{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T11:32:27Z","timestamp":1766748747547,"version":"build-2065373602"},"reference-count":187,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T00:00:00Z","timestamp":1562198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/115396\/2016, SFRH\/BD\/114886\/2016, UID\/Multi\/04378\/2019, IF\/00052\/2014, IF\/01310\/2013"],"award-info":[{"award-number":["SFRH\/BD\/115396\/2016, SFRH\/BD\/114886\/2016, UID\/Multi\/04378\/2019, IF\/00052\/2014, IF\/01310\/2013"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Nature has tailored a wide range of metalloenzymes that play a vast array of functions in all living organisms and from which their survival and evolution depends on. These enzymes catalyze some of the most important biological processes in nature, such as photosynthesis, respiration, water oxidation, molecular oxygen reduction, and nitrogen fixation. They are also among the most proficient catalysts in terms of their activity, selectivity, and ability to operate at mild conditions of temperature, pH, and pressure. In the absence of these enzymes, these reactions would proceed very slowly, if at all, suggesting that these enzymes made the way for the emergence of life as we know today. In this review, the structure and catalytic mechanism of a selection of diverse metalloenzymes that are involved in the production of highly reactive and unstable species, such as hydroxide anions, hydrides, radical species, and superoxide molecules are analyzed. The formation of such reaction intermediates is very difficult to occur under biological conditions and only a rationalized selection of a particular metal ion, coordinated to a very specific group of ligands, and immersed in specific proteins allows these reactions to proceed. Interestingly, different metal coordination spheres can be used to produce the same reactive and unstable species, although through a different chemistry. A selection of hand-picked examples of different metalloenzymes illustrating this diversity is provided and the participation of different metal ions in similar reactions (but involving different mechanism) is discussed.<\/jats:p>","DOI":"10.3390\/molecules24132462","type":"journal-article","created":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T11:13:18Z","timestamp":1562238798000},"page":"2462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Formation of Unstable and very Reactive Chemical Species Catalyzed by Metalloenzymes: A Mechanistic Overview"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9280-1838","authenticated-orcid":false,"given":"Henrique S.","family":"Fernandes","sequence":"first","affiliation":[{"name":"UCIBIO@REQUIMTE, BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8422-9392","authenticated-orcid":false,"given":"Carla S. Silva","family":"Teixeira","sequence":"additional","affiliation":[{"name":"UCIBIO@REQUIMTE, BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-5284","authenticated-orcid":false,"given":"S\u00e9rgio F.","family":"Sousa","sequence":"additional","affiliation":[{"name":"UCIBIO@REQUIMTE, BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Nuno M. F. S. A.","family":"Cerqueira","sequence":"additional","affiliation":[{"name":"UCIBIO@REQUIMTE, BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"D1112","DOI":"10.1093\/nar\/gkw978","article-title":"Proteome-pi: Proteome isoelectric point database","volume":"45","author":"Kozlowski","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Ying, H., and Xu, Y. (2019). Comparative genomics and metagenomics of the metallomes. Metallomics.","DOI":"10.1039\/c9mt00023b"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Pernil, R., and Schleiff, E. (2019). Metalloproteins in the biology of heterocysts. Life, 9.","DOI":"10.3390\/life9020032"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.sbi.2018.12.008","article-title":"New metal cofactors and recent metallocofactor insights","volume":"59","author":"Hausinger","year":"2019","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1039\/b703112m","article-title":"Metal and cofactor insertion","volume":"24","author":"Mendel","year":"2007","journal-title":"Nat. Prod. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1107\/S0909049502022434","article-title":"Introductory overview: X-ray absorption spectroscopy and structural genomics","volume":"10","author":"Ascone","year":"2003","journal-title":"J. Synchrotron Radiat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0091-679X(08)00810-8","article-title":"Structure and dynamics of metalloproteins in live cells","volume":"90","author":"Cook","year":"2008","journal-title":"Methods Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1146\/annurev.bi.33.070164.001555","article-title":"Metalloproteins","volume":"33","author":"Malmstrom","year":"1964","journal-title":"Annu. Rev. Biochem"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/460813a","article-title":"Metalloproteins","volume":"460","author":"Finkelstein","year":"2009","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1038\/nchembio.1918","article-title":"Metalloproteins: Simple structure, complex function","volume":"11","author":"Lombardi","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1073\/pnas.59.2.498","article-title":"Metalloenzymes: The entatic nature of their active sites","volume":"59","author":"Vallee","year":"1968","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1126\/science.7688141","article-title":"Metalloenzymes, structural motifs, and inorganic models","volume":"261","author":"Karlin","year":"1993","journal-title":"Science"},{"key":"ref_13","unstructured":"Tan, X. (2020). Metalloproteins and Metalloenzymes: Roles and Mechanisms of Metals in Functional Proteins, World Scientific Publishing. [1st ed.]."