRAF6 coiled-coil oligomerization domain primes its interaction with Ubc13/Ub~Ubc13 to confer processivity.
- Lin Hu
- , Jiafeng Xu
- & Zongping Xia
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Article
| Open AccessThe autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
AMPK is involved in sensing of metabolic stress. The authors show that the autophagy initiator ULK1 phosphorylates β1-Ser108 on the regulatory β1-subunit, sensitizing AMPK to allosteric drugs, and activates signaling pathways that appear independent of Thr172 phosphorylation in the kinase activation loop.
- Toby A. Dite
- , Naomi X. Y. Ling
- & Jonathan S. Oakhill
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Article
| Open AccessEngineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors
A major drawback in the clinical use of the oral anticoagulants that directly inhibit factor Xa in order to prevent blood clot formation is the potential for life threatening bleeding events. Here the authors describe factor Xa variants that are refractory to inhibition by these anticoagulants and could serve as rescue agents in treated patients.
- Daniël Verhoef
- , Koen M. Visscher
- & Mettine H. A. Bos
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Article
| Open Accessp190RhoGAP proteins contain pseudoGTPase domains
A growing number of ‘pseudoenzymes’ with a regulatory role in signal transduction processes but without catalytic activity are being identified. Here, the authors identify two pseudoGTPase domains in p190RhoGAP, characterize them biochemically and structurally and show that they influence RhoGAP activity.
- Amy L. Stiegler
- & Titus J. Boggon
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Article
| Open AccessConstruction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme
Catalytic mechanisms of enzymes are well understood, but achieving diverse reaction chemistries in re-engineered proteins can be difficult. Here the authors show a highly efficient and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H2O2.
- Daniel W. Watkins
- , Jonathan M. X. Jenkins
- & J. L. Ross Anderson
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Article
| Open AccessUncoupling conformational states from activity in an allosteric enzyme
Active and inactive state ATP-phosphoribosyltransferases (ATP-PRTs) are believed to have different conformations. Here the authors show that in both states, ATP-PRT has a similar structural arrangement, suggesting that dynamic alterations are involved in ATP-PRT regulation by allosteric modulators.
- João P. Pisco
- , Cesira de Chiara
- & Luiz Pedro S. de Carvalho
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Article
| Open AccessCrystal structure of a Pseudomonas malonate decarboxylase holoenzyme hetero-tetramer
Some aerobic bacteria contain a biotin-independent malonate decarboxylase (MDC), which allows them to use malonate as the sole carbon source. Here, the authors present the crystal structure of a Pseudomonas MDC and give insights into its catalytic mechanism and function.
- Riyaz Maderbocus
- , Blanche L. Fields
- & Liang Tong
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Article
| Open AccessStructural basis for dolichylphosphate mannose biosynthesis
The generation of glycolipid dolichylphosphate mannose (Dol-P-Man) is a critical step for protein glycosylation and GPI anchor synthesis. Here the authors report the structure of dolichylphosphate mannose synthase in complex with bound nucleotide and donor to provide insight into the mechanism of Dol-P-Man synthesis.
- Rosaria Gandini
- , Tom Reichenbach
- & Christina Divne
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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 AccessThe structural and functional characterization of human RecQ4 reveals insights into its helicase mechanism
RecQ helicases are important for maintaining genomic integrity. Here, the authors present functional data and the crystal structure of human RecQ4, which exerts a helicase mechanism that may be more closely related to bacterial RecQ helicases than to its human family members.
- Sebastian Kaiser
- , Florian Sauer
- & Caroline Kisker
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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 AccessA synthetic biochemistry platform for cell free production of monoterpenes from glucose
Terpenes are bioactive natural products derived from plants with several commercial applications. Here, the authors engineer a cell-free system composed of 27 enzymes that convert glucose into terpenes, highlighting the potential of synthetic biochemistry approaches for biocompounds production.
- Tyler P. Korman
- , Paul H. Opgenorth
- & James U. Bowie
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Article
| Open AccessGlobal mapping of CARM1 substrates defines enzyme specificity and substrate recognition
Arginine methylation is an abundant post-translational modification catalysed by protein arginine methyltransferases (PRMTs). Here the authors use quantitative mass spectrometry to globally profile the substrates of the PRMT CARM1 in breast cancer cells, and establish a role for CARM1’s N-terminus in substrate recognition.
