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| Open AccessA bacterial checkpoint protein for ribosome assembly moonlights as an essential metabolite-proofreading enzyme
Adventitious oxidation of erythrose-4-phosphate generates 4-phosphoerythronate, which is detoxified by metabolite-proofreading phosphatases in eukaryotes. Here, Sachla & Helmann show that a similar function is carried out in Bacillus subtilis by a checkpoint protein involved in ribosome assembly.
- Ankita J. Sachla
- & John D. Helmann
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Article
| Open AccessSynthetic ligands for PreQ1 riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure
RNA sensors—Riboswitches—respond to the binding of small molecules ligands through structure modification. Here the authors identify synthetic small molecules that bind and regulate the activity of PreQ1 Riboswitches despite having no obvious chemical similarity to the cognate ligand.
- Colleen M. Connelly
- , Tomoyuki Numata
- & John S. Schneekloth Jr.
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Article
| Open AccessThe anti-cancer drugs curaxins target spatial genome organization
Curaxins are a recently discovered class of anti-cancer agents that disturbs DNA/histone interactions within. Here the authors provide evidence that curaxins affect the spatial genome organization and compromise enhancer-promoter communication necessary for expression of several oncogenes, including MYC.
- Omar L. Kantidze
- , Artem V. Luzhin
- & Sergey V. Razin
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Article
| Open AccessNucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma
Protein kinase A (PKA) is typically activated by cAMP. Here, Bachmaier et al. show that PKA of Trypanosoma is activated by nucleoside-related ligands, explain the ligand selectivity swap by a co-crystal structure of trypanosome PKAR, and identify potential downstream targets by phosphoproteomics.
- Sabine Bachmaier
- , Yuri Volpato Santos
- & Michael Boshart
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Article
| Open AccessSpatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells
Measuring metabolic fluxes in cellular compartments is a challenge. Here, the authors introduce an approach to infer fluxes in mitochondria and cytosol, and find that IDH1 is the major producer of cytosolic citrate in HeLa cells and that in SDH- deficient cells citrate synthase functions in reverse.
- Won Dong Lee
- , Dzmitry Mukha
- & Tomer Shlomi
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Article
| Open AccessPhototrophic extracellular electron uptake is linked to carbon dioxide fixation in the bacterium Rhodopseudomonas palustris
Extracellular electron uptake (EEU) is the ability of microbes to take up electrons from solid-phase conductive substances such as metal oxides. Here, Guzman et al. show that electrons enter the photosynthetic electron transport chain and are used for CO2 fixation during EEU in a phototrophic bacterium.
- Michael S. Guzman
- , Karthikeyan Rengasamy
- & Arpita Bose
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Article
| Open AccessReversible histone glycation is associated with disease-related changes in chromatin architecture
Proteins continuously undergo non-enzymatic modifications such as glycation, which accumulate under physiological conditions but can be enhanced in disease. Here the authors characterise histone glycation, provide evidence that it affects chromatin, particularly in breast cancer, and identify DJ-1 as a deglycase.
- Qingfei Zheng
- , Nathaniel D. Omans
- & Yael David
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Article
| Open AccessPhotoregulated fluxional fluorophores for live-cell super-resolution microscopy with no apparent photobleaching
Super-resolution microscopy with spontaneously blinking dyes is dependent on pH and polarity of the medium. Here the authors introduce a photoactivatable fluxional fluorophore for live cell imaging that allows control over the fraction of spontaneously blinking molecules independently of medium properties.
- Elias A. Halabi
- , Dorothea Pinotsi
- & Pablo Rivera-Fuentes
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Article
| Open AccessNetwork-based prediction of drug combinations
Combination therapy holds great promise, but discovery remains challenging. Here, the authors propose a method to identify efficacious drug combinations for specific diseases, and find that successful combinations tend to target separate neighbourhoods of the disease module in the human interactome.
- Feixiong Cheng
- , István A. Kovács
- & Albert-László Barabási
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Article
| Open AccessNeurotrophin receptor tyrosine kinases regulated with near-infrared light
Optical control over receptor tyrosine kinase (RTK) activity can find application in both basic biology and synthetic biology. Here the authors combine the photosensory module of DrBphP bacterial phytochrome with the Trk family of RTKs to obtain Trks that are reversibly switchable with near-infrared and far-red light.