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3495","DOI":"10.1021\/cr400458x","article-title":"Protein design: Toward functional metalloenzymes","volume":"114","author":"Yu","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1039\/c3mt00086a","article-title":"Transition metals in plant photosynthesis","volume":"5","author":"Yruela","year":"2013","journal-title":"Metallomics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.1021\/cr4004874","article-title":"Mn4ca cluster in photosynthesis: Where and how water is oxidized to dioxygen","volume":"114","author":"Yano","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1002\/anie.201410967","article-title":"Electron tunneling rates in respiratory complex i are tuned for efficient energy conversion","volume":"54","author":"Dorner","year":"2015","journal-title":"Angew. Chem. (International ed in English)"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ccr.2012.05.022","article-title":"Energy transduction by respiratory metallo-enzymes: From molecular mechanism to cell physiology","volume":"257","year":"2013","journal-title":"Coord. Chem. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1080\/00268976.2018.1428375","article-title":"Theory of chemical bonds in metalloenzymes xxi. Possible mechanisms of water oxidation in oxygen evolving complex of photosystem ii","volume":"116","author":"Yamaguchi","year":"2018","journal-title":"Mol. Phys."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6057","DOI":"10.1021\/ja909143d","article-title":"Systematic perturbation of the trinuclear copper cluster in the multicopper oxidases: The role of active site asymmetry in its reduction of O2 to H2O","volume":"132","author":"Augustine","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Solomon, E.I., Augustine, A.J., and Yoon, J. (2008). O2 reduction to H2O by the multicopper oxidases. Dalton Trans., 3921\u20133932.","DOI":"10.1039\/b800799c"},{"key":"ref_22","first-page":"971","article-title":"Structural basis of biological nitrogen fixation","volume":"363","author":"Rees","year":"2005","journal-title":"Philos. Trans. A Math. Phys. Eng. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1021\/ar500227u","article-title":"Mysteries of metals in metalloenzymes","volume":"47","author":"Valdez","year":"2014","journal-title":"Acc. Chem. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"28095","DOI":"10.1074\/jbc.R114.588145","article-title":"Metal preferences and metallation","volume":"289","author":"Foster","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"638","DOI":"10.3389\/fchem.2018.00638","article-title":"Computational understanding of the selectivities in metalloenzymes","volume":"6","author":"Wei","year":"2018","journal-title":"Front. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0079-6107(97)88477-5","article-title":"Structural chemistry and biology of manganese metalloenzymes","volume":"67","author":"Christianson","year":"1997","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.gde.2016.03.006","article-title":"Roles of Fe\u2013S proteins: From cofactor synthesis to iron homeostasis to protein synthesis","volume":"38","author":"Pain","year":"2016","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1432-1327.1999.00186.x","article-title":"Cobalt proteins","volume":"261","author":"Kobayashi","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jinorgbio.2011.11.024","article-title":"Coordination chemistry of copper proteins: How nature handles a toxic cargo for essential function","volume":"107","author":"Rubino","year":"2012","journal-title":"J. Inorg. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1437S","DOI":"10.1093\/jn\/130.5.1437S","article-title":"Function and mechanism of zinc metalloenzymes","volume":"130","author":"McCall","year":"2000","journal-title":"J. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Piovesan, D., Profiti, G., Martelli, P.L., and Casadio, R. (2012). The human \u201cmagnesome\u201d: Detecting magnesium binding sites on human proteins. BMC Bioinformatics, 13.","DOI":"10.1186\/1471-2105-13-S14-S10"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13165","DOI":"10.1074\/jbc.R113.455311","article-title":"The molybdenum cofactor","volume":"288","author":"Mendel","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hille, R., Schulzke, C., and Kirk, M.L. (2016). Molybdenum and tungsten enzymes: Bioinorganic chemistry, The Royal Society of Chemistry. [1st ed.].","DOI":"10.1039\/9781782628828"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1021\/cr60290a003","article-title":"Interactions of histidine and other imidazole derivatives with transition metal ions in chemical and biological systems","volume":"74","author":"Sundberg","year":"1974","journal-title":"Chem. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/S1074-5521(03)00174-1","article-title":"Metal and redox modulation of cysteine protein function","volume":"10","author":"Giles","year":"2003","journal-title":"Chem. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/jcc.25755","article-title":"Coordination chemistry of Zn2+ with sal(ph)en ligands: Tetrahedral coordination or penta-coordination? A dft analysis","volume":"40","author":"Lamine","year":"2019","journal-title":"J. Comput. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1002\/cphc.201800514","article-title":"Unexpected structure of a helical N4-schiff-base Zn(ii) complex and its demetallation: Experimental and theoretical studies","volume":"19","author":"Lamine","year":"2018","journal-title":"Chemphyschem"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1039\/C8NP90023J","article-title":"Metalloenzymes in natural product biosynthetic pathways","volume":"35","author":"Ryan","year":"2018","journal-title":"Nat. Prod. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1126\/science.1056991","article-title":"Autoionization in liquid water","volume":"291","author":"Geissler","year":"2001","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Crichton, R.R. (2012). Chapter 12\u2014zinc\u2014lewis acid and gene regulator. Biological Inorganic Chemistry (Second Edition), Elsevier.","DOI":"10.1016\/B978-0-444-53782-9.00012-7"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0163-7258(96)00198-2","article-title":"Structure and mechanism of carbonic anhydrase","volume":"74","author":"Lindskog","year":"1997","journal-title":"Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/0014-5793(77)80028-8","article-title":"Structure and function of carbonic anhydrases. Imidazole binding to human carbonic anhydrase b and the mechanism of action of carbonic anhydrases","volume":"73","author":"Kannan","year":"1977","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s10534-019-00190-8","article-title":"Molecular structure of thermostable and zinc-ion-binding gamma-class carbonic anhydrases","volume":"32","author":"Wang","year":"2019","journal-title":"BioMetals"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1002\/med.10025","article-title":"Carbonic anhydrase inhibitors","volume":"23","author":"Supuran","year":"2003","journal-title":"Med. Res. