{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T14:56:22Z","timestamp":1775919382808,"version":"3.50.1"},"reference-count":34,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5314","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[1997,5,9]]},"abstract":"<jats:p>\n            A mechanism is proposed to explain the activity of orotidine 5\u2032-monophosphate decarboxylase (ODCase). This enzyme is the one of the most proficient known, with a catalytic proficiency (\n            <jats:italic>k<\/jats:italic>\n            <jats:sub>cat<\/jats:sub>\n            \/\n            <jats:italic>K<\/jats:italic>\n            <jats:sub>m<\/jats:sub>\n            )\/\n            <jats:italic>k<\/jats:italic>\n            <jats:sub>non<\/jats:sub>\n            = 10\n            <jats:sup>23<\/jats:sup>\n            M\n            <jats:sup>\u22121<\/jats:sup>\n            . Quantum mechanical calculations predict a mechanism involving a stabilized carbene intermediate, which represents a previously unrecognized mode of enzymatic activity for ODCase. The proposed mechanism involves proton transfer from a weak acid (p\n            <jats:italic>K<\/jats:italic>\n            <jats:sub>a<\/jats:sub>\n            = 7, where\n            <jats:italic>K<\/jats:italic>\n            <jats:sub>a<\/jats:sub>\n            is the acid constant) concerted with decarboxylation, in a nonpolar enzyme environment. Such a mechanism makes possible different approaches to the design of ODCase inhibitors. Furthermore, the prediction that general acid catalysis may only be effective in low dielectric media is of general significance for understanding the activity of many enzymes.\n          <\/jats:p>","DOI":"10.1126\/science.276.5314.942","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:50:14Z","timestamp":1027763414000},"page":"942-945","source":"Crossref","is-referenced-by-count":150,"title":["A Proficient Enzyme Revisited: The Predicted Mechanism for Orotidine Monophosphate Decarboxylase"],"prefix":"10.1126","volume":"276","author":[{"given":"Jeehiun K.","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K. N.","family":"Houk","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7809611"},{"key":"e_1_3_1_3_2","doi-asserted-by":"crossref","first-page":"4699","DOI":"10.1021\/bi00561a024","volume":"19","author":"McClard R. W.","year":"1980","unstructured":"McClard R. W., Black M. J., Livingstone L. R., Jones M. E., Biochemistry 19, 4699 (1980).","journal-title":"Biochemistry"},{"key":"e_1_3_1_4_2","unstructured":"T. C. Bruice and S. Benkovic in Bioorganic Mechanisms (Benjamin New York 1966) vol. 2 pp. 188\u2013194."},{"key":"e_1_3_1_5_2","unstructured":"M. L. Bender in Mechanisms of Homogeneous Catalysis from Protons to Proteins (Wiley-Interscience New York 1971) pp. 165\u2013175 and 586\u2013594."},{"key":"e_1_3_1_6_2","doi-asserted-by":"crossref","first-page":"3601","DOI":"10.1021\/ja00428a035","volume":"98","author":"Beak P.","year":"1976","unstructured":"Beak P., Siegel B., J. Am. Chem. Soc. 98, 3601 (1976).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_1_7_2","doi-asserted-by":"crossref","first-page":"3198","DOI":"10.1021\/bi00465a007","volume":"29","author":"Acheson S. A.","year":"1990","unstructured":"Acheson S. A., Bell J. B., Jones M. E., Wolfenden R., Biochemistry 29, 3198 (1990).","journal-title":"Biochemistry"},{"key":"e_1_3_1_8_2","first-page":"6216","volume":"30","author":"Smiley J. A.","year":"1991","unstructured":"Smiley J. A., Paneth P., O\u2019Leary M. H., Bell J. B., Jones M. E., ibid. 30, 6216 (1991).","journal-title":"ibid."},{"key":"e_1_3_1_9_2","doi-asserted-by":"crossref","unstructured":"H. L. Levine R. S. Brody F. H. Westheimer ibid. 19 4993 (1980).","DOI":"10.1021\/bi00563a010"},{"key":"e_1_3_1_10_2","doi-asserted-by":"crossref","first-page":"8319","DOI":"10.1073\/pnas.91.18.8319","volume":"91","author":"Smiley J. A.","year":"1994","unstructured":"Smiley J. A., Benkovic S. J., Proc. Natl. Acad. Sci. U.S.A. 91, 8319 (1994).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_11_2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/prot.340090208","volume":"9","author":"Bell J. B.","year":"1991","unstructured":"Bell J. B., Jones M. E., Carter C. W. J., Proteins 9, 143 (1991).","journal-title":"Proteins"},{"key":"e_1_3_1_12_2","unstructured":"Attempts to obtain the crystal structure of ODCase are underway (C. Carter personal communication)."},{"key":"e_1_3_1_13_2","doi-asserted-by":"crossref","first-page":"12162","DOI":"10.1021\/bi00163a027","volume":"31","author":"Smiley J. A.","year":"1992","unstructured":"Smiley J. A., Jones M. E., Biochemistry 31, 12162 (1992).","journal-title":"Biochemistry"},{"key":"e_1_3_1_14_2","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1021\/ja00118a028","volume":"117","author":"Smiley J. A.","year":"1995","unstructured":"Smiley J. A., Benkovic S. J., J. Am. Chem. Soc. 117, 3877 (1995).