- Anna V. Leopold
- , Konstantin G. Chernov
- & Vladislav V. Verkhusha
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Article
| Open AccessImaging inflammation using an activated macrophage probe with Slc18b1 as the activation-selective gating target
Attempts to image activated macrophages in vivo have been hampered by selectivity and delivery problems. Here the authors develop a small molecule fluorescent probe specific to activated M1 and M2 macrophages, identify the orphan receptor Slc18b1/SLC18B1 as the mechanism of uptake, and use it to image atherosclerosis in mice.
- Sung-Jin Park
- , Beomsue Kim
- & Young-Tae Chang
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Article
| Open AccessAnti-quenching NIR-II molecular fluorophores for in vivo high-contrast imaging and pH sensing
Fluorophores operating in the second near-infrared window suffer from solvatochromism-caused fluorescence quenching in biological aqueous solution. Here, the authors synthesized a series of pH-responsive pentamethine cyanine fluorophores that afford stable absorption/emission beyond 1000 nm.
- Shangfeng Wang
- , Yong Fan
- & Fan Zhang
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Article
| Open AccessHelical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9
Amphihelical antimicrobial peptides (AMPs) are bactericidal host defense factors, but their function as immunomodulators is emerging. Here the authors show that several AMPs organize DNA into periodic nanocrystals by self-assembling into superhelical protofibril scaffolds, which potentiates DNA sensing by TLR9.
- Ernest Y. Lee
- , Changsheng Zhang
- & Gerard C. L. Wong
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Article
| Open AccessPocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site
Taxanes are natural products which bind beta-tubulin, stabilize microtubules and have a broad spectrum of anticancer activity. Here authors employ a computational binding site similarity screen and cell-based assays to reveal a SERM cross-reactivity between the estrogen receptor and the beta-tubulin taxane binding pocket.
- Yu-Chen Lo
- , Olga Cormier
- & Russ B. Altman
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Article
| Open AccessA dual role in regulation and toxicity for the disordered N-terminus of the toxin GraT
The Pseudomonas putida toxin GraT and antitoxin GraA form a type II toxin-antoxin module. Here the authors present the crystal structures of the GraA dimer, GraTA and GraA-DNA complexes and show that GraT contains a functionally important N-terminal intrinsic disordered region that prevents the binding of the GraTA complex to the operator.
- Ariel Talavera
- , Hedvig Tamman
- & Remy Loris
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Article
| Open AccessAssembly and functionality of the ribosome with tethered subunits
The tethered ribosome system Ribo-T supports cell proliferation though at a reduced rate. Here the authors show this is due to slower ribosome assembly instead of reduced functionality.
- Nikolay A. Aleksashin
- , Margus Leppik
- & Alexander S. Mankin
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Article
| Open AccessPeptide-oligourea hybrids analogue of GLP-1 with improved action in vivo
The peptide hormone GLP-1 has the potential to be a remedy for diabetes type II, yet is unstable. Here, the authors synthesized α-peptide-oligourea hybrid analogues of GLP-1 some of which showing significantly prolonged activity in vivo.
- Juliette Fremaux
- , Claire Venin
- & Sébastien R. Goudreau
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Article
| Open AccessA linear nonribosomal octapeptide from Fusarium graminearum facilitates cell-to-cell invasion of wheat
Fusarium graminearum is a fungal pathogen of wheat and other cereals. Here the authors identify a gene cluster in F. graminearum encoding the production of a non-ribosomal peptide that is required for infection of wheat through cell-to-cell penetration.
- Lei-Jie Jia
- , Hao-Yu Tang
- & Wei-Hua Tang
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Article
| Open AccessRationally designed azobenzene photoswitches for efficient two-photon neuronal excitation
Two-photon absorption capacity of azobenzene photoswitches usually comes with a reduction in thermal stability. Here, the authors developed photoswitches with high two-photon sensitivity and enhanced cis isomer thermal lifetime for the control of glutamate receptors.
- Gisela Cabré
- , Aida Garrido-Charles
- & Ramon Alibés
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Article
| Open AccessSensing intracellular calcium ions using a manganese-based MRI contrast agent
There are only few MRI-compatible calcium reporters and they are limited to measuring extracellular calcium levels. Here the authors develop and validate a cell-permeable, manganese-based paramagnetic MRI contrast agent that enables monitoring intracellular calcium signals in vivo in the rat brain.
