Metal-free ribonucleotide reduction powered by a DOPA radical in Mycoplasma pathogens

Nature, Journal Year: 2018, Volume and Issue: 563(7731), P. 416 - 420

Published: Oct. 30, 2018

Language: Английский

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Interchangeable utilization of metals: New perspectives on the impacts of metal ions employed in ancient and extant biomolecules

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 297(6), P. 101374 - 101374

Published: Oct. 31, 2021

Metal ions provide considerable functionality across biological systems, and their utilization within biomolecules has adapted through changes in the chemical environment to maintain activity they facilitate. While ancient earth's atmosphere was rich iron manganese low oxygen, periods of atmospheric oxygenation significantly altered availability certain metal ions, resulting ion replacement biomolecules. This adaptation mechanism given rise phenomenon cofactor interchangeability, whereby contemporary proteins nucleic acids interact with multiple interchangeably, different coordinated metals influencing activity, stability, toxic potential. The ability extant organisms adapt fluctuating remains relevant a number crucial biomolecules, including superoxide dismutases antioxidant defense systems ribonucleotide reductases. These well-studied enzymes illustrate potential for interchangeability adaptive utilization. More recently, ribosome also been demonstrated exhibit interchangeable interactions impacts on function, stress adaptation. Using these other examples, here we review significance from new angle that combines both biochemical evolutionary viewpoints. geochemical pressures properties underlie are discussed context impact modern disease states treatments. unique numerous facilitate extensive all areas cellular fundamental processes, such as respiration, metabolism, nitrogen fixation, photosynthesis, DNA replication, transcription, protein synthesis (1Bellenger J.P. Wichard T. Xu Y. Kraepiel A.M.L. Essential fixation free-living N2-fixing bacterium: Chelation, homeostasis high use efficiency.Environ. Microbiol. 2011; 13: 1395-1411Crossref PubMed Scopus (0) Google Scholar, 2Garcia-Diaz M. Bebenek K. Krahn J.M. Pedersen L.C. Kunkel T.A. Role catalytic during polymerization by polymerase lambda.DNA Repair. 2007; 6: 1333-1340Crossref 3Guth-Metzler R. Bray M.S. Frenkel-Pinter Suttapitugsakul S. Montllor-Albalate C. Bowman J.C. Wu Reddi A.R. Okafor C.D. Glass J.B. Williams L.D. Cutting in-line iron: Ribosomal function non-oxidative RNA cleavage.Nucleic Acids Res. 2020; 48: 8663-8674Crossref (4) 4Klein D.J. contribution structural stability large ribosomal subunit.RNA. 2004; 10: 1366-1379Crossref (211) 5Li L. Yang X. essential element manganese, oxidative stress, metabolic diseases: Links interactions.Oxid. Med. Cell Longev. 2018; https://doi.org/10.1155/2018/7580707Crossref (123) 6Steffens G.C.M. Soulimane Wolff G. Buse Stoichiometry redox behaviour cytochrome-c oxidase.Eur. J. Biochem. 1993; 213: 1149-1157Crossref 7Thiele Metal-regulated transcription eukaryotes.Nucleic 1992; 20: 1183-1191Crossref 8Yruela I. Transition plant photosynthesis.Metallomics. 2013; 5: 1090-1109Crossref (128) Scholar). At least ten elements considered most forms life (9Maret W. periodic system elements: Concepts conjectures.Int. Mol. Sci. 2016; 17: 1-8Crossref Scholar), six d-block table: (Mn), (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn) ((10Crans D.C. Kostenkova Open questions roles first-row transition metals.Commun. Chem. 3: 1-4Crossref Scholar) Fig. 1A). characterized form partially filled d-subshells (shown 1A, blue). electron configuration facilitates oxidation states, defining many properties. called metals, biologically examples appearing first row table (Fig. dark cyan squares). Although important, Zn is excluded some definitions because possession complete d-subshell human body contains amounts magnesium (Mg), Fe, gram range, whereas milligram Mn, Cu, Co, molybdenum present 11Zoroddu M.A. Aaseth Crisponi Medici Peana Nurchi V.M. humans: A brief overview.J. Inorg. 2019; 195: 120-129Crossref (163) perform structure-stabilizing predominantly available divalent cations (possessing two fewer electrons than neutral state). In fact, approximately 40% known structures depend upon at one (12Andreini Bertini Cavallaro Holliday G.L. Thornton catalysis: From enzyme databases general principles.J. Biol. 2008; 1205-1218Crossref (633) Analysis metal-binding domains proteome suggests metal-mediated folds proportional size kingdoms life, specific predicted be utilized reveal distinct history (13Dupont C.L. Butcher A. Valas R.E. Bourne P.E. Caetano-Anollés History inferred phylogenomic analysis structures.Proc. Natl. Acad. U. 2010; 107: 10567-10572Crossref (201) earth may predate protein-oriented biology, metal-rich prebiotic hypothesized generate earliest enzymatic mechanisms. Much proteins, employed cofactors species (14Freisinger E. Sigel R.K.O. nucleotides ribozymes-a comparison binding properties.Coord. Rev. 251: 1834-1851Crossref anionic sugar phosphate backbone nucleotide bases (4Klein 14Freisinger similarly (15Morris D.L. DNA-bound ions: Recent developments.Biomol. Concepts. 