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.abb.2015.03.022","article-title":"Theoretical investigation on the restoring step of the carbonic anhydrase catalytic cycle for natural and promiscuous substrates","volume":"582","author":"Piazzetta","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s00214-007-0274-x","article-title":"New computational evidence for the catalytic mechanism of carbonic anhydrase","volume":"118","author":"Miscione","year":"2007","journal-title":"Theor. Chem. Acc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/qua.560360313","article-title":"Theoretical study of carbonic anhydrase-catalyzed hydration of CO2: A brief review","volume":"36","author":"Liang","year":"1989","journal-title":"Int. J. Quantum Chem"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1073\/pnas.87.10.3675","article-title":"Binding of substrate CO2 to the active site of human carbonic anhydrase ii: A molecular dynamics study","volume":"87","author":"Liang","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1021\/bi0480279","article-title":"Structural and kinetic characterization of active-site histidine as a proton shuttle in catalysis by human carbonic anhydrase ii","volume":"44","author":"Fisher","year":"2005","journal-title":"Biochemistry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1021\/ar9501232","article-title":"Carbonic anhydrase: Evolution of the zinc binding site by nature and by design","volume":"29","author":"Christianson","year":"1996","journal-title":"Acc. Chem. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1021\/ar00145a005","article-title":"The catalytic mechanism of carbonic anhydrase: Implications of a rate-limiting protolysis of water","volume":"21","author":"Silverman","year":"2002","journal-title":"Acc. Chem. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/newbio235131a0","article-title":"Crystal structure of human carbonic anhydrase c","volume":"235","author":"Liljas","year":"1972","journal-title":"Nat. New Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1101\/SQB.1972.036.01.030","article-title":"Crystal structure of human erythrocyte carbonic anhydrase c. Vi. The three-dimensional structure at high resolution in relation to other mammalian carbonic anhydrases","volume":"36","author":"Kannan","year":"1972","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1021\/ar000001w","article-title":"Model studies for molecular recognition of carbonic anhydrase and carboxypeptidase","volume":"34","author":"Kimura","year":"2001","journal-title":"Acc. Chem. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1021\/bi9526692","article-title":"Reversal of the hydrogen bond to zinc ligand histidine-119 dramatically diminishes catalysis and enhances metal equilibration kinetics in carbonic anhydrase ii","volume":"35","author":"Huang","year":"1996","journal-title":"Biochemistry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"15780","DOI":"10.1021\/bi971296x","article-title":"Histidine --> carboxamide ligand substitutions in the zinc binding site of carbonic anhydrase ii alter metal coordination geometry but retain catalytic activity","volume":"36","author":"Lesburg","year":"1997","journal-title":"Biochemistry"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9161","DOI":"10.1021\/jp9524791","article-title":"Carbonic anhydrase catalysis: A volume profile analysis","volume":"100","author":"Zhang","year":"1996","journal-title":"J. Phys. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5861","DOI":"10.1021\/ja010301o","article-title":"Bicarbonate as a proton donor in catalysis by Zn(ii)- and Co(ii)-containing carbonic anhydrases","volume":"123","author":"Tu","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1006\/jtbi.2002.2528","article-title":"Hydrogen bonds and the catalytic mechanism of human carbonic anhydrase ii","volume":"215","author":"Thoms","year":"2002","journal-title":"J. Theor. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5087","DOI":"10.1002\/anie.200351440","article-title":"A gas-phase reaction as a functional model for the activation of carbon dioxide by carbonic anhydrase","volume":"42","author":"Schwarz","year":"2003","journal-title":"Angew. Chem. (International ed in English)"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5293","DOI":"10.1021\/bi00391a012","article-title":"Hydration of carbon dioxide by carbonic anhydrase: Internal protein transfer of Zinc(2+)-bound bicarbonate","volume":"26","author":"Liang","year":"2002","journal-title":"Biochemistry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5636","DOI":"10.1021\/ja00197a021","article-title":"The mode of action of carbonic anhydrase","volume":"111","author":"Merz","year":"1989","journal-title":"J. Am. Chem. Soc."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6426","DOI":"10.1021\/ja00017a011","article-title":"Active site ionicity and the mechanism of carbonic anhydrase","volume":"113","author":"Krauss","year":"1991","journal-title":"J. Am. Chem. Soc."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10498","DOI":"10.1021\/ja00052a054","article-title":"Mechanism of the human carbonic anhydrase ii-catalyzed hydration of carbon dioxide","volume":"114","author":"Zheng","year":"1992","journal-title":"J. Am. Chem. Soc."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1021\/ja00029a010","article-title":"Ab initio study of the hydration of carbon dioxide by carbonic anhydrase. A comparison between the lipscomb and lindskog mechanisms","volume":"114","author":"Sola","year":"1992","journal-title":"J. Am. Chem. Soc."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"17789","DOI":"10.1021\/j100050a019","article-title":"The pka of the zinc-bound water in carbonic anhydrase and its model compounds as studied by the am1 calculation coupled with a reaction field theory","volume":"99","author":"Sakurai","year":"1995","journal-title":"J. Phys. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1021\/ja963296a","article-title":"Binding of bicarbonate to human carbonic anhydrase ii: A continuum of binding states","volume":"119","author":"Merz","year":"1997","journal-title":"J. Am. Chem. Soc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4006","DOI":"10.1021\/ja973397o","article-title":"Proton transfer in the enzyme carbonic anhydrase: Anab initiostudy","volume":"120","author":"Lu","year":"1998","journal-title":"J. Am. Chem. Soc."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1021\/ja983579y","article-title":"Solvent dynamics and mechanism of proton transfer in human carbonic anhydrase ii","volume":"121","author":"Toba","year":"1999","journal-title":"J. Am. Chem. Soc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1021\/ja983930f","article-title":"Dynamics of functional water in the active site of native carbonic anhydrase from17o magnetic relaxation dispersion","volume":"121","author":"Denisov","year":"1999","journal-title":"J. Am. Chem. Soc."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/1439-7633(20010302)2:3<190::AID-CBIC190>3.0.CO;2-7","article-title":"New insights into the mechanistic details of the carbonic anhydrase cycle as derived from the model system [(NH3)3Zn(OH)]+\/CO2: How does the H2O\/HCO3\u2212 replacement step occur?","volume":"2","author":"Mauksch","year":"2001","journal-title":"ChemBioChem"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1021\/ic0010510","article-title":"Quantitative reactivity model for the hydration of carbon dioxide by biomimetic zinc complexes","volume":"41","author":"Weston","year":"2002","journal-title":"Inorg. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1021\/ja0210594","article-title":"Kinetic isotope effects for concerted multiple proton transfer: A direct dynamics study of an active-site model of carbonic anhydrase ii","volume":"125","author":"Smedarchina","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1021\/jp961759t","article-title":"Carbonic anhydrase reactivity, mutation, and inhibition probed with a model of ab initioquantum chemistry within a protein","volume":"101","author":"Garmer","year":"1997","journal-title":"J. Phys. Chem. B"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1021\/jp021931v","article-title":"Is a \u201cproton wire\u201d concerted or stepwise? A model study of proton transfer in carbonic anhydrase","volume":"107","author":"Cui","year":"2003","journal-title":"J. Phys. Chem. B"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S0166-1280(98)00455-2","article-title":"Ab initio Mo study on the catalytic mechanism in the active site of carbonic anhydrase","volume":"461-462","author":"Muguruma","year":"1999","journal-title":"J. Mol. Struct. THEOCHEM"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1021\/ja030336j","article-title":"New model for a theoretical density functional theory investigation of the mechanism of the carbonic anhydrase: How does the internal bicarbonate rearrangement occur?","volume":"126","author":"Bottoni","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"D542","DOI":"10.1093\/nar\/gky1048","article-title":"Brenda in 2019: A european elixir core data resource","volume":"47","author":"Jeske","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1039\/c0cp01053g","article-title":"Catalytic activity of a zeta-class zinc and cadmium containing carbonic anhydrase. Compared work mechanisms","volume":"13","author":"Amata","year":"2011","journal-title":"PCCP"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5884","DOI":"10.1021\/acs.jpcb.6b00997","article-title":"Histone deacetylase 8: Characterization of physiological divalent metal catalysis","volume":"120","author":"Nechay","year":"2016","journal-title":"J. Phys. Chem. B"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ejmech.2018.12.039","article-title":"Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overview","volume":"164","author":"Banerjee","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"11636","DOI":"10.1021\/ja501548p","article-title":"Inhibition and mechanism of HDAC8 revisited","volume":"136","author":"Chen","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1021\/acs.biochem.5b01327","article-title":"General base-general acid catalysis in human histone deacetylase 8","volume":"55","author":"Gantt","year":"2016","journal-title":"Biochemistry"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"9471","DOI":"10.1021\/ja103932d","article-title":"A proton-shuttle reaction mechanism for histone deacetylase 8 and the catalytic role of metal ions","volume":"132","author":"Wu","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6170","DOI":"10.1021\/bi060212u","article-title":"Catalytic activity and inhibition of human histone deacetylase 8 is dependent on the identity of the active site metal ion","volume":"45","author":"Gantt","year":"2006","journal-title":"Biochemistry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"10983","DOI":"10.1021\/ic401072d","article-title":"Zinc coordination spheres in protein structures","volume":"52","author":"Laitaoja","year":"2013","journal-title":"Inorg. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jinorgbio.2011.11.018","article-title":"New perspectives of zinc coordination environments in proteins","volume":"111","author":"Maret","year":"2012","journal-title":"J. Inorg. Biochem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4682","DOI":"10.1021\/cr800556u","article-title":"Coordination dynamics of zinc in proteins","volume":"109","author":"Maret","year":"2009","journal-title":"Chem. Rev."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3394","DOI":"10.1021\/ic1022517","article-title":"Can human prolidase enzyme use different metals for full catalytic activity?","volume":"50","author":"Alberto","year":"2011","journal-title":"Inorg. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.1365-2672.2012.05310.x","article-title":"Prolidase function in proline metabolism and its medical and biotechnological applications","volume":"113","author":"Kitchener","year":"2012","journal-title":"J. Appl. Microbiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1096\/fasebj.9.9.7601338","article-title":"Proline motifs in peptides and their biological processing","volume":"9","author":"Vanhoof","year":"1995","journal-title":"FASEB J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1271\/bbb.60.1118","article-title":"Purification and characterization of a prolidase from aureobacterium esteraromaticum","volume":"60","author":"Fujii","year":"1996","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1111\/febs.14158","article-title":"Substrate specificity and reaction mechanism of human prolidase","volume":"284","author":"Wilk","year":"2017","journal-title":"FEBS J."