- Ali Barandov
- , Benjamin B. Bartelle
- & Alan Jasanoff
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Article
| Open AccessDesign strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction
The enzyme serine hydroxymethyltransferase (SHMT) has been implicated in several diseases, however is hard to investigate. Here, the authors used a design strategy based on the retro-aldol-type reaction catalyzed by SHMT to develop SHMT-responsive fluorescence and 19F NMR molecular probes.
- Hiroshi Nonaka
- , Yuki Nakanishi
- & Shinsuke Sando
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Article
| Open AccessMeasuring luteinising hormone pulsatility with a robotic aptamer-enabled electrochemical reader
Assessment of luteinising hormone pulsatility is important in the diagnosis of reproductive disorders. Here the authors develop a DNA aptamer-based electrochemical analysis integrated into a robotic platform for high-throughput and sensitive analysis.
- Shaolin Liang
- , Andrew B. Kinghorn
- & Julian A. Tanner
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Article
| Open AccessEngineered transfer RNAs for suppression of premature termination codons
Premature termination codon suppression therapy could be used to treat a range of genetic disorders. Here the authors present a high-throughput cell-based assay to identify anticodon engineered tRNAs with high suppression activity.
- John D. Lueck
- , Jae Seok Yoon
- & Christopher A. Ahern
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Article
| Open AccessPrecise tuning of gene expression levels in mammalian cells
Analogue regulation of gene expression is important for normal function in mammals but existing genetic technologies are designed to achieve ON/OFF control. Here the authors develop synthetic microRNA silencing-mediated fine-tuners (miSFITs) to precisely control target gene expression levels.
- Yale S. Michaels
- , Mike B. Barnkob
- & Tudor A. Fulga
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Article
| Open AccessDisulfide-mediated conversion of 8-mer bowl-like protein architecture into three different nanocages
Shape transformation of proteins created by design in the laboratory is challenging. Here, the authors present a disulfide-mediated approach for the preparation of 16-mer, 24-mer, and 48-mer nanocages from an 8-mer bowl-like protein building block.
- Jiachen Zang
- , Hai Chen
- & Guanghua Zhao
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Article
| Open AccessA cell-free platform for the prenylation of natural products and application to cannabinoid production
Producing individual cannabinoids by metabolically engineered microbes has proven challenging. Here, the authors develop a cell-free enzymatic prenylating system to generate isoprenyl pyrophosphate substrates directly from glucose and produce both common and rare cannabinoids at >1 g/L.
- Meaghan A. Valliere
- , Tyler P. Korman
- & James U. Bowie
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Article
| Open AccessCyanobacterial antimetabolite 7-deoxy-sedoheptulose blocks the shikimate pathway to inhibit the growth of prototrophic organisms
Mother Nature is a valuable resource for the discovery of drug and agricultural chemicals. Here, the authors show that 7-deoxy-sedoheptulose produced by a cyanobacterium is an antimicrobial and herbicidal compound that acts through inhibition of 3-dehydroquniate synthase in the shikimate pathway.
- Klaus Brilisauer
- , Johanna Rapp
- & Karl Forchhammer
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Article
| Open AccessTemplate-directed RNA polymerization and enhanced ribozyme catalysis inside membraneless compartments formed by coacervates
Membraneless compartments have been theorized to be prebiotic micro-compartments as they spontaneously encapsulate RNA and proteins. Here, the authors report membraneless compartments can enhance RNA chemistries, affecting template directed RNA polymerization and stimulating nucleic acid enzymes.
- Raghav R. Poudyal
- , Rebecca M. Guth-Metzler
- & Philip C. Bevilacqua
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Article
| Open AccessA natural in situ fabrication method of functional bacterial cellulose using a microorganism
Bacterial cellulose (BC) is a ubiquitous biomaterial, but functionalization relies on modification processes which have low reaction efficiency and can cause pollution. Here the authors develop an environmental friendly in-situ fermentation method using fluorescein labelled glucose to produce fluorescent BC.
- Minghong Gao
- , Juan Li
- & Haibo Zhang
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Article
| Open AccessCopper amine oxidases catalyze the oxidative deamination and hydrolysis of cyclic imines
Little is known about the degradation pathway of cyclic imines that are frequently found in bioactive secondary metabolites. Here, the authors found and characterised a copper amine oxidase, HarA that catalyses a ring-opening reaction of cyclic imine in harmaline and oxidative deamination of amines.
