R964C Mutation of DNA Polymerase γ Imparts Increased Stavudine Toxicity by Decreasing Nucleoside Analog Discrimination and Impairing Polymerase Activity

被引：34

作者：

Bailey, Christopher M. ^{[1
]}

Kasiviswanathan, Rajesh ^{[2
]}

Copeland, William C. ^{[2
]}

Anderson, Karen S. ^{[1
]}

机构：

[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

[2] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2009年 / 53卷 / 06期

关键词：

MITOCHONDRIAL TOXICITY; ANTIRETROVIRAL THERAPY; REVERSE-TRANSCRIPTASE; SUBUNIT; INHIBITORS; DRUGS;

D O I：

10.1128/AAC.01659-08

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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.

引用

页码：2610 / 2612

页数：3

共 22 条

[1] How E-coli DNA polymerase I (Klenow fragment) distinguishes between deoxy- and dideoxynucleotides [J].

Astatke, M ;

Grindley, NDF ;

Joyce, CM .

JOURNAL OF MOLECULAR BIOLOGY, 1998, 278 (01) :147-165

[2] Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy? [J].

Brinkman, K ;

Kakuda, TN .

CURRENT OPINION IN INFECTIOUS DISEASES, 2000, 13 (01) :5-11

[3]

CHAN SS, BIOCH BIOPH IN PRESS

[4] Relationship Between Polymerase Gamma (POLG) Polymorphisms and Antiretroviral Therapy-Induced Lipodystrophy in HIV-1 Infected Patients: A Case-Control Study [J].

Chiappini, Franck ;

Teicher, Elina ;

Saffroy, Raphael ;

Debuire, Brigitte ;

Vittecoq, Daniel ;

Lemoine, Antoinette .

CURRENT HIV RESEARCH, 2009, 7 (02) :244-253

[5] Insights into the molecular mechanism of mitochondrial toxicity by AIDS drugs [J].

Feng, JY ;

Johnson, AA ;

Johnson, KA ;

Anderson, KS .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (26) :23832-23837

[6] Expression, purification, and initial kinetic characterization of the large subunit of the human mitochondrial DNA polymerase [J].

Graves, SW ;

Johnson, AA ;

Johnson, KA .

BIOCHEMISTRY, 1998, 37 (17) :6050-6058

[7] Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia [J].

Graziewicz, MA ;

Longley, MJ ;

Bienstock, RJ ;

Zeviani, M ;

Copeland, WC .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2004, 11 (08) :770-776

[8] Antiretroviral treatment of adult HIV infection - 2008 recommendations of the International AIDS Society USA panel [J].

Hammer, Scott M. ;

Eron, Joseph J., Jr. ;

Reiss, Peter ;

Schooley, Robert T. ;

Thompson, Melanie A. ;

Walmsley, Sharon ;

Cahn, Pedro ;

Fischl, Margaret A. ;

Gatell, Jose M. ;

Hirsch, Martin S. ;

Jacobsen, Donna M. ;

Montaner, Julio S. G. ;

Richman, Douglas D. ;

Yeni, Patrick G. ;

Volberding, Paul A. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2008, 300 (05) :555-570

[9] Human mitochondrial DNA polymerase holoenzyme: Reconstitution and characterization [J].

Johnson, AA ;

Tsai, YC ;

Graves, SW ;

Johnson, KA .

BIOCHEMISTRY, 2000, 39 (07) :1702-1708

[10] Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase [J].

Johnson, AA ;

Ray, AS ;

Hanes, J ;

Suo, ZC ;

Colacino, JM ;

Anderson, KS ;

Johnson, KA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (44) :40847-40857

← 1 2 3 →