Metabolic pathways

  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Cofactor F420 plays crucial roles in bacterial and archaeal metabolism, but its biosynthetic pathway is not fully understood. Here, the authors present the structure of one of the enzymes and provide experimental evidence for a substantial revision of the pathway, including the identification of a new intermediate.

    • Ghader Bashiri
    • , James Antoney
    •  & Colin J. Jackson
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Assimilating the abundant one-carbon compounds by an industrially-relevant microorganism can broaden the substrate range and achieve reactions that are difficult for chemical process. Here the authors show a modified serine cycle can convert methanol and CO2 to two-carbon compounds in an engineered E. coli strain.

    • Hong Yu
    •  & James C. Liao
  • Article
    | Open Access

    5-Deoxyribose is formed from 5′-deoxyadenosine, a toxic byproduct of radical S-adenosylmethionine enzymes. Here, the authors identify and biochemically characterize a bacterial salvage pathway for 5-deoxyribose, consisting of three enzymes, and solve the crystal structure of the key aldolase.

    • Guillaume A. W. Beaudoin
    • , Qiang Li
    •  & Andrew D. Hanson
  • Article
    | Open Access

    It is known that the five carbon platform chemical glutarate can be catabolized by the glutaryl-CoA dehydrogenation pathway. Here, the authors discover an additional glutarate catabolic pathway involving l-2-hydroxyglutarate and show increased glutarate production by blocking both catabolic pathways.

    • Manman Zhang
    • , Chao Gao
    •  & Ping Xu
  • Article
    | Open Access

    Serine catabolism to formate supplies one-carbon units for biosynthesis. Here the authors show that formate production in murine cancers with high oxidative metabolism exceeds the biosynthetic demand and that high formate levels promotes invasion of cancer cells.

    • Johannes Meiser
    • , Anne Schuster
    •  & Alexei Vazquez
  • Article
    | Open Access

    The antibiotics trimethoprim (TMP) and sulfamethoxazole (SMX) synergistically inhibit bacterial tetrahydrofolate biosynthesis, apparently because SMX potentiates TMP activity. Here, Minato et al. identify a metabolic feedback loop in this pathway, revealing that TMP also potentiates SMX activity.

    • Yusuke Minato
    • , Surendra Dawadi
    •  & Anthony D. Baughn
  • Article
    | Open Access

    The citric acid cycle (TCA) is a fundamental metabolic pathway to release stored energy in living organisms. Here, the authors report two linked cycles of reactions that each oxidize glyoxylate into CO2 and generate intermediates shared with the modern TCA cycle, shedding light into a plausible TCA protometabolism.

    • Greg Springsteen
    • , Jayasudhan Reddy Yerabolu
    •  & Ramanarayanan Krishnamurthy
  • Article
    | Open Access

    Tissue-resident marcophages have both generic and tissue-specific functions, but how the latter functions are imbued is still unclear. Here the authors show that peritoneal macrophages express a specialised genetic programme to utilise the locally enriched glutamate for a metabolic setting that facilitates protective in situ immunity.

    • Luke C. Davies
    • , Christopher M. Rice
    •  & Daniel W. McVicar
  • Article
    | Open Access

    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
  • Article
    | Open Access

    The lipogenic pathway is often upregulated in liver tumours and regarded as a therapeutic target. Here, the authors show instead that blocking lipogenesis via knockout of acetyl-CoA carboxylase genes results in increased susceptibility to liver tumorigenesis associated with an increased antioxidant defence.

    • Marin E. Nelson
    • , Sujoy Lahiri
    •  & Kyle L. Hoehn
  • Article
    | Open Access

    Enzyme I, a component of the phosphoenolpyruvate-carbohydrate phosphotransferase system (PTS), converts phosphoenolpyruvate to pyruvate. Here, the authors show that Enzyme I facilitates also the reverse reaction during both gluconeogenic and glycolytic growth inE. coli.

    • Christopher P. Long
    • , Jennifer Au
    •  & Maciek R. Antoniewicz
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Raising cellular levels of the metabolic cofactor NAD+ reverses key indicators of aging. Here, Ratajczak et al. show that cellular levels of NAD+ depend on the extracellular catalytic activity of NRK1, which processes two NAD+precursors, nicotinamide mononucleotide and nicotinamide riboside, in mice.

