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J. Biol. Chem., Vol. 276, Issue 26, 23616-23623, June 29, 2001
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From the Laboratory of Molecular Genetics, NIEHS, National
Institutes of Health,
Research Triangle Park, North Carolina 27709
Mitochondrial toxicity can result
from antiviral nucleotide analog therapy used to control human
immunodeficiency virus type 1 infection. We evaluated the ability of
such analogs to inhibit DNA synthesis by the human mitochondrial DNA
polymerase (pol
Differential Incorporation and Removal of Antiviral
Deoxynucleotides by Human DNA Polymerase
*
) by comparing the insertion and exonucleolytic
removal of six antiviral nucleotide analogs. Apparent steady-state
Km and kcat values for
insertion of 2',3'-dideoxy-TTP (ddTTP), 3'-azido-TTP (AZT-TP),
2',3'-dideoxy-CTP (ddCTP), 2',3'-didehydro-TTP (D4T-TP), (-)-2',3'-dideoxy-3'-thiacytidine (3TC-TP), and carbocyclic
2',3'-didehydro-ddGTP (CBV-TP) indicated incorporation of all six
analogs, albeit with varying efficiencies. Dideoxynucleotides and
D4T-TP were utilized by pol in vitro as efficiently as
natural deoxynucleotides, whereas AZT-TP, 3TC-TP, and CBV-TP were only
moderate inhibitors of DNA chain elongation. Inefficient excision of
dideoxynucleotides, D4T, AZT, and CBV from DNA predicts persistence
in vivo following successful incorporation. In contrast,
removal of 3'-terminal 3TC residues was 50% as efficient as natural 3'
termini. Finally, we observed inhibition of exonuclease activity by
concentrations of AZT-monophosphate known to occur in cells. Thus,
although their greatest inhibitory effects are through incorporation
and chain termination, persistence of these analogs in DNA and
inhibition of exonucleolytic proofreading may also contribute to
mitochondrial toxicity.
*
This work was supported by a National Institutes of Health
intramural AIDS award (to W. C. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Laboratory of
Molecular Genetics, NIEHS, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709 . Tel.: 919-541-4792; Fax:
919-541-7613; E-mail: copelan1@niehs.nih.gov.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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