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| Open AccessOne substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse
With structural models now available on a proteome scale, Malatesta et al. show that structure-based screening can help identify proteins catalyzing orphan reactions in metabolic pathways, offering functional insights beyond sequence-based approaches.
- Marco Malatesta
- , Emanuele Fornasier
- & Riccardo Percudani
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| Open AccessA modular and synthetic biosynthesis platform for de novo production of diverse halogenated tryptophan-derived molecules
De novo fermentation and synthetic pathway construction for halogen-containing molecules remain relatively underexplored. Here, the authors report a mix-and-match co-culture platform to de novo generate a large array of halogenated tryptophan derivatives in E. coli from glucose.
- Kevin B. Reed
- , Sierra M. Brooks
- & Hal S. Alper
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| Open AccessWidespread extracellular electron transfer pathways for charging microbial cytochrome OmcS nanowires via periplasmic cytochromes PpcABCDE
How do cells put electrons to rest? Using a minimal pathway to get rid of excess metabolic electrons, diverse environmentally important microbes overcome large spatial, kinetic, and thermodynamic barriers in order to survive in extreme anoxic conditions.
- Pilar C. Portela
- , Catharine C. Shipps
- & Nikhil S. Malvankar
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| Open AccessEpigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Efforts to treat heart failure with antioxidants have failed. Here, authors reveal a robust sex-dependent endogenous defense against oxidative damage and demonstrate antioxidative treatment’s efficacy solely in subjects with inadequate redox capacity.
- Zaher ElBeck
- , Mohammad Bakhtiar Hossain
- & Christer Betsholtz
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| Open AccessA citric acid cycle-deficient Escherichia coli as an efficient chassis for aerobic fermentations
While tricarboxylic acid cycle (TCA cycle) is required for heterotrophic microbes, it reduces carbon yield of industrial products due to the release of excess CO2. Here, the authors construct an E. coli strain without a functional TCA cycle and demonstrate its feasibility as a chassis strain for production of four separate compounds.
- Hang Zhou
- , Yiwen Zhang
- & Baixue Lin
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| Open AccessDJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride
Human protein DJ-1 displays neuroprotective properties. Here, the authors demonstrate that DJ-1 hydrolyzes cyclic 3-phosphoglyceric anhydride (cPGA), thereby protecting proteins from acylation by this highly reactive metabolite spontaneously forming in glycolysis.
- Aizhan Akhmadi
- , Adilkhan Yeskendir
- & Darkhan Utepbergenov
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Article
| Open AccessIncreased CO2 fixation enables high carbon-yield production of 3-hydroxypropionic acid in yeast
CO2 fixation plays an important role to make bioproduction cost competitive. Here, the authors take 3-hydroxypropionic acid as an example to showcase how to achieve high carbon yield production through increasing the accessible bicarbonate, minimizing native CO2 release and avoiding carbon waste.
- Ning Qin
- , Lingyun Li
- & Zihe Liu
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Article
| Open AccessEvolutionarily related host and microbial pathways regulate fat desaturation in C. elegans
Fatty acid desaturation is central to metazoan lipid metabolism. Here, using C. elegans as a model, the authors show that both endogenous and microbiota-dependent small molecule signals converge to promote lipid desaturation via the nuclear receptor NHR-49/PPARα.
- Bennett W. Fox
- , Maximilian J. Helf
- & Frank C. Schroeder
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Article
| Open AccessPlastid ancestors lacked a complete Entner-Doudoroff pathway, limiting plants to glycolysis and the pentose phosphate pathway
The Enter-Doudoroff (ED) pathway is an alternative to glycolysis present in some prokaryotes. Evans et al. show that its dehydratase enzyme, evolved from a branched chain amino acid pathway paralog, acquired a new function through mutations in its active site.
- Sonia E. Evans
- , Anya E. Franks
- & Michael A. Phillips
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| Open AccessSystems engineering of Escherichia coli for high-level glutarate production from glucose
Glutarate is a platform chemical widely used in the production of polyesters and polyamindes. Here, the authors design the shortest and thermodynamically favorable pathway, and increase glutarate production from glucose through systematic engineering of E. coli.