2014; 397-407Crossref charge density allows RNAs complexes closely packed tertiary interactions, facilitating elaborate dynamic structures, ribosome—the protein-synthesizing machine operates every living cell. bind throughout rRNA loosely sites, Mg being major contributing small subunits 16Sigel Vaidya Pyle A.M. sites group II intron core.Nat. Struct. 2000; 7: 1111-1116Crossref Despite an effort, drawing definitive conclusions about physiological cells technically challenging task, hindered several experimental issues. include dissociation biomolecule purification, physical limit detection models, broader overexpressing (17Högbom reductase R2, di-iron, di-manganese heterodinuclear - intricate bioinorganic workaround same reaction.Metallomics. 110-120Crossref Further complications elucidation usage arise wherein able occupy biomolecular site. cases, self-assemble into (18Griese J.J. Roos Cox N. Shafaat H.S. Branca R.M.M. Lehtiö Gräslund Lubitz Siegbahn P.E.M. Högbom Direct observation structurally encoded discrimination ether bond formation metalloprotein.Proc. 110: 17189-17194Crossref (27) and, such, can greatly influenced intracellular dictated particular or environmental condition. Therefore, flexibility preference more prevalent currently understood. Thus, view single native site may, unfavorably strict categorization. healthy cell, cytosolic organellar cation levels tightly regulated means protection against undesired elements, while imbalances manifest diseased states. identified link between non-native ion(s), which abolish correct leading mitigation disease, supports need further knowledge molecular mechanisms governing interchangeability. Such investigation will advance our understanding etiology progression, therapeutical intervention strategies. Particular progress revealing structure made recently technological developments. An emerging example interest ribosome. content ribosomes Mg2+, published study replicated anoxic Fe Mn oxygen revealed Mg2+ replaced Fe2+ Mn2+ without affecting (19Athavale S.S. Petrov A.S. Hsiao Watkins D. Prickett Gossett Lie O'Neill Bernier C.R. Hud N.V. Wartell R.M. Harvey S.C. folding catalysis mediated (II).PLoS One. 2012; 7e38024Crossref (60) 20Bray Lenz T.K. Haynes J.W. Multiple mediate translation.Proc. 115: 12164-12169Crossref (23) Besides important features medicine-related translational science, this advanced approach provided scientific community model investigating origin evolution molecules. recapitulated conditions mimicking supported hypothesis represents extraordinarily well-conserved RNA–protein existed complex when depleted (3Guth-Metzler studies were corroborated assays conducted Saccharomyces cerevisiae, it eukaryotic maintained selected under normal conditions. possibility atavism might play role regulation synthesis, faultless processivity contributes neurodegenerative diseases (21Zinskie J.A. Ghosh Trainor B.M. Shedlovskiy Pestov D.G. Shcherbik Iron-dependent cleavage yeast cerevisiae.J. 293: 14237-14248Abstract Full Text PDF (15) recent developments biology open up requiring investigation. Flexibility not only limited but documented metalloproteins. commonly observed vitro assays, assessed presence identify confers greatest activity. addition, Mg, directly detectable spectroscopic difficult crystallographic (22Maguire M.E. Cowan Magnesium chemistry biochemistry.Biometals. 2002; 15: 203-210Crossref (399) 23Weston Biochemistry magnesium.in: PATAI'S Chemistry Functional Groups. John Wiley & Sons, Ltd, 2009: 1-45Crossref readily substituted alternative purposes assessment (24Bock C.W. Katz A.K. Markham G.D. Glusker Manganese zinc: ions.J. Am. Soc. 1999; 121: 7360-7372Crossref (224) 25Cowan activation acid biochemistry.Chem. 1998; 98: 1067-1087Crossref indicating relative ease replace another. Large-scale accompanied accumulation atmosphere, groundbreaking event occurred course dated billions years ago, drove selecting had capability defend highly reactive products derived incomplete reduction (known [ROS]) utilize catalyze reactions. One prominent how mirrored host–pathogen interface. innate immune orchestrates assaults invading pathogens cases display responses. For example, connection biochemistry central phagocytic response, employs oxidant assault nutrient limitation (26Jakubovics N.S. Streptococcal stress.Biochem. 476: 699-703Crossref Many sensitive either side relatively narrow window, host exploit (27Hood M.I. Skaar E.P. Nutritional immunity: pathogen-host interface.Nat. 525-537Crossref (816) During infection organism, bacterial experience conditions, overload trace well severe (28Imlay Where world do bacteria stress?.Environ. 