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_1_15_2","first-page":"6434","volume":"104","author":"Silverman R. B.","year":"1982","unstructured":"Silverman R. B., Groziak M. P., ibid. 104, 6434 (1982).","journal-title":"ibid."},{"key":"e_1_3_1_16_2","doi-asserted-by":"crossref","first-page":"12155","DOI":"10.1021\/bi00163a026","volume":"31","author":"Shostak K.","year":"1992","unstructured":"Shostak K., Jones M. E., Biochemistry 31, 12155 (1992).","journal-title":"Biochemistry"},{"key":"e_1_3_1_17_2","unstructured":"Gaussian 94 revision B.3 (M. J. Frisch et al. Gaussian Inc. Pittsburgh PA 1995). RHF MP2 and basis sets are described by W. J. Hehre L. Radom P. v. R. Schleyer and J. A. Pople [ Ab Initio Molecular Orbital Theory (Wiley New York 1986)]. Density functional theory (Becke3LYP) is described by W. Kohn A. D. Becke and R. G. Parr [ J. Phys. Chem. 100 12974 (1996)]."},{"key":"e_1_3_1_18_2","unstructured":"Unless otherwise specified the calculated \u0394H \u2021 is for 0 K."},{"key":"e_1_3_1_19_2","doi-asserted-by":"crossref","first-page":"11898","DOI":"10.1021\/ja961954l","volume":"118","author":"Lavorato D.","year":"1996","unstructured":"Lavorato D., et al., J. Am. Chem. Soc. 118, 11898 (1996).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_1_19_3","unstructured":"and references therein."},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr00081a001"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5296.67"},{"key":"e_1_3_1_22_2","doi-asserted-by":"crossref","first-page":"6812","DOI":"10.1021\/ja00094a040","volume":"116","author":"Arduengo A. J.","year":"1994","unstructured":"Arduengo A. J., et al., J. Am. Chem. Soc. 116, 6812 (1994).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_1_22_3","unstructured":"and references therein."},{"key":"e_1_3_1_23_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/hlca.19700530210","volume":"53","author":"Wagner R.","year":"1970","unstructured":"Wagner R., von Philipsborn W., Helv. Chim. Acta 53, 299 (1970).","journal-title":"Helv. Chim. Acta"},{"key":"e_1_3_1_24_2","unstructured":"S. G. Lias et al. J. Phys. Chem. Ref. Data 17 (suppl. no. 1) (1988)."},{"key":"e_1_3_1_25_2","unstructured":"Using the difference in the p K a of acetic acid and malonic acid to estimate the effect of a CO 2 \u2212 group we estimate the p K a of protonated orotate to be \u223c1.5."},{"key":"e_1_3_1_26_2","unstructured":"J. A. Dean in Lange\u2019s Handbook of Chemistry (McGraw-Hill San Francisco CA 1992) pp. 8.19\u20138.71."},{"key":"e_1_3_1_27_2","doi-asserted-by":"crossref","first-page":"4731","DOI":"10.1021\/ja00768a052","volume":"94","author":"Jencks W. P.","year":"1972","unstructured":"Jencks W. P., J. Am. Chem. Soc. 94, 4731 (1972).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_1_28_2","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1002\/bip.360251106","volume":"25","author":"Gilson M. K.","year":"1986","unstructured":"Gilson M. K., Honig B. H., Biopolymers 25, 2097 (1986).","journal-title":"Biopolymers"},{"key":"e_1_3_1_29_2","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1063\/1.461760","volume":"95","author":"King G.","year":"1991","unstructured":"King G., Lee F. S., Warshel A., J. Chem. Phys. 95, 4366 (1991).","journal-title":"J. Chem. Phys."},{"key":"e_1_3_1_30_2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1146\/annurev.bb.20.060191.001411","volume":"20","author":"Warshel A.","year":"1991","unstructured":"Warshel A., \u00c5qvist J., Annu. Rev. Biophys. Biophys. Chem. 20, 267 (1991).","journal-title":"Annu. Rev. Biophys. Biophys. Chem."},{"key":"e_1_3_1_31_2","doi-asserted-by":"crossref","first-page":"8452","DOI":"10.1021\/ja960884f","volume":"118","author":"Simonson T.","year":"1996","unstructured":"Simonson T., Brooks C. L., J. Am. Chem. Soc. 118, 8452 (1996).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_1_32_2","unstructured":"Solvation was modeled with the SCI-PCM method available in Gaussian 94 (16). Solvation energies were obtained by calculating RHF\/6-31+G* energies in solvent of a given dielectric and comparing that value to the gas-phase energy. These solvation energies were then used to correct MP2\/6-31+G* energies to obtain \u0394H \u2021 values in solution."},{"key":"e_1_3_1_33_2","unstructured":"We are grateful to NSF and NIH (postdoctoral fellowship to J.K.L.) for financial support of this work and to the UCLA Office of Academic Computing and the National Center for Supercomputing Applications for computational resources."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.276.5314.942","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T05:47:16Z","timestamp":1705124836000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.276.5314.942"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,5,9]]},"references-count":34,"journal-issue":{"issue":"5314","published-print":{"date-parts":[[1997,5,9]]}},"alternative-id":["10.1126\/science.276.5314.942"],"URL":"https:\/\/doi.org\/10.1126\/science.276.5314.942","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,5,9]]}}}