- Zhilan Zhang
- , Ruyin Chu
- & Cong Gao
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Article
| Open AccessDe novo biosynthesis of antiarrhythmic alkaloid ajmaline
Ajmaline is an antiarrhythmic monoterpenoid indole alkaloid produced by the root of Rauwolfia serpentina. Here, the authors complete the ajmaline biosynthetic pathway by identifying two reductases and two esterases, and achieve the de novo ajmaline biosynthesis by engineering Baker’s yeast.
- Jun Guo
- , Di Gao
- & Yang Qu
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Article
| Open AccessEngineering a synthetic energy-efficient formaldehyde assimilation cycle in Escherichia coli
One-carbon substrates are attractive feedstocks for circular bioeconomy. Here, the authors design an erythrulose monophosphate (EuMP) cycle for formaldehyde assimilation, demonstrate the activity of the core reactions in E. coli, and show its integration with pathway reactions existed in pentose phosphate pathway and glycolysis.
- Tong Wu
- , Paul A. Gómez-Coronado
- & Hai He
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Article
| Open AccessMechanistic insights into glycoside 3-oxidases involved in C-glycoside metabolism in soil microorganisms
Integrated experimental and computational approaches reveal functional and structural details of a key catabolic enzyme that oxidizes recalcitrant C-glycosides, abundant and biologically significant natural molecules, before deglycosylation.
- André Taborda
- , Tomás Frazão
- & Lígia O. Martins
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Article
| Open AccessPyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming
Nitric oxide has been shown to target mitochondrial aconitase 2 and pyruvate dehydrogenase to reprogramme macrophage metabolism. Here, the authors extend these findings to show that lipoate is used to generate nitroxyl in this process.
- Erika M. Palmieri
- , Ronald Holewinski
- & Daniel W. McVicar
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Article
| Open AccessSimultaneous sulfide and methane oxidation by an extremophile
Aerobic methanotrophic bacteria oxidize methane in sulfide-rich environments, even though hydrogen sulfide (H2S) inhibits methane oxidation and aerobic respiration. Here, Schmitz et al. show that a single microorganism can oxidize methane and H2S simultaneously, and this is associated with upregulation of a sulfide-insensitive terminal oxidase.
- Rob A. Schmitz
- , Stijn H. Peeters
- & Arjan Pol
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Article
| Open AccessDe novo cholesterol biosynthesis in bacteria
Production of highly modified sterols, such as cholesterol, is essential to eukaryotic physiology but has not been yet reported for bacteria. Here, Lee et al. show that a marine myxobacterium produces cholesterol, and provide evidence for further downstream modifications in this and other bacterial species.
- Alysha K. Lee
- , Jeremy H. Wei
- & Paula V. Welander
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Article
| Open AccessInositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction
Pipercevic et al resolve how inositol molecules activate the VTC protein complex. The VTC complex stores phosphate in yeast and is controlled by SPX domains. The inositol molecules break an interaction between SPX domains to activate the complex.
- Joka Pipercevic
- , Bastian Kohl
- & Sebastian Hiller
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| Open AccessNicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity
Nicotine, a metabolite of the NAD+ metabolic pathway, has been found to possess anti-inflammatory and neuroprotective properties, yet the underlying molecular mechanisms remained unknown. Here, the authors show that low-dose nicotine promotes SIRT1 deacetylation of NAMPT and enhanced NAMPT activity which boosts NAD generation and improves age related symptoms.
- Liang Yang
- , Junfeng Shen
- & Xiang Li
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Article
| Open AccessA genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase
The authors develop a Vitamin K-dependent apoptotic reporter cell line for large-scale screening of enzymes associated with Vitamin K-dependent carboxylation and identify ferroptosis suppressor protein 1 (FSP1) as responsible for warfarin-resistant vitamin K reduction.
- Da-Yun Jin
- , Xuejie Chen
- & Jian-Ke Tie
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Article
| Open AccessDiverse secondary metabolites are expressed in particle-associated and free-living microorganisms of the permanently anoxic Cariaco Basin
Genome mining for biosynthetic gene clusters (BGCs) can be used for the discovery of new compounds of biotechnological interest. Here, the authors use metagenomics and metatranscriptomics to identify diverse BGCs in free-living and particle-associated microbial communities through the stratified water column of the Cariaco Basin, Venezuela.