21: 521-530Crossref (70) 29Sultana Foti Dahl J.U. Bacterial neutrophilic hypochlorous acid.Infect. Immun. 88: 1-17Crossref 30Turner A.G. Djoko K.Y. Ong lynn Barnett T.C. Walker M.J. McEwan Group Streptococcus co-ordinates import efflux response hydrogen peroxide 595-611Crossref (8) viruses' survival pathogenesis. Relevant time, much research acute respiratory syndrome coronavirus 2 (SARS-CoV2)–related pathologies. remain unanswered, clear SARS-CoV2 propagation, manifestations 2019 (COVID-19), dysfunction, inflammation, hypercoagulation, hyperferritinemia, have linked (31Habib H.M. Ibrahim Zaim W.H. pathogenesis COVID-19 possible treatment lactoferrin chelators.Biomed. Pharmacother. 2021; 136: 111228Crossref ambiguity assignments associations along physiologically indicates existing gap diverse topics briefly mentioned previously. To gain up-to-date picture phenomenon, here, discuss current made. As outline deeply embedded nature macromolecules place risk damage, oxygen-rich environment. since establishment then relate best-studied describe (SODs), R2 subunit reductases (RNRs), We choose frontline research, providing information each meet various cues. Finally, flexible viral infections immunity. focus cofactors, discussed. stated previously, ∼40% suggesting physiology, importance terms properties, density, radii, reactivity. Redox relevance prescribes capabilities. inactive cations, common tend stabilize negative charges, functioning Lewis activate substrates accepting lone pair no net change state 32Valasatava Rosato Furnham Andreini what extent affect function?.J. 179: 40-53Crossref 33Valdez C.E. Smith Q.A. Nechay M.R. Alexandrova A.N. Mysteries metalloenzymes.Acc. 47: 3110-3117Crossref (81) active, Ni, 1A) lost, allowing act acids, used reactions, transfer results state. Both formed factors binding. described Irving–Williams series (Mg2+ < Ni2+ Co2+ Cu2+ > Zn2+) (34Miličević Branica Raos Irving-Williams order framework connectivity index 3χv enables simultaneous prediction constants bivalent complexes.Molecules. 16: 1103-1112Crossref (19) illustrates increases atomic until reaching Zn, does possess unpaired d-shell thus less stable (35Irving H. R.J.P. Order complexes.Nature. 1948; 162: 746-747Crossref However, associate competitive Fe2+, monovalent potassium sodium, even interactions. tight concentrations accomplished effort transporters buffering chaperones regulating free (36Foster A.W. Osman Robinson N.J. preferences metallation.J. 289: 28095-28103Abstract (206) affinity toward ensures concentrations. heme Fe–sulfur (Fe–S) cluster complexes, transport chain transport, translation termination, pathways. background Fe–S assembly detailed informative reviews (37Cardenas-Rodriguez Chatzi Tokatlidis Iron–sulfur clusters: mitochondria biogenesis disease.J. 23: 509-520Crossref (29) 38Srour B. Gervason Monfort D'Autréaux Mechanism iron–sulfur assembly: intimacy sulfur encounter.Inorganics. 8: 55Crossref (5) catalyzed UV light reduced species, earth, supporting early clusters (39Bonfio Valer Scintilla Shah Evans Jin Szostak Sasselov D.D. Sutherland J.D. Mansy UV-light-driven iron-sulfur clusters.Nat. 2017; 9: 1229-1234Crossref propensity partner reflect First, evolve prefer excluding similar suboptimal, nonfunctional, deleterious, there overlapping characteristics impede absolute specificity. Second, evidence selective advantages gained retaining acquiring exchange tolerance beneficial circumstances. divergent convergent produced organisms, consistent environments varying limitations. Early volcanic processes contributors composition oceans. reducing, oceans soluble (40Konhauser K.O. Pecoits Lalonde S.V. Papineau Nisbet E.G. Barley Arndt N.T. Zahnle Kamber B.S. Oceanic depletion methanogen famine before Great Oxidation Event.Nature. 2009; 458: 750-753Crossref 41Robbins L.J. Planavsky Partin C.A. Reinhard C.T. Kendall Scott Hardisty D.S. Gill B.C. Alessi Dupont Saito Crowe S.A. Poulton S.W. Bekker et al.Trace intersection marine evolution.Earth-Sci. 163: 323-348Crossref (75) 42Williams Fraústo Da Silva J.J.R. Evolution chemically constrained.J. Theor. 2003; 220: 323-343Crossref time line discussion (43Case A.J. On dismutase: perspective superoxide-mediated signaling.Antioxidants. https://doi.org/10.3390/antiox6040082Crossref (53) 44Nisbet Grassineau Howe C.J. Abell P.I. Regelous R.E.R. age Rubisco: oxygenic photosynthesis.Geobiology. 311-335Crossref (78) thought 3 billion great event. likely transpired 1 ago (neoproterozoic event), significant ocean (45Canfield D.E. oxygen: Homage Robert Garrels.Annu. Earth Planet. 2005; 33: 1-36Crossref (646) shifts subsequent (44Nisbet 45Canfield involving fluctuations stores primary source https://doi.org/10.3390/antiox6040082Cros