- Evgenia Shishkova
- , Hao Zeng
- & Wei Xu
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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 AccessSignal recognition particle prevents N-terminal processing of bacterial membrane proteins
Bacterial proteins are synthesized with formyl-methionine in their N-terminus, but most of them are co-translationally deformylated. Here, the authors show that inner-membrane proteins are protected from deformylation by the binding of the signal recognition particle (SRP) during translation.
- Amitabh Ranjan
- , Evan Mercier
- & Wolfgang Wintermeyer
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Article
| Open AccessHistone deacetylase 10 structure and molecular function as a polyamine deacetylase
Polyamines bind to nucleic acids and their function is regulated by reversible acetylation. Here, the authors show that histone deacetylase 10 is a polyamine deacetylase and present its crystal structure with a bound polyamine transition state analogue inhibitor.
- Yang Hai
- , Stephen A. Shinsky
- & David W. Christianson
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Article
| Open AccessThe cohesin-like RecN protein stimulates RecA-mediated recombinational repair of DNA double-strand breaks
RecN is a cohesin-like molecule involved in the bacterial response to DNA double-strand breaks. Here the authors provide evidence that RecN stimulates the DNA strand invasion step of RecA-mediated recombination.
- Lee A. Uranga
- , Emigdio D. Reyes
- & Shelley L. Lusetti
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Article
| Open AccessProtein-protein interactions and metabolite channelling in the plant tricarboxylic acid cycle
A metabolon is a complex of sequential metabolic enzymes that channels substrates directly between enzymes, thus optimizing metabolic flux. Here Zhanget al. provide protein interaction and isotope dilution data that support the existence of a metabolon that channels both citrate and fumarate in the plant TCA cycle.
- Youjun Zhang
- , Katherine F. M. Beard
- & Toshihiro Obata
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Article
| Open AccessActivity-based protein profiling as a robust method for enzyme identification and screening in extremophilic Archaea
Activity-based protein profiling (ABPP) is a chemical proteomics method to profile activity states of enzymes under physiological conditions. Here the authors show that ABPP can be applied to archaeal serine hydrolases in the model organismSulfolobus acidocaldariusand can be used to identify novel putative serine hydrolases.
- Susanne Zweerink
- , Verena Kallnik
- & Markus Kaiser
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Article
| Open AccessIdentification and characterization of a heterotrimeric archaeal DNA polymerase holoenzyme
The current model for B-family DNA polymerases in archaea is one of single-subunit enzymes in contrast to the multi-subunit complexes in eukaryotes. Here the authors show that PolB1 fromSulfolobus solfataricusexists as a heterotrimeric complex in cell extracts.
- Jiangyu Yan
- , Thomas R. Beattie
- & Stephen D. Bell
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Article
| Open AccessCrystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity
Cytidine deaminases are evolutionarily conserved enzymes that edit genomes by deaminating cytidine to uridine. Here the authors present the crystal structure of APOBEC3A with a single-stranded DNA substrate bound in the active site to shed light on the mechanism and specificity of substrate recognition.
- Takahide Kouno
- , Tania V. Silvas
- & Celia A. Schiffer
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Article
| Open AccessGlutaredoxin catalysis requires two distinct glutathione interaction sites
Glutaredoxins have important roles in redox processes. Here the authors show that the enzymatic activity of glutaredoxins requires two distinct glutathione interactions sites, one recognizing the glutathione disulfide substrate and one activating glutathione as a reducing agent.
- Patricia Begas
- , Linda Liedgens
- & Marcel Deponte
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Article
| Open AccessUSP9X regulates centrosome duplication and promotes breast carcinogenesis
USP9X is a deubiquitinating enzyme with many known substrates and functions; it has been linked to cancer but the mechanisms remain unclear. Here Liet al. report that USP9X stabilizes the centrosomal protein CEP131 leading to centrosome amplification and breast cancer development.
