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Antimicrob Agents Chemother. 2009 Jun;53(6):2610-2. doi: 10.1128/AAC.01659-08. Epub 2009 Apr 13.

R964C mutation of DNA polymerase gamma imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activity.

Author information

1
Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520, USA.

Abstract

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.

PMID:
19364868
PMCID:
PMC2687208
DOI:
10.1128/AAC.01659-08
[Indexed for MEDLINE]
Free PMC Article

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