Reconciliation of Chemical, Enzymatic, Spectroscopic and Computational Data To Assign the Absolute Configuration of the DNA Base Lesion Spiroiminodihydantoin.
The diastereomeric spiroiminodihydantoin-2'-deoxyribonucleoside (dSp) lesions resulting from 2'-deoxyguanosine (dG) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (dOG) oxidation have generated much attention due to their highly mutagenic nature. Their propeller-like shape leads these molecules to display m...
| Publicado en: | Journal of the American Chemical Society Vol. 135; no. 48; pp. 18191 - 18205 |
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| Autores principales: | , , , , , |
| Formato: | Artículo |
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American Chemical Society
12/4/2013
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| Materias: | |
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=93312307&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 93312307 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 12/4/2013 vid: 135 iid: 48 pid: 997 pub: American Chemical Society artinfo: ui: 93312307 10.1021/ja409254z ppf: 18191 ppct: 14 formats: tig: atl: Reconciliation of Chemical, Enzymatic, Spectroscopic and Computational Data To Assign the Absolute Configuration of the DNA Base Lesion Spiroiminodihydantoin. aug: au: Fleming, Aaron M. Orendt, Anita M. Yanan He Zhu, Judy Dukor, Rina K. Burrows, Cynthia J. affil: Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States Center for High Performance Computing, University of Utah, 155 South 1452 East, Salt Lake City, Utah 84112-0190, United States BioTools, Inc. 17546 Bee Line Hwy, Jupiter, Florida 33458, United States su: Deoxyribonucleotides Deoxyguanosine Oxidation Circular dichroism Isomers Density functional theory DNA damage sug: subj: Deoxyribonucleotides Deoxyguanosine Oxidation Circular dichroism Isomers Density functional theory DNA damage ab: The diastereomeric spiroiminodihydantoin-2'-deoxyribonucleoside (dSp) lesions resulting from 2'-deoxyguanosine (dG) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (dOG) oxidation have generated much attention due to their highly mutagenic nature. Their propeller-like shape leads these molecules to display mutational profiles in vivo that are stereochemically dependent. However, there exist conflicting absolute configuration assignments arising from electronic circular dichroism (ECD) and NOESY-NMR experiments; thus, providing definitive assignments of the 3D structure of these molecules is of great interest. In the present body of work, we present data inconsistent with the reported ECD assignments for the dSp diastereomers in the nucleoside context, in which the first eluting isomer from a Hypercarb HPLC column was assigned to be the S configuration, and the second was assigned the R configuration. The following experiments were conducted: (1) determination of the diastereomer ratio of dSp products upon one-electron oxidation of dG in chiral hybrid or propeller G-quadruplexes that expose the re or si face to solvent, respectively; (2) absolute configuration analysis using vibrational circular dichroism (VCD) spectroscopy; (3) reinterpretation of the ECD experimental spectra using time-dependent density functional theory (TDDFT) with the inclusion of 12 explicit H-bonding waters around the Sp free bases; and (4) reevaluation of calculated specific rotations for the Sp enantiomers using the hydration model in the TDDFT calculations. These new insights provide a fresh look at the absolute configuration assignments of the dSp diastereomers in which the first eluting from a Hypercarb-HPLC column is (-)-(R)-dSp and the second is (+)-(S)-dSp. These assignments now provide the basis for understanding the biological significance of the stereochemical dependence of enzymes that process this form of DNA damage. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2013 holdings: @attributes: islocal: N |
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