scholarly journals Toxicity of Antiviral Nucleoside Analogs and the Human Mitochondrial DNA Polymerase

2001 ◽  
Vol 276 (44) ◽  
pp. 40847-40857 ◽  
Author(s):  
Allison A. Johnson ◽  
Adrian S. Ray ◽  
Jeremiah Hanes ◽  
Zucai Suo ◽  
Joseph M. Colacino ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Nucleoside Analogs ◽  
Human Mitochondrial Dna ◽  
Mitochondrial Dna Polymerase ◽  
Antiviral Nucleoside

scholarly journals Exonuclease Removal of Dideoxycytidine (Zalcitabine) by the Human Mitochondrial DNA Polymerase

2007 ◽  
Vol 52 (1) ◽  
pp. 253-258 ◽  
Author(s):  
Jeremiah W. Hanes ◽  
Kenneth A. Johnson
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Tight Binding ◽  
Nucleoside Analogs ◽  
Physiological Concentration ◽  
Human Mitochondrial Dna ◽  
Immunodeficiency Virus ◽  
Mitochondrial Dna Polymerase ◽  
Kinetics Of ◽  
Low Rate

ABSTRACT The toxicity of nucleoside analogs used for the treatment of human immunodeficiency virus infection is due primarily to the inhibition of replication of the mitochondrial genome by the human mitochondrial DNA polymerase (Pol γ). The severity of clinically observed toxicity correlates with the kinetics of incorporation versus excision of each analog as quantified by a toxicity index, spanning over six orders of magnitude. Here we show that the rate of excision of dideoxycytidine (zalcitabine; ddC) was reduced fourfold (giving a half-life of ∼2.4 h) by the addition of a physiological concentration of deoxynucleoside triphosphates (dNTPs) due to the formation of a tight ternary enzyme-DNA-dNTP complex at the polymerase site. In addition, we provide a more accurate measurement of the rate of excision and show that the low rate of removal of ddCMP results from both the unfavorable transfer of the primer strand from the polymerase to the exonuclease site and the inefficient binding and/or hydrolysis at the exonuclease site. The analogs ddC, stavudine, and ddATP (a metabolite of didanosine) each bind more tightly at the polymerase site during incorporation than normal nucleotides, and this tight binding contributes to slower excision by the proofreading exonuclease, leading to increased toxicity toward mitochondrial DNA.

Human Mitochondrial DNA Polymerase Holoenzyme: Reconstitution and Characterization†

Biochemistry ◽  
2000 ◽  
Vol 39 (7) ◽  
pp. 1702-1708 ◽  
Author(s):  
Allison A. Johnson ◽  
Yu-chih Tsai ◽  
Steven W. Graves ◽  
Kenneth A. Johnson
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Human Mitochondrial Dna ◽  
Mitochondrial Dna Polymerase

scholarly journals Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome

2005 ◽  
Vol 14 (14) ◽  
pp. 1907-1920 ◽  
Author(s):  
Petri T. Luoma ◽  
Ningguang Luo ◽  
Wolfgang N. Löscher ◽  
Carol L. Farr ◽  
Rita Horvath ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Human Mitochondrial Dna ◽  
Mitochondrial Dna Polymerase ◽  
Functional Defects

scholarly journals Networked Communication between Polymerase and Exonuclease Active Sites in Human Mitochondrial DNA Polymerase

2019 ◽  
Vol 141 (27) ◽  
pp. 10821-10829
Author(s):  
Mark L. Sowers ◽  
Andrew P. P. Anderson ◽  
James O. Wrabl ◽  
Y. Whitney Yin
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Active Sites ◽  
Human Mitochondrial Dna ◽  
Mitochondrial Dna Polymerase

scholarly journals Functional Human Mitochondrial DNA Polymerase γ Forms a Heterotrimer

2005 ◽  
Vol 281 (1) ◽  
pp. 374-382 ◽  
Author(s):  
Elena Yakubovskaya ◽  
Zhixin Chen ◽  
José A. Carrodeguas ◽  
Caroline Kisker ◽  
Daniel F. Bogenhagen
Keyword(s):  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Human Mitochondrial Dna ◽  
Mitochondrial Dna Polymerase ◽  
Dna Polymerase Γ
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