    • Joanna Ratajczak
    • , Magali Joffraud
    •  & Carles Cantó
  • Article
    | Open Access

    Several inhibitors of the electron transport chain (ETC) are active against Mycobacterium tuberculosis. Here, Lamprecht et al. show that a combination of known inhibitors (bedaquiline, Q203 and clofazimine) displays synergistic effects on the M. tuberculosis ETC and improved antibacterial activity in vitro.

    • Dirk A. Lamprecht
    • , Peter M. Finin
    •  & Adrie J. C. Steyn
  • Article
    | Open Access

    Lytic polysaccharide monooxygenases are proteins involved in the degradation of plant biomass and are promising biotechnological tools for biofuel production. Here, the authors show that their catalytic activity is significantly boosted when they are combined with photopigments and exposed to light.

    • D. Cannella
    • , K. B. Möllers
    •  & C. Felby
  • Article
    | Open Access

    The biochemical pathways of central carbon metabolism are highly conserved across all domains of life. Here, Courtet al. use a computational approach to test all possible pathways of glycolysis and gluconeogenesis and find that the existing trunk pathways may represent a maximal flux solution selected for during evolution.

    • Steven J. Court
    • , Bartlomiej Waclaw
    •  & Rosalind J. Allen
  • Article
    | Open Access

    Mycobacterium tuberculosis feeds on host fatty acids during infection, a process that requires a fructose bisphosphatase (FBPase) enzyme for gluconeogenesis. Here, Ganapathy et al.show that the bacterium has two different FBPases and that this enzymatic activity is required for full virulence.

    • Uday Ganapathy
    • , Joeli Marrero
    •  & Sabine Ehrt
  • Article
    | Open Access

    Adverse drug reactions are an important clinical problem. Here the authors combine information about drug-induced gene expression changes and genetic variability of patients with a genome-scale metabolic model to identify drug-induced changes in cellular metabolism that may be linked to drug side effects.

    • Daniel C. Zielinski
    • , Fabian V. Filipp
    •  & Bernhard O. Palsson
  • Article |

    In vitro biochemical pathways could provide the high yields required for economical commodity chemical production, but require circuitry development to regulate high-energy cofactors. Here, the authors design and test a simple purge valve system to maintain NADP+/NADPH balance in E. coli.

    • Paul H. Opgenorth
    • , Tyler P. Korman
    •  & James U. Bowie
  • Article |

    Incomplete oxidation of fuels is a common problem in enzymatic fuel cells and it leads to low energy densities. Zhu et al. report the complete oxidation of sugar in an enzymatic fuel cell through a synthetic enzymatic pathway, which exhibits higher energy densities than lithium-ion batteries.

    • Zhiguang Zhu
    • , Tsz Kin Tam
    •  & Y. -H. Percival Zhang
  • Article |

    The ability to induce metabolic pathways in response to a changing environment is an important component of bacterial fitness. Bartl et al. identify optimal programmes for metabolic pathway activation depending on protein synthesis capacity constraints, and demonstrate their impact on operonic organization.

    • Martin Bartl
    • , Martin Kötzing
    •  & Christoph Kaleta
  • Article
    | Open Access

    It has been hypothesized that the steroidal alkaloid dendrogenin A (DDA) is a natural metabolite. de Medina et al.show that DDA is produced in mammalian tissues from 5,6α-epoxy-cholesterol and histamine metabolism, and that the compound displays cell differentiation and anti-tumour activities.

    • Philippe de Medina
    • , Michael R. Paillasse
    •  & Marc Poirot
  • Article |

    Genome-wide variation in the directed evolution of metabolite-overproducing microbes requires high-throughput screening platforms. Yang et al.show that synthetic RNA devices can sense target metabolites, enrich pathway optimisation, and expedite the evolution of metabolite-producing microbes.

    • Jina Yang
    • , Sang Woo Seo
    •  & Gyoo Yeol Jung
  • Article
    | Open Access

    Many mammals are born with an immature intestinal epithelium, which adapts to a changing diet during the weaning period. Muncanet al. show that the transcriptional repressor Blimp1is expressed in the intestine of mice at birth, and that expression is lost at the transition to the weaning stage.

    • Vanesa Muncan
    • , Jarom Heijmans
    •  & Gijs R. van den Brink
  • Article
    | Open Access

    Frataxin is an essential protein that has been linked to iron–sulphur cluster assembly, and reduced levels are associated with Friedrich's ataxia. In this study, a combination of techniques is used to probe the interactions of the bacterial frataxin orthologue CyaY with the iron–sulphur cluster assembly machinery.

    • Filippo Prischi
    • , Petr V. Konarev
    •  & Annalisa Pastore