- Xin Li
- , Nan Song
- & Lei Shi
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Article
| Open AccessPlant cysteine oxidases are dioxygenases that directly enable arginyl transferase-catalysed arginylation of N-end rule targets
The N-end rule pathway targets substrate proteins for proteasomal degradation. Here, Whiteet al. show that ArabidopsisPLANT CYSTEINE OXIDASEs show dioxygenase activity producing Cys-sulfinic acid at the N-terminus of target proteins, which then act as direct substrates for arginyl transferase.
- Mark D. White
- , Maria Klecker
- & Emily Flashman
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Article
| Open AccessA substrate-bound structure of cyanobacterial biliverdin reductase identifies stacked substrates as critical for activity
Biliverdin reductase (BVR) catalyses the last step in haem degradation. Here the authors present the crystal structure of cyanobacterial BVR bound to its substrate biliverdin and oxidised cofactor NADP+, which was used to propose the catalytic mechanism of this enzyme.
- Haruna Takao
- , Kei Hirabayashi
- & Kei Wada
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Correspondence
| Open AccessCorrespondence: Spontaneous secondary mutations confound analysis of the essential two-component system WalKR in Staphylococcus aureus
- Ian R. Monk
- , Benjamin P. Howden
- & Timothy P. Stinear
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Article
| Open AccessUfd2p synthesizes branched ubiquitin chains to promote the degradation of substrates modified with atypical chains
How ubiquitination affects the proteins it modifies varies according to the type of linkage between ubiquitin moieties. Here, Liuet al. show how yeast Udf2p promotes K48 linkage formation onto K29-linked chains to generate branched K29-K48 ubiquitin chains that target its substrate to the proteasome.
- Chao Liu
- , Weixiao Liu
- & Wei Li
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Article
| Open AccessThe ancient CYP716 family is a major contributor to the diversification of eudicot triterpenoid biosynthesis
Cytochrome P450 family enzymes have an essential role in the creation of triterpenoid diversity in plants. Here, the authors describe triterpenoid synthesis as mediated by CYP716 enzymes in medicinal plant species, and perform phylogenetic analysis to describe CYP716 molecular evolution in plants.
- Karel Miettinen
- , Jacob Pollier
- & Alain Goossens
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Article
| Open AccessA RuBisCO-mediated carbon metabolic pathway in methanogenic archaea
Although not photosynthetic, some archaea possess RuBisCO, one of the enzymes characteristic of the photosynthetic Calvin-Benson cycle, but apparently lack another one, phosphoribulokinase (PRK). Here the authors describe a carbon metabolic pathway in methanogenic archaea, involving RuBisCO and PRK.
- Takunari Kono
- , Sandhya Mehrotra
- & Hiroki Ashida
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Article
| Open AccessStructural basis of human PCNA sliding on DNA
DNA sliding clamps are ring-shaped proteins that encircle DNA and harbour polymerases and other factors that promote processive DNA replication. Here the authors use X-ray crystallography, NMR and MD simulations to propose a model for a PCNA sliding mechanism that relies on short-lived polar interactions.
- Matteo De March
- , Nekane Merino
- & Alfredo De Biasio
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Article
| Open AccessProximity does not contribute to activity enhancement in the glucose oxidase–horseradish peroxidase cascade
The activity enhancement of the glucose oxide and horseradish peroxidase enzymatic cascade on DNA scaffolds has been linked to proximity effects. Here, the authors challenge this view and suggest that the activity improvement is rather due to the pH near the DNA surface.
- Yifei Zhang
- , Stanislav Tsitkov
- & Henry Hess
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Article
| Open AccessCoupled ATPase-adenylate kinase activity in ABC transporters
ATP-binding cassette (ABC) transporters hydrolyse ATP to transport molecules across the cell membrane. Here Vogelet al. show that the ABC exporter MsBA can couple ATP hydrolyse to an adenylate kinase activity that seems to be predominant at low ATP levels and a general feature of ABC exporters.
- Hundeep Kaur
- , Andrea Lakatos-Karoly
- & Clemens Glaubitz
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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 AccessA diverse intrinsic antibiotic resistome from a cave bacterium
Antibiotic resistance is common in environmental bacteria, including those living in isolated caves. Here, Pawlowskiet al. study one of these bacterial strains, showing that it is resistant to most clinically used antibiotics through a remarkable variety of mechanisms, some of which are new to science.
- Andrew C. Pawlowski
- , Wenliang Wang
- & Gerard D. Wright