Language: Английский

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The Last Universal Common Ancestor of Ribosome-Encoding Organisms: Portrait of LUCA

Journal of Molecular Evolution, Journal Year: 2024, Volume and Issue: 92(5), P. 550 - 583

Published: Aug. 19, 2024

Language: Английский

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Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit

eLife, Journal Year: 2018, Volume and Issue: 7

Published: Feb. 1, 2018

Ribonucleotide reductases (RNRs) are key enzymes in DNA metabolism, with allosteric mechanisms controlling substrate specificity and overall activity. In RNRs, the activity master-switch, ATP-cone, has been found exclusively catalytic subunit. two class I RNR subclasses whose subunit lacks we discovered ATP-cones radical-generating The ATP-cone Leeuwenhoekiella blandensis regulates via quaternary structure induced by binding of nucleotides. ATP induces enzymatically competent dimers, whereas dATP non-productive tetramers, resulting different holoenzymes. tetramer forms interactions between ATP-cones, shown a 2.45 Å crystal structure. We also present evidence for an MnIIIMnIV metal center. summary, lack domain was compensated transfer to To our knowledge, this represents first observation components same enzyme complex.

Language: Английский

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Identification of prognostic markers of lung cancer through bioinformatics analysis and in vitro experiments

International Journal of Oncology, Journal Year: 2019, Volume and Issue: unknown

Published: Nov. 28, 2019

Lung cancer is one of the most common types worldwide. Understanding molecular mechanisms underlying development and progression lung may improve early diagnosis, treatment prognosis. The aim present study was to examine pathogenesis identify potentially novel biomarkers. Gene expression datasets patients with were obtained from Expression Omnibus. Genes which closely associated (core genes) screened by weighted gene co‑expression network analysis. In vitro cell based experiments further utilized verify effects core genes on proliferation cells, adhesion between cells matrix, metabolic pathways. Based WGCNA screening, two modules five cancer, including immunoglobulin superfamily member 10 (IGSF10) turquoise module, ribonucleotide reductase regulatory subunit M2, protein regulator cytokinesis 1, kinesin family (KIF)14 KIF2C brown module identified as relevant. Survival analysis differential showed that there significant differences in IGSF10 levels healthy controls cancer. decreased, overall survival time significantly shortened. An MTT colony formation assay IGSF10‑knockout increased Transwell assays suggested matrix cells. Set Enrichment Analysis level activation integrin‑β1/focal kinase (FAK) pathway. Western blotting revealed knockout resulted integrin‑β1/FAK pathway, integrin‑β1, phosphorylated (p)‑FAK p‑AKT upregulated. Activation following IGSF10, affected Therefore, my serve a potential prognostic marker

Language: Английский

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Minimal cobalt metabolism in the marine cyanobacterium Prochlorococcus

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(27), P. 15740 - 15747

Published: June 23, 2020

Significance Photosynthetic phytoplankton are the foundation of marine ecosystems. Their growth in sunlit ocean depends on ample supply over a dozen essential elements. Of these elemental nutrients, metal cobalt is found at lowest concentrations seawater, but it unknown whether scarcity impacts growth. We have measured minimum requirements photosynthetic bacterium Prochlorococcus , which flourishes nutrient-poor regions where many other cannot survive. can grow with less than 50 atoms per cell, an extraordinarily small requirement that explains how this organism persist low-cobalt environments. These results enable predictions ecosystems respond to climate-driven changes nutrient supply.