- David Geller-McGrath
- , Paraskevi Mara
- & Maria Pachiadaki
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| Open AccessHost-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid
Here, using a mouse model, the authors report a previously undescribed role for medium-chain acyl-CoA dehydrogenase in host metabolism of gut microbiota metabolites, and show that circulating compounds, including the abundant organic acid hippurate, depend on host-microbe co-metabolism of phenylalanine by Clostridium sporogenes.
- Kali M. Pruss
- , Haoqing Chen
- & Dylan Dodd
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| Open AccessPharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease
The Lin28/let-7 axis regulates metabolic pathways in normal and pathological contexts. Here the authors show that pharmacological inhibition of Lin28 protects against lipid accumulation in multiple preclinical models of nonalcoholic fatty liver disease.
- Evangelia Lekka
- , Aleksandra Kokanovic
- & Jonathan Hall
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Article
| Open AccessGlycolytic flux control by drugging phosphoglycolate phosphatase
Targeting cellular glucose metabolism is a therapeutic strategy in human diseases such as autoimmunity or cancer. Here, the authors demonstrate the druggability of phosphoglycolate phosphatase, and validate an alternative approach to control glycolysis.
- Elisabeth Jeanclos
- , Jan Schlötzer
- & Antje Gohla
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| Open AccessElucidation of divergent desaturation pathways in the formation of vinyl isonitrile and isocyanoacrylate
While canonical oxygen-rebound pathway has been utilized by several Fe/2OG enzymes, insights into the desaturation process remain to be elucidated. Here, the authors suggest that a carbocation might be deployed to enable chemically divergent desaturations through decarboxylation and deprotonation.
- Wantae Kim
- , Tzu-Yu Chen
- & Wei-chen Chang
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Article
| Open AccessA Catharanthus roseus Fe(II)/α-ketoglutarate-dependent dioxygenase catalyzes a redox-neutral reaction responsible for vindolinine biosynthesis
Catharanthus roseus is the source for anticancer drug vinblastine and other medicinal monoterpenoid indole alkaloids. Here the authors characterize an Fe/2OG dioxygenase, vindolinine synthase, which catalyzes an unusual redox-neutral reaction leading to alkaloid diversity.
- Jasmine Ga May Eng
- , Mohammadamin Shahsavarani
- & Yang Qu
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| Open AccessCell-free prototyping enables implementation of optimized reverse β-oxidation pathways in heterotrophic and autotrophic bacteria
An attractive route for carbon-negative synthesis of biochemical products is the reverse β-oxidation pathway coupled to the Wood-Ljungdahl pathway. Here the authors use a high-throughput in vitro prototyping workflow to screen 762 unique pathway combinations using cell-free extracts tailored for r-BOX to identify enzyme sets for enhanced product selectivity.
- Bastian Vögeli
- , Luca Schulz
- & Michael C. Jewett
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| Open AccessMetabolite trafficking enables membrane-impermeable-terpene secretion by yeast
The engineering of metabolite secretion from microorganisms can lead to many applications in synthetic biology. In this article, the authors engineer a metabolite trafficking system for the secretion of medicinal terpenes.
- So-Hee Son
- , Jae-Eung Kim
- & Ju Young Lee
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Article
| Open AccessA negative-solvatochromic fluorescent probe for visualizing intracellular distributions of fatty acid metabolites
Metabolic distribution of fatty acids to organelles is an essential biological process for energy homeostasis. Here the authors report a fluorescent probe that allows multicolour visualisation of the intracellular distribution of exogenous fatty acids, metabolically incorporated as lipid components.
- Keiji Kajiwara
- , Hiroshi Osaki
- & Masayasu Taki
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| Open AccessBiosynthesizing structurally diverse diols via a general route combining oxidative and reductive formations of OH-groups
Diols are important bulk and fine chemicals, but bioproduciton of branch-chain diols is hampered by the unknown biological route. Here, the authors report the expanding of amino acid metabolism for biosynthesis of branch-chain diols via a general route of combined oxidative and reductive formations of hydroxyl groups.
- Yongfei Liu
- , Wei Wang
- & An-Ping Zeng
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| Open AccessIdentification of a protein responsible for the synthesis of archaeal membrane-spanning GDGT lipids
The cell membranes of many archaea contain characteristic membrane-spanning lipids known as glycerol dibiphytanyl glycerol tetraethers. Here, Zeng et al. identify a protein that participates in a key step of the synthesis of these lipids from diether precursors.