- Toshiki Nagakubo
- , Takuto Kumano
- & Michihiko Kobayashi
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Article
| Open AccessNoninvasive optical activation of Flp recombinase for genetic manipulation in deep mouse brain regions
Most approaches to control gene expression in vivo require generation of knock-in mouse lines and often lack spatiotemporal control. Here the authors develop a photo-activatable Flp recombinase system and demonstrate its use by controlling object-exploration behavior in mice through Cav3.1 silencing.
- Hyunjin Jung
- , Seong-Wook Kim
- & Won Do Heo
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Article
| Open AccessA minimal biochemical route towards de novo formation of synthetic phospholipid membranes
The origin of phospholipids, the primary constituents of cell membranes, is uncertain. Here, the authors develop an in vitro system to synthesize phospholipid molecules from water-soluble single-chain amphiphilic precursors via a reaction catalysed by the mycobacterial ligase FadD10.
- Ahanjit Bhattacharya
- , Roberto J. Brea
- & Neal K. Devaraj
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Article
| Open AccessCharacterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation
The systemic understanding of oncogenic kinase signalling is still limited. Here, the authors combine chemical proteomics with functional screens to assess the impact of oncogenic Src on the expressed kinome and identify SGK1 as a critical mediator of Src-induced cell transformation.
- Xiuquan Ma
- , Luxi Zhang
- & Roger J. Daly
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Article
| Open AccessKinetic analysis of multistep USP7 mechanism shows critical role for target protein in activity
Deubiquitinating enzymes (DUBs) are critical regulators of cellular processes by removing ubiquitin from specific targets. Here global kinetic modelling reveals the mechanism by which the low intrinsic activity of USP7 is substantially enhanced on a specific physiological target.
- Robbert Q. Kim
- , Paul P. Geurink
- & Titia K. Sixma
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Article
| Open AccessTrodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes
Transient oligomeric species of the amyloid-β peptide (Aβ42) have been identified as key pathogenic agents in Alzheimer’s disease. Here the authors find that the aminosterol trodusquemine enhances Aβ42 aggregation and suppresses Aβ42-induced toxicity by displacing oligomers from cell membranes.
- Ryan Limbocker
- , Sean Chia
- & Christopher M. Dobson
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Article
| Open AccessDinitroimidazoles as bifunctional bioconjugation reagents for protein functionalization and peptide macrocyclization
The selective formation of protein bioconjugates under physiological conditions is a challenging task. Here, the authors report that 1,4-dinitroimidazoles are reagents of choice for protein bioconjugation at either cysteine or lysine sites within short times and provide facile access to peptide macrocycles.
- Qunfeng Luo
- , Youqi Tao
- & Huan Wang
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Article
| Open AccessDifferential PROTAC substrate specificity dictated by orientation of recruited E3 ligase
PROTACs enable targeted protein degradation by recruiting an E3 ligase to a specific substrate but the determinants of selectivity are not fully understood. Here, the authors show that varying the linker between warhead and E3 ligand and the orientation of the E3 ligase allow tuning PROTAC selectivity toward different p38 isoforms.
- Blake E. Smith
- , Stephen L. Wang
- & Craig M. Crews
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Article
| Open AccessShifts in the selectivity filter dynamics cause modal gating in K+ channels
Spontaneous activity shifts at constant experimental conditions are widespread among ion channels but the molecular origins are poorly understood. Here, using solid-state NMR and MD simulations, the authors reveal that modal gating shifts in K + channels are caused by large shifts in the channel dynamics which perturb the selectivity filter.
- Shehrazade Jekhmane
- , João Medeiros-Silva
- & Markus Weingarth
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Article
| Open AccessStructure and inhibition mechanism of the catalytic domain of human squalene epoxidase
Squalene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and is a target for hypercholesteremia and cancer drug development. Here the authors present the crystal structures of the human SQLE catalytic domain alone and bound with small molecule inhibitors, which will facilitate the development of next-generation SQLE inhibitors.
- Anil K. Padyana
- , Stefan Gross
- & Gromoslaw A. Smolen
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Article
| Open AccessHistone H3 binding to the PHD1 domain of histone demethylase KDM5A enables active site remodeling
The demethylase activity of KDM5A is allosterically enhanced by binding of histone H3 to its PHD1 reader domain, through an unknown mechanism. Here the authors show that the PHD1 domain drives ligand-induced allosteric stimulation by stabilizing the binding of substrate to the catalytic domain.