Language: Английский

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Radicals in Biology: Your Life Is in Their Hands

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(34), P. 13463 - 13472

Published: Aug. 23, 2021

Radicals in biology, once thought to all be bad actors, are now known play a central role many enzymatic reactions. Of the radical-based enzymes, ribonucleotide reductases (RNRs) pre-eminent as they essential biology of organisms by providing building blocks and controlling fidelity DNA replication repair. Intense examination RNRs has led development new tools guiding framework for study radicals pointing way future frontiers radical enzymology.

Language: Английский

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Comprehensive phylogenetic analysis of the ribonucleotide reductase family reveals an ancestral clade

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Sept. 1, 2022

Ribonucleotide reductases (RNRs) are used by all free-living organisms and many viruses to catalyze an essential step in the de novo biosynthesis of DNA precursors. RNRs remarkably diverse primary sequence cofactor requirement, while sharing a conserved fold radical-based mechanism for nucleotide reduction. Here, we structurally aligned RNR family catalytic barrel reconstruct first large-scale phylogeny consisting 6779 sequences that unites extant classes performed evo-velocity analysis independently validate our evolutionary model. With robust in-hand, uncovered novel, phylogenetically distinct clade is placed as ancestral I II RNRs, which have termed Ø. We employed small-angle X-ray scattering (SAXS), cryogenic-electron microscopy (cryo-EM), AlphaFold2 investigate member this from Synechococcus phage S-CBP4 report most minimal architecture to-date. Based on analyses, propose model diversification delineate how can be roadmap targeted future study.

Language: Английский

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Diversity in Overall Activity Regulation of Ribonucleotide Reductase

Journal of Biological Chemistry, Journal Year: 2015, Volume and Issue: 290(28), P. 17339 - 17348

Published: May 14, 2015

Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to corresponding deoxyribonucleotides, which are used as building blocks for DNA replication and repair. This process is tightly regulated via two allosteric sites, specificity site (s-site) overall activity (a-site). The a-site resides in an N-terminal ATP cone domain that binds dATP or functions on/off switch, whereas composite s-site ATP, dATP, dTTP, dGTP determines substrate reduce. There three classes RNRs, class I RNRs consist different combinations α β subunits. In eukaryotic Escherichia coli inhibits enzyme through formation inactive α6 α4β4 complexes, respectively. Here we show Pseudomonas aeruginosa RNR has a duplicated represents third mechanism regulation. Each polypeptide molecules, critical binding dATPs because truncated protein lacking this could only bind its s-site. activates solely by preventing from binding. dATP-induced form α4 complex, can interact with β2 non-productive α4β2 complex. Other effectors induce mixture α2 forms, former being able active α2β2 complexes. unique features P. interesting both evolutionary drug discovery perspectives.

Language: Английский

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Structural Basis for Superoxide Activation of Flavobacterium johnsoniae Class I Ribonucleotide Reductase and for Radical Initiation by Its Dimanganese Cofactor

Biochemistry, Journal Year: 2018, Volume and Issue: 57(18), P. 2679 - 2693

Published: April 2, 2018

A ribonucleotide reductase (RNR) from Flavobacterium johnsoniae ( Fj) differs fundamentally known (subclass a-c) class I RNRs, warranting its assignment to a new subclass, Id. Its β subunit shares with Ib counterparts the requirements for manganese(II) and superoxide (O2-) activation, but it does not require O2--supplying flavoprotein (NrdI) needed in systems, instead scavenging oxidant solution. Although Fj has tyrosine at appropriate sequence position (Tyr 104), this residue is oxidized radical upon as occurs Ia/b proteins. Rather, directly deploys an dimanganese cofactor initiation. In treatment one-electron reductants, can undergo cooperative three-electron reduction II/II state, contrast quantitative univalent inactive "met" (III/III) forms seen I(a-c) βs. This tendency makes unusually robust, form readily be reactivated. The structure of protein rationalizes distinctive traits. distortion core helix ferritin-like architecture renders active site open, introduces cavity near cofactor, positions subclass-d-specific Lys shepherd O2- Mn2II/II cluster. Relative tyrosines proteins, unreactive Tyr 104 held away by hydrogen bond Thr residue. Structural comparisons, considered uniquely simple mode suggest that Id might most closely resemble primordial RNR-β.

Language: Английский

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