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.1111\/febs.14620","article-title":"Structural basis for prolidase deficiency disease mechanisms","volume":"285","author":"Wilk","year":"2018","journal-title":"FEBS J."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"14885","DOI":"10.1021\/ja9045394","article-title":"A combined qm\/mm study on the reductive half-reaction of xanthine oxidase: Substrate orientation and mechanism","volume":"131","author":"Metz","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1139\/o89-005","article-title":"Purification and characterization of activated human erythrocyte prolidase","volume":"67","author":"Richter","year":"1989","journal-title":"Biochem. Cell Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"9934","DOI":"10.1021\/ja3043239","article-title":"Wide-open flaps are key to urease activity","volume":"134","author":"Roberts","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1007\/s00775-012-0926-8","article-title":"Temperature- and pressure-dependent stopped-flow kinetic studies of jack bean urease. Implications for the catalytic mechanism","volume":"17","author":"Krajewska","year":"2012","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1080\/13543776.2019.1584612","article-title":"A patent update on therapeutic applications of urease inhibitors (2012\u20132018)","volume":"29","author":"Hameed","year":"2019","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Carlsson, H., and Nordlander, E. (2010). Computational modeling of the mechanism of urease. Bioinorg. Chem. Appl.","DOI":"10.1155\/2010\/364891"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Mazzei, L., Cianci, M., Benini, S., and Ciurli, S. (2019). The structure of the elusive urease-urea complex unveils the mechanism of a paradigmatic nickel-dependent enzyme. Angew. Chem. (International ed. in English).","DOI":"10.1002\/anie.201903565"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"8575","DOI":"10.1021\/bi000613o","article-title":"Kinetic and structural characterization of urease active site variants","volume":"39","author":"Pearson","year":"2000","journal-title":"Biochemistry"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"15324","DOI":"10.1021\/ja030145g","article-title":"Ureases: Quantum chemical calculations on cluster models","volume":"125","author":"Suarez","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"6932","DOI":"10.1021\/ja049327g","article-title":"The hydrolysis of urea and the proficiency of urease","volume":"126","author":"Estiu","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_105","first-page":"795","article-title":"Human aminopeptidases: A review of the literature","volume":"26","author":"Sanderink","year":"1988","journal-title":"J. Clin. Chem. Clin. Biochem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1515\/BC.2006.191","article-title":"Leucine aminopeptidases: Diversity in structure and function","volume":"387","author":"Matsui","year":"2006","journal-title":"Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1096\/fasebj.7.2.8440407","article-title":"Aminopeptidases: Structure and function","volume":"7","author":"Taylor","year":"1993","journal-title":"FASEB J."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"4581","DOI":"10.1021\/cr0101757","article-title":"Metalloaminopeptidases: Common functional themes in disparate structural surroundings","volume":"102","author":"Lowther","year":"2002","journal-title":"Chem. Rev."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Liew, S.M., Tay, S.T., and Puthucheary, S.D. (2013). Enzymatic and molecular characterisation of leucine aminopeptidase of burkholderia pseudomallei. BMC Microbiol., 13.","DOI":"10.1186\/1471-2180-13-110"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"11151","DOI":"10.1073\/pnas.96.20.11151","article-title":"A bicarbonate ion as a general base in the mechanism of peptide hydrolysis by dizinc leucine aminopeptidase","volume":"96","author":"Sun","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1021\/pr050361j","article-title":"Counting the zinc-proteins encoded in the human genome","volume":"5","author":"Andreini","year":"2006","journal-title":"J. Proteome Res."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Sousa, S.F., Lopes, A.B., Fernandes, P.A., and Ramos, M.J. (2009). The zinc proteome: A tale of stability and functionality. Dalton Trans., 7946\u20137956.","DOI":"10.1039\/b904404c"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1021\/bi4016617","article-title":"Designing hydrolytic zinc metalloenzymes","volume":"53","author":"Zastrow","year":"2014","journal-title":"Biochemistry"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s00775-011-0843-2","article-title":"Mechanism of peptide hydrolysis by co-catalytic metal centers containing leucine aminopeptidase enzyme: A DFT approach","volume":"17","author":"Zhu","year":"2012","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1021\/ar500301y","article-title":"Theoretical insights into the functioning of metallopeptidases and their synthetic analogues","volume":"48","author":"Zhang","year":"2015","journal-title":"Acc. Chem. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"3778","DOI":"10.1021\/bi00285a010","article-title":"Kinetic parameters of metal-substituted leucine aminopeptidase from bovine lens","volume":"22","author":"Allen","year":"1983","journal-title":"Biochemistry"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3226","DOI":"10.1021\/bi052069v","article-title":"Metal ion substitution in the catalytic site greatly affects the binding of sulfhydryl-containing compounds to leucyl aminopeptidase","volume":"45","author":"Cappiello","year":"2006","journal-title":"Biochemistry"},{"key":"ref_118","first-page":"1","article-title":"Xanthine oxidase: Isolation, assays of activity, and inhibition","volume":"2015","author":"Ickovski","year":"2015","journal-title":"J. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1515\/bmc-2017-0011","article-title":"Assembly pathway of a bacterial complex iron sulfur molybdoenzyme","volume":"8","author":"Cherak","year":"2017","journal-title":"Biomol. Concepts"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1107\/S0907444903009934","article-title":"The 1.2 \u00c5 structure of the human sulfite oxidase cytochrome b5 domain","volume":"59","author":"Rudolph","year":"2003","journal-title":"Acta crystallographica. Section D"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1021\/cr400443z","article-title":"The mononuclear molybdenum enzymes","volume":"114","author":"Hille","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ccr.2012.05.020","article-title":"Periplasmic nitrate reductases and formate dehydrogenases: Biological control of the chemical properties of mo and w for fine tuning of reactivity, substrate specificity and metabolic role","volume":"257","author":"Gonzalez","year":"2013","journal-title":"Coord. Chem. Rev."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s00775-014-1218-2","article-title":"Molybdenum and tungsten-dependent formate dehydrogenases","volume":"20","author":"Maia","year":"2015","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1021\/jp909999s","article-title":"Qm\/mm studies of xanthine oxidase: Variations of cofactor, substrate, and active-site glu802","volume":"114","author":"Metz","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1093\/jb\/mvm053","article-title":"Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: Roles of active site residues in binding and activation of purine substrate","volume":"141","author":"Yamaguchi","year":"2007","journal-title":"J. Biochem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"7242","DOI":"10.1021\/bi1008485","article-title":"Elucidating the catalytic mechanism of sulfite oxidizing enzymes using structural, spectroscopic, and kinetic analyses","volume":"49","author":"Tollin","year":"2010","journal-title":"Biochemistry"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s00775-015-1237-7","article-title":"Theoretical studies on mechanisms of some mo enzymes","volume":"20","author":"Cerqueira","year":"2015","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1021\/acs.accounts.5b00333","article-title":"Periplasmic nitrate reductase and formate dehydrogenase: Similar molecular architectures with very different enzymatic activities","volume":"48","author":"Cerqueira","year":"2015","journal-title":"Acc. Chem. Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1021\/acs.biochem.6b00002","article-title":"The molybdenum active site of formate dehydrogenase is capable of catalyzing c-h bond cleavage and oxygen atom transfer reactions","volume":"55","author":"Hartmann","year":"2016","journal-title":"Biochemistry"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/pro.3498","article-title":"Molybdenum- and tungsten-containing formate dehydrogenases and formylmethanofuran dehydrogenases: Structure, mechanism, and cofactor insertion","volume":"28","author":"Niks","year":"2019","journal-title":"Protein Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1007\/s00775-011-0813-8","article-title":"The mechanism of formate oxidation by metal-dependent formate dehydrogenases","volume":"16","author":"Mota","year":"2011","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"10766","DOI":"10.1021\/ic3028034","article-title":"The sulfur shift: An activation mechanism for periplasmic nitrate reductase and formate dehydrogenase","volume":"52","author":"Cerqueira","year":"2013","journal-title":"Inorg. Chem."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.jmb.2011.03.016","article-title":"The crystal structure of cupriavidus necator nitrate reductase in oxidized and partially reduced states","volume":"408","author":"Coelho","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.1021\/ic502880y","article-title":"\u2018Sulfido and cysteine ligation changes at the molybdenum cofactor during substrate conversion by formate dehydrogenase (FDH) from rhodobacter capsulatus","volume":"54","author":"Schrapers","year":"2015","journal-title":"Inorg. Chem."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"9927","DOI":"10.1021\/jacs.7b03958","article-title":"Oxidation-state-dependent binding properties of the active site in a mo-containing formate dehydrogenase","volume":"139","author":"Robinson","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1007\/s00775-006-0129-2","article-title":"Formate-reduced e-coli formate dehydrogenase h: The reinterpretation of the crystal structure suggests a new reaction mechanism","volume":"11","author":"Raaijmakers","year":"2006","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1007\/s00775-018-1608-y","article-title":"Reaction mechanism of formate dehydrogenase studied by computational methods","volume":"23","author":"Dong","year":"2018","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"13731","DOI":"10.1016\/S0021-9258(18)92760-2","article-title":"Kinetics for formate dehydrogenase of escherichia coli formate-hydrogenlyase","volume":"266","author":"Axley","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"12651","DOI":"10.1021\/ja002286d","article-title":"Factors influencing the thermodynamics of zinc alkoxide formation by alcoholysis of the terminal hydroxide complex, [tp(but,me)]znoh: An experimental and theoretical study relevant to the mechanism of action of liver alcohol dehydrogenase","volume":"122","author":"Bergquist","year":"2000","journal-title":"J. Am. Chem. Soc."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1111\/j.1432-1033.1980.tb05981.x","article-title":"Unified mechanism for proton-transfer reactions affecting the catalytic activity of liver alcohol-dehydrogenase","volume":"103","author":"Kvassman","year":"1980","journal-title":"Eur. J. Biochem."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s12088-019-00795-0","article-title":"Cloning, expression and characterization of a highly active alcohol dehydrogenase for production of ethyl (S)-4-chloro-3-hydroxybutyrate","volume":"59","author":"Zhu","year":"2019","journal-title":"Indian J. Med. Microbiol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.cbi.2019.01.040","article-title":"Substitution of cysteine-153 ligated to the catalytic zinc in yeast alcohol dehydrogenase with aspartic acid and analysis of mechanisms of related medium chain dehydrogenases","volume":"302","author":"Kim","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.jinorgbio.2017.07.022","article-title":"Quantum chemical study of mechanism and stereoselectivity of secondary alcohol dehydrogenase","volume":"175","author":"Moa","year":"2017","journal-title":"J. Inorg. Biochem."