- James E. Longbotham
- , Cynthia M. Chio
- & Danica Galonić Fujimori
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Article
| Open AccessA chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition
Cancer cells are metabolically adaptable and the identification of specific vulnerabilities is challenging. Here the authors identify a subset of neuroendocrine cell lines exquisitely sensitive to inhibition of SQLE, an enzyme in the cholesterol biosynthetic pathway, due to the toxic accumulation of pathway intermediate squalene.
- Christopher E. Mahoney
- , David Pirman
- & Gromoslaw A. Smolen
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Article
| Open AccessMolecular recognition of the native HIV-1 MPER revealed by STED microscopy of single virions
The Membrane-Proximal External Region (MPER) of the HIV Env gp41 subunit is a target for broadly neutralizing antibodies. Here, the authors apply super-resolution stimulated emission depletion (STED) microscopy on single virions and provide insights into how the MPER epitope is recognized.
- Pablo Carravilla
- , Jakub Chojnacki
- & José L. Nieva
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Article
| Open AccessThe transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
The oncogene STAT5 is involved in cancer cell proliferation. Here, the authors use STAT5 protein to assemble its own small molecule inhibitors via Mannich ligation (three-component-reactions) and show that the resultant ligands can inhibit the proliferation of cancer cells in a mouse model.
- Ee Lin Wong
- , Eric Nawrotzky
- & Jörg Rademann
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Article
| Open AccessFibril formation and therapeutic targeting of amyloid-like structures in a yeast model of adenine accumulation
Small molecule metabolites like phenylalanine can form amyloid-like structures but so far this has only been demonstrated in vitro. Here the authors generate a yeast in vivo model of adenine self-assembly and characterize the adenine assemblies in cells by indicative amyloid dye and anti-adenine assemblies antibodies.
- Dana Laor
- , Dorin Sade
- & Ehud Gazit
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Article
| Open AccessInward- and outward-facing X-ray crystal structures of homodimeric P-glycoprotein CmABCB1
P-glycoprotein, an ATP-binding cassette (ABC) transporter, extrudes a large variety of xenobiotics from the cell which protects tissues from toxins. Here authors solve a pair of X-ray structures of homodimeric P-glycoprotein and resolve structural elements proposed to participate in the mechanism of the transporter.
- Atsushi Kodan
- , Tomohiro Yamaguchi
- & Hiroaki Kato
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Article
| Open AccessA chemical biology toolbox to study protein methyltransferases and epigenetic signaling
Protein methyltransferases (PMTs) are epigenetic regulatory enzymes with significant therapeutic relevance. Here the authors describe a collection of chemical inhibitors and antagonists to modulate most of the key methylation marks on histones H3 and H4, and use the collection to study of the role of PMTs in mouse and human T cell differentiation.
- Sebastian Scheer
- , Suzanne Ackloo
- & Cheryl H. Arrowsmith
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Article
| Open AccessSerine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism
Serine synthesis from glucose is required even when serine is available from the environment. Here, the authors explain this paradox by showing that the enzyme PHGDH enables nucleotide synthesis by coordinating anabolic fluxes related to central carbon metabolism, independent of its role in serine production.
- Michael A. Reid
- , Annamarie E. Allen
- & Jason W. Locasale
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Article
| Open AccessAn electrogenic redox loop in sulfate reduction reveals a likely widespread mechanism of energy conservation
The bacterial complex QrcABCD plays a key role in the bioenergetics of sulfate respiration. Here, Duarte et al. show that this complex is electrogenic, with protons and electrons required for quinone reduction being extracted from opposite sides of the membrane.
- Américo G. Duarte
- , Teresa Catarino
- & Inês A. C. Pereira
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Article
| Open AccessLithium hexamethyldisilazide initiated superfast ring opening polymerization of alpha-amino acid N-carboxyanhydrides
Ring-opening polymerizations of α-amino acid N-carboxyanhydrides to form polypeptides are usually sensitive to moisture, slow and can undergo side reactions. Here the authors use lithium hexamethyldisilazide to initiate α-amino acid N-carboxyanhydride polymerizations that is very fast and can be conducted in an open vessel.
- Yueming Wu
- , Danfeng Zhang
- & Runhui Liu
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