- Zhirui Zeng
- , Huahui Chen
- & Paula V. Welander
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Article
| Open AccessEndogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity
Formaldehyde (FA) is known to exert cytotoxicity through DNA damage. Here, the authors show that FA also triggers cellular redox imbalance by reacting with glutathione (GSH), and that FA cytotoxicity is prevented by GSH synthesis and by ADH5, an enzyme that metabolizes FA-GSH products.
- Carla Umansky
- , Agustín E. Morellato
- & Lucas B. Pontel
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| Open AccessA d-2-hydroxyglutarate biosensor based on specific transcriptional regulator DhdR
d-2-hydroxyglutarate (d-2-HG) is a metabolite that can be aberrantly accumulated and acts as a biomarker in many cancers. Here the authors report a d-2-HG biosensor based on the allosteric transcription factor DhdR which they use for detection in serum and urine.
- Dan Xiao
- , Wen Zhang
- & Ping Xu
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| Open AccessGeneration of a Gluconobacter oxydans knockout collection for improved extraction of rare earth elements
Bioleaching of rare earth elements using microorganisms offers an environmentally friendly alternative to thermochemical extraction. Here, Schmitz et al. generate a whole-genome knockout collection of mutants for one such microorganism, Gluconobacter oxydans, and identify genes affecting the production of acidic biolixiviant and thus bioleaching efficacy.
- Alexa M. Schmitz
- , Brooke Pian
- & Buz Barstow
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Article
| Open AccessMultiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection
The pathogen Mycobacterium tuberculosis depends on host fatty acids and cholesterol as carbon sources. Here, Beites et al. identify a protein complex that is essential for fatty acid and cholesterol utilization and thus for survival of M. tuberculosis during infection, supporting this pathway as a potential target for tuberculosis drug development.
- Tiago Beites
- , Robert S. Jansen
- & Sabine Ehrt
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Article
| Open AccessRegulation of local GTP availability controls RAC1 activity and cell invasion
Changes in intracellular GTP levels are not considered as a regulatory event in RAC1 activation in live cells since total GTP levels are substantially higher than the RAC1 GTP dissociation constant determined in vitro. Here, the authors demonstrate that the availability of free GTP in live cells controls the activity of RAC1 and cell invasion.
- Anna Bianchi-Smiraglia
- , David W. Wolff
- & Mikhail A. Nikiforov
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| Open AccessTemporal evolution of master regulator Crp identifies pyrimidines as catabolite modulator factors
Microbial evolution often involves transient phenotypes and sequential development of multiple mutations of unclear relevance. Here, the authors show that the evolution of non-growing E. coli cells can be driven by alterations in pyrimidine nucleoside levels associated with colony ageing and/or due to mutations in metabolic or regulatory genes.
- Ida Lauritsen
- , Pernille Ott Frendorf
- & Morten H. H. Nørholm
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Article
| Open AccessSpontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters
Analogues of α-ketoglutarate are used in many cellular studies but assumptions are made about cellular uptake. Here, the authors show that esterified analogues rapidly hydrolyse in aqueous medium resulting in an analogue which can be quickly taken up by many cell lines, contrary to prevailing assumptions.
- Seth J. Parker
- , Joel Encarnación-Rosado
- & Alec C. Kimmelman
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Article
| Open AccessInitiating polyketide biosynthesis by on-line methyl esterification
Aurantinins are polyketides with unusual connectivities and broad antibacterial activity. Here the authors show the biosynthesis of aurantinins, which proceeds via an on-line methyl esterification at the terminus that enables the iterative chain elongations prior to condensation and cyclization.
- Pengwei Li
- , Meng Chen
- & Yihua Chen
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Article
| Open AccessD-mannose suppresses macrophage IL-1β production
Mannose is present at trace levels in blood and regulates cancer growth. Here the authors show that supraphysiological levels of mannose can also regulate macrophages, limiting their production of IL-1β and increasing resistance of mice to LPS-induced endotoxemia and DSS-induced colitis.
- Simone Torretta
- , Alessandra Scagliola
- & Simone Cardaci
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Article
| Open AccessStructure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride
Human steroid 5α-reductase 2 (SRD5A2) is an integral membrane enzyme and catalyzes 5α-reduction of testosterone to dihydrotestosterone. Structural analysis accompanied by computational and mutagenesis studies reveal the mechanisms of catalysis and inhibition by clinically relevant drugs targeting SRD5A2.
