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Antimicrobial Agents and Chemotherapy, June 2009, p. 2610-2612, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01659-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

R964C Mutation of DNA Polymerase {gamma} Imparts Increased Stavudine Toxicity by Decreasing Nucleoside Analog Discrimination and Impairing Polymerase Activity{triangledown}

Christopher M. Bailey,1 Rajesh Kasiviswanathan,2 William C. Copeland,2 and Karen S. Anderson1*

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520,1 Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 277092

Received 17 December 2008/ Returned for modification 18 February 2009/ Accepted 27 March 2009

The R964C mutation of human DNA polymerase {gamma} was recently linked to stavudine (d4T)-mediated mitochondrial toxicity. We utilized pre-steady-state kinetics to determine the effect of this mutation on incorporation of natural substrate dTTP and the active metabolite of d4T (d4TTP). The R964C polymerase {gamma} holoenzyme demonstrated a 33% decrease in dTTP incorporation efficiency and a threefold-lower d4TTP discrimination relative to that of the wild-type polymerase {gamma}, providing a mechanistic basis for genetic predisposition to nucleoside reverse transcriptase inhibitor toxicity.

* Corresponding author. Mailing address: Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Phone: (203) 785-4526. Fax: (203) 785-7670. E-mail: karen.anderson{at}yale.edu

{triangledown} Published ahead of print on 13 April 2009.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2610-2612, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01659-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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