Tautomerism, ionization and protonation of - article (neat)

Tautomerism, ionization and protonation of - article (neat)...

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Unformatted text preview: NucleicAcids Research, Vol. 19,No. 5 1041 Structure ofoxidatively damaged nucleicacid adducts. 3. Tautomerism, ionization and protonation of 8-hydroxyadenosine studied by 15N NMR spectroscopy Bongsup P.Cho and Frederick E.Evans* NationalCenterfor ToxicologicalResearch, Food and DrugAdministration, Jefferson, AR 72079, USA Received December 11, 1990; Revised and Accepted February 4,1991 ABSTRACT Natural abundance 15N NMR spectroscopy and ancillary spectroscopic techniques have been employed to study the solution structure of 8-hydroxyadenosine. 8-Hydroxyadenosine isanaturally occurringoxidizednucleicacidadductthatisgenerally impliedtohavean 8-hydroxytautomericstructure.15N NMR chemicalshiftsandcouplingconstants,however, indicate that the modified base exists as an 8-keto tautomer. The pH dependence of 15N NMR and UV spectra showedthepresenceoftwo pKa's, at2.9and 8.7,correspondingtoprotonationat Ni andionization at N7,respectively.The latterresultsintheformation of an 8-enolatestructure.Unusualupfieldshiftsofthe 1H and 15N resonances of the NH2 group, and a reductionintheone-bond couplingconstant 1JN6H6, is indicative of an unfavorable steric or electronic interaction between the NH2 group and the adjacent N7-Hproton.Thisinteractionresultsinasubtlechange inthestructureqftheNH2 group.Inadditiontobeing a possible mechanism for alteration of hydrogen bondinginoxidizedDNA,thistypeofinteractiongives a better understanding into N7-N9 tautomerism of adenine. Furthermore, the structure of 8-hydroxyadenosine has been related to possible mechanisms formutations. INTRODUCTION TheC8-oxidationofthepurineDNA bases,guanineandadenine, isoneofthemajorformsofoxidativebasedamage,whichcan resultfromtheactionofionizingradiation(1)andotheroxygen radical generatingsystems(2).Thesechemicalmodificationsare thoughttohaveimportantbiologicalimplicationsinagingand cancer (3,4).We have previouslycharacterizedthestructureof themutagenic adduct 8-oxo-2'-deoxyguanosineanditsribosyl analog 8-oxoguanosine(5,6).AnotherC8-oxidizedpurinebase is8-hydroxyadenine(7),whichhasbeendetectedin neoplastic liveroffish(8),aswellasinurine samplesofferretsandhumans (9). Recently,Guyetal.(10)preparedandcharacterizedseveral oligodeoxynucleotidescontaining8-hydroxyadeninemoietiesand showed (11) thata modified oligomer was threetimes more susceptibletoDNA chainruptureswhentreatedwith-y-irradiation andheatedinthepresenceofpiperidine.Immunological (12), high performance liquid chromatography-electrochemical (HPLC-EC) (13),andgaschromatography-massspectral(GC- MS) (8,9)assayshavebeendevelopedforthismodifiedbase. Despite the potential biological significance, structural informationaboutthisimportantlesionanditsderivatives,aswell aspossiblestructurefunctionrelationships,islimited.Previous infraredspectralanalyseshave tentativelyassignedthestructure of8-hydroxy-2'-deoxyadenosineinthesolidstateasthe8-keto form (10).Inaddition, 8-hydroxyadenosinehasbeenreported toexistinthesynconformationabouttheglycosylbond(14,15).toexistinthesynconformationabouttheglycosylbond(14,15)....
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This note was uploaded on 10/18/2010 for the course CHE 326 taught by Professor Fowler during the Fall '08 term at SUNY Stony Brook.

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Tautomerism, ionization and protonation of - article (neat)...

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