- Qingpin Xiao
- , Lei Wang
- & Cheng Zhang
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Article
| Open AccessThe precursor of PI(3,4,5)P3 alleviates aging by activating daf-18(Pten) and independent of daf-16
Phosphatidylinositol 3-kinase catalyzes the reaction from PI(4,5)P2 to PI(3,4,5)P3 and is encoded by the age-1 gene known to regulate lifespan. Here the researchers found that the metabolite myo-inositol, which can be converted to PI(3,4,5)P3 extends worm lifespan and alleviates worm as well as mouse health decline during aging.
- Dawei Shi
- , Xian Xia
- & Jing-Dong J. Han
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Article
| Open AccessDefining the ATPome reveals cross-optimization of metabolic pathways
Energy metabolism and ATP levels are controlled by an interlocking network of pathways. Here, the authors apply a genome-wide CRISPR screen to define genes that increase or decrease ATP levels to define the “ATPome”, a map of pathways that contribute to cellular ATP regulation.
- Neal K. Bennett
- , Mai K. Nguyen
- & Ken Nakamura
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Article
| Open AccessStructure and catalytic regulation of Plasmodium falciparum IMP specific nucleotidase
Plasmodium falciparum IMP-specific 5′-nucleotidase 1 (PfISN1) is of interest as a potential malaria drug target. Here, the authors report that IMP is a substrate, and ATP an allosteric activator, of PfISN1 and present PfISN1 crystal structures in the ligand-free state and bound to either IMP or ATP.
- Loïc Carrique
- , Lionel Ballut
- & Nushin Aghajari
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| Open AccessAnalysis of human metabolism by reducing the complexity of the genome-scale models using redHUMAN
The complexity of genome-scale metabolic networks (GEMs) hinders their application in specific physiological contexts. Here, the authors introduce a framework to reduce thermodynamically curated GEMs to the subnetworks of interest and demonstrate its application by deriving leukemia-specific models.
- Maria Masid
- , Meric Ataman
- & Vassily Hatzimanikatis
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Article
| Open AccessA severe leakage of intermediates to shunt products in acarbose biosynthesis
Biosynthetic mechanism for the type 2 diabetes treatment drug acarbose is not fully revealed. Here, the authors show that shunt pathways and inefficient amino-deoxyhexose biosynthesis lead to 1-epi-valienol and valienol accumulation, and minimizing the flux to these shunt products can increase acarbose titer in Actinoplanes species.
- Qinqin Zhao
- , Yuchang Luo
- & Zixin Deng
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Article
| Open AccessAmino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines
Hepatocytes grown in a dish are immature and do not metabolize compounds as a real liver would. Here, the authors supply stem cell-derived hepatocytes with amino acids at a higher concentration than nutritionally necessary, changing the metabolism of these cells, making them more mature and useful for drug screening and toxicity studies.
- Ruben Boon
- , Manoj Kumar
- & Catherine M. Verfaillie
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Article
| Open AccessA high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells
Many cancer cells have increased glucose consumption compared to normal cells, a feature that can be exploited therapeutically. Here, the authors carry out a chemical screen and identify compounds that selectively blocks glucose metabolism in non-small-cell lung cancer cell lines.
- Chiara Ghezzi
- , Alicia Wong
- & Peter M. Clark
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Article
| Open AccessEndogenous nicotinamide riboside metabolism protects against diet-induced liver damage
Nicotinamide adenine dinucleotide (NAD+) sustains cellular energy metabolism, functions as a substrate of Sirt and PARP enzymes, and its supplementation is explored therapeutically in aging and other contexts. Here the authors provide insight into the role of endogenous NAD+ metabolism by studying nicotinamide riboside kinase 1 (NRK1) deficient mice.
- Audrey Sambeat
- , Joanna Ratajczak
- & Carles Canto
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Article
| Open AccessOrthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate
Titers of monoterpenoids production in yeast are low due to the fact that the geranyl diphosphate (GPP)-based pathway can redirect metabolic fluxes to growth. Here, the authors build an orthogonal pathway by selecting the cis isomer of GPP as an alternative precursor and achieve high titer monoterpene production.
- Codruta Ignea
- , Morten H. Raadam
- & Sotirios C. Kampranis