Document Detail


Effect of β,γ-CHF- and β,γ-CHCl-dGTP halogen atom stereochemistry on the transition state of DNA polymerase β.
MedLine Citation:
PMID:  23043620     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-19
Journal Detail:
Title:  Biochemistry     Volume:  51     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-03-19     Revised Date:  2013-10-22    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8491-501     Citation Subset:  IM    
Affiliation:
Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.
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MeSH Terms
Descriptor/Qualifier:
Catalytic Domain / 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:
5-U19-CA105010/CA/NCI NIH HHS; R01 GM021422/GM/NIGMS 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:
0/Deoxyguanine Nucleotides; 0/Halogens; 2564-35-4/deoxyguanosine triphosphate; 9007-49-2/DNA; EC 2.7.7.-/DNA Polymerase beta
Comments/Corrections

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