| Effect of β,γ-CHF- and β,γ-CHCl-dGTP halogen atom stereochemistry on the transition state of DNA polymerase β. | |
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MedLine Citation:
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PMID: 23043620 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Recently, we synthesized the first individual β,γ-CHX-dGTP diastereomers [(R)- or (S)-CHX, where X is F or Cl] and determined their structures in ternary complexes with DNA polymerase β (pol β). We now report stereospecificity by pol β on the mixed β,γ-CHX diastereomer pairs using nuclear magnetic resonance and on the separate diastereomers using transient kinetics. For both the F and Cl diastereomers, the R isomer is favored over the S isomer for G·C correct incorporation, with stereospecificities [(k(pol)/K(d))(R)/(k(pol)/K(d))(S)] of 3.8 and 6.3, respectively, and also for G·T misincorporation, with stereospecificities of 11 and 7.8, respectively. Stereopreference for the (R)-CHF-dGTP diastereomer was abolished for k(pol) but not K(d) with mutant pol β (R183A). These compounds constitute a new class of stereochemical probes for active site interactions involving halogen atoms. As Arg183 is unique in family X pols, the design of CXY deoxyribonucleotide analogues to enhance interaction is a possible strategy for inhibiting BER selectively in cancer cells. |
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Authors:
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Keriann Oertell; Yue Wu; Valeria M Zakharova; Boris A Kashemirov; David D Shock; William A Beard; Samuel H Wilson; Charles E McKenna; Myron F Goodman |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-10-19 |
Journal Detail:
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Title: Biochemistry Volume: 51 ISSN: 1520-4995 ISO Abbreviation: Biochemistry Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2013-01-18 Completed Date: 2013-03-19 Revised Date: 2013-04-05 |
Medline Journal Info:
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Nlm Unique ID: 0370623 Medline TA: Biochemistry Country: United States |
Other Details:
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Languages: eng Pagination: 8491-501 Citation Subset: IM |
Affiliation:
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Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Catalytic Domain
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drug effects DNA / metabolism DNA Polymerase beta / chemistry, genetics, metabolism* Deoxyguanine Nucleotides / chemistry*, pharmacology* Halogens / chemistry*, pharmacology* Humans Kinetics Nuclear Magnetic Resonance, Biomolecular Point Mutation Stereoisomerism Substrate Specificity |
| Grant Support | |
ID/Acronym/Agency:
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5-U19-CA105010/CA/NCI NIH HHS; R01-GM21422/GM/NIGMS NIH HHS; R37 GM021422/GM/NIGMS NIH HHS; U19 CA105010/CA/NCI NIH HHS; Z01 ES050158-11/ES/NIEHS NIH HHS; Z01 ES050159-11/ES/NIEHS NIH HHS; Z01-ES050158/ES/NIEHS NIH HHS; Z01-ES050159/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Deoxyguanine Nucleotides; 0/Halogens; 2564-35-4/deoxyguanosine triphosphate; 9007-49-2/DNA; EC 2.7.7.-/DNA Polymerase beta |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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