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"4803","DOI":"10.1021\/ja994456w","article-title":"Computational studies of the mechanism for proton and hydride transfer in liver alcohol dehydrogenase","volume":"122","author":"Agarwal","year":"2000","journal-title":"J. Am. Chem. Soc."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.biochem.75.103004.142800","article-title":"Relating protein motion to catalysis","volume":"75","author":"Benkovic","year":"2006","journal-title":"Annu. Rev. Biochem"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/pro.5560060223","article-title":"Thermoanaerobacter brockii alcohol dehydrogenase: Characterization of the active site metal and its ligand amino acids","volume":"6","author":"Bogin","year":"1997","journal-title":"Protein Sci."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1126\/science.1196347","article-title":"Biochemistry. A never-ending story","volume":"329","author":"Sjoberg","year":"2010","journal-title":"Science"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2174\/157489207779561408","article-title":"Ribonucleotide reductase: A critical enzyme for cancer chemotherapy and antiviral agents","volume":"2","author":"Cerqueira","year":"2007","journal-title":"Recent Pat. Anticancer. Drug Discov."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.2174\/0929867054020981","article-title":"Overview of ribonucleotide reductase inhibitors: An appealing target in anti-tumour therapy","volume":"12","author":"Cerqueira","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.theochem.2003.10.073","article-title":"New insights into a critical biological control step of the mechanism of ribonucleotide reductase","volume":"709","author":"Cerqueira","year":"2004","journal-title":"J. Mol. Struct."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.2174\/092986710792065054","article-title":"Ribonucleotide reductase: A mechanistic portrait of substrate analogues inhibitors","volume":"17","author":"Perez","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s11515-014-1302-6","article-title":"Ribonucleotide reductase metallocofactor: Assembly, maintenance and inhibition","volume":"9","author":"Zhang","year":"2014","journal-title":"Front. Biol. (Beijing)"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.sbi.2008.11.007","article-title":"The manganese(iv)\/iron(iii) cofactor of chlamydia trachomatis ribonucleotide reductase: Structure, assembly, radical initiation, and evolution","volume":"18","author":"Bollinger","year":"2008","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1021\/bi101881d","article-title":"Escherichia coli class ib ribonucleotide reductase contains a dimanganese(iii)-tyrosyl radical cofactor in vivo","volume":"50","author":"Cotruvo","year":"2011","journal-title":"Biochemistry"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1021\/acs.biochem.8b01252","article-title":"Structures of class id ribonucleotide reductase catalytic subunits reveal a minimal architecture for deoxynucleotide biosynthesis","volume":"58","author":"Rose","year":"2019","journal-title":"Biochemistry"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1570-9639(04)00054-8","article-title":"Structure, function, and mechanism of ribonucleotide reductases","volume":"1699","author":"Kolberg","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0079-6107(01)00014-1","article-title":"Structure and function of the radical enzyme ribonucleotide reductase","volume":"77","author":"Eklund","year":"2001","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1021\/ar4000407","article-title":"Reversible, long-range radical transfer in E. Coli class ia ribonucleotide reductase","volume":"46","author":"Minnihan","year":"2013","journal-title":"Acc. Chem. Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1021\/bi011429l","article-title":"Crystal structure of the di-iron\/radical protein of ribonucleotide reductase from corynebacterium ammoniagenes","volume":"41","author":"Hogbom","year":"2002","journal-title":"Biochemistry"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.1002\/1521-3773(20010803)40:15<2782::AID-ANIE2782>3.0.CO;2-P","article-title":"Dioxygen activation and methane hydroxylation by soluble methane monooxygenase: A tale of two irons and three proteins a list of abbreviations can be found in section 7","volume":"40","author":"Merkx","year":"2001","journal-title":"Angew. Chem. (International ed. in English)"},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Buckel, W. (2019). Enzymatic reactions involving ketyls: From a chemical curiosity to a general biochemical mechanism. Biochemistry.","DOI":"10.1021\/acs.biochem.9b00171"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1021\/bi011653a","article-title":"A comprehensive model for the allosteric regulation of mammalian ribonucleotide reductase. Functional consequences of ATP- and dATP-induced oligomerization of the large subunit","volume":"41","author":"Kashlan","year":"2002","journal-title":"Biochemistry"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"10071","DOI":"10.1021\/bi034374r","article-title":"Pre-steady-state and steady-state kinetic analysis of E. Coliclass i ribonucleotide reductase","volume":"42","author":"Ge","year":"2003","journal-title":"Biochemistry"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"4027","DOI":"10.1021\/ja312457t","article-title":"Mechanism of assembly of the dimanganese-tyrosyl radical cofactor of class ib ribonucleotide reductase: Enzymatic generation of superoxide is required for tyrosine oxidation via a Mn(iii)Mn(iv) intermediate","volume":"135","author":"Cotruvo","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.1021\/bi201925t","article-title":"The dimanganese(ii) site of bacillus subtilis class ib ribonucleotide reductase","volume":"51","author":"Boal","year":"2012","journal-title":"Biochemistry"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1146\/annurev.biochem.72.121801.161828","article-title":"The many faces of vitamin b12: Catalysis by cobalamin-dependent enzymes","volume":"72","author":"Banerjee","year":"2003","journal-title":"Annu. Rev. Biochem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"10096","DOI":"10.1021\/acscatal.8b02321","article-title":"Catalytic mechanism of the serine hydroxymethyltransferase: A computational oniom qm\/mm study","volume":"8","author":"Fernandes","year":"2018","journal-title":"ACS Catal."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nsb738","article-title":"Domain alternation switches b(12)-dependent methionine synthase to the activation conformation","volume":"9","author":"Bandarian","year":"2002","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1126\/science.7992050","article-title":"How a protein binds b 12: A 3.0 \u00e5 x-ray structure of b 12 -binding domains of methionine synthase","volume":"266","author":"Drennan","year":"1994","journal-title":"Science"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/0959-440X(94)90275-5","article-title":"Cobalamin-dependent methionine synthase: The structure of a methylcobalamin-binding fragment and implications for other b12-dependent enzymes","volume":"4","author":"Drennan","year":"1994","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"16044","DOI":"10.1021\/jp4093145","article-title":"Mechanistic insights for formation of an organometallic Co-C bond in the methyl transfer reaction catalyzed by methionine synthase","volume":"117","author":"Kumar","year":"2013","journal-title":"J. Phys. Chem. B"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"13880","DOI":"10.1021\/bi001431x","article-title":"Protonation state of methyltetrahydrofolate in a binary complex with cobalamin-dependent methionine synthase","volume":"39","author":"Smith","year":"2000","journal-title":"Biochemistry"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"13970","DOI":"10.1021\/ja034697a","article-title":"Conversion of homocysteine to methionine by methionine synthase: A density functional study","volume":"125","author":"Jensen","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"7638","DOI":"10.1021\/jp066972w","article-title":"Reductive cleavage mechanism of methylcobalamin: Elementary steps of Co-C bond breaking","volume":"111","author":"Kozlowski","year":"2007","journal-title":"J. Phys. Chem. B"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"12965","DOI":"10.1021\/jp1043738","article-title":"Reductive cleavage mechanism of Co-C bond in cobalamin-dependent methionine synthase","volume":"114","author":"Biarnes","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jphotobiol.2018.09.015","article-title":"Mechanism of the photo-induced activation of CoC bond in methylcobalamin-dependent methionine synthase","volume":"189","author":"Ghosh","year":"2018","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1021\/bi952389m","article-title":"Mutations in the b12-binding region of methionine synthase: How the protein controls methylcobalamin reactivity","volume":"35","author":"Jarrett","year":"1996","journal-title":"Biochemistry"},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Kapoor, A., Shandilya, M., and Kundu, S. (2011). Structural insight of dopamine beta-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026509"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"e1500980","DOI":"10.1126\/sciadv.1500980","article-title":"The crystal structure of human dopamine beta-hydroxylase at 2.9 a resolution","volume":"2","author":"Vendelboe","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"12035","DOI":"10.1073\/pnas.1614807113","article-title":"Mechanism of O2 activation and substrate hydroxylation in noncoupled binuclear copper monooxygenases","volume":"113","author":"Cowley","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"26032","DOI":"10.1074\/jbc.271.42.26032","article-title":"Reduction of dopamine \u03b2-monooxygenase: A unified model for apparent negative cooperativity and fumarate activation","volume":"271","author":"Wimalasena","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1021\/bi00530a013","article-title":"Dopamine beta-hydroxylase: Activity and inhibition in the presence of beta-substituted phenethylamines","volume":"21","author":"Klinman","year":"1982","journal-title":"Biochemistry"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1042\/bj2420227","article-title":"Interaction of dopamine \u03b2-mono-oxygenase with substituted imidazoles and pyrazoles. Catalysis and inhibition","volume":"242","author":"Sirimanne","year":"1987","journal-title":"Biochem. J."},{"key":"ref_184","doi-asserted-by":"crossref","unstructured":"Bollinger, J.M., Diao, Y., Matthews, M.L., Xing, G., and Krebs, C. (2009). Myo-inositol oxygenase: A radical new pathway for O2 and C-H activation at a nonheme diiron cluster. Dalton Trans., 905\u2013914.","DOI":"10.1039\/B811885J"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"17206","DOI":"10.1021\/ja905296w","article-title":"Insights into the (superoxo)Fe(iii)Fe(iii) intermediate and reaction mechanism of myo-inositol oxygenase: Dft and ONIOM(DFT:MM) study","volume":"131","author":"Hirao","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"15032","DOI":"10.1073\/pnas.0605143103","article-title":"Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism","volume":"103","author":"Brown","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_187","doi-asserted-by":"crossref","unstructured":"Arner, R.J., Prabhu, K.S.T., Thompson, J.R., Hildenbrandt, G.D., Liken, A., and Reddy, C.C. (2001). Myo-inositol oxygenase: Molecular cloning and expression of a unique enzyme that oxidizes myo-inositol and D-chiro-inositol. Biochem. J., 360.","DOI":"10.1042\/0264-6021:3600313"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/13\/2462\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:02:39Z","timestamp":1760187759000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/13\/2462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,4]]},"references-count":187,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["molecules24132462"],"URL":"https:\/\/doi.org\/10.3390\/molecules24132462","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2019,7,4]]}}}