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An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors
2009
PLoS Computational Biology
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The model predicts an approximately 1000-fold difference in the activated drug concentration required for a 50% probability of mtDNA strand termination between the activated di-deoxy analogs d4T, ddC, ...
Therefore AZT mitochondrial toxicity is likely due to a mechanism that does not involve strand termination of mtDNA replication. ...
We tested that idea by analyzing data for the interaction of several AIDS drugs with the mitochondrial DNA polymerase, the protein responsible for copying mitochondrial DNA. ...
doi:10.1371/journal.pcbi.1000261
pmid:19132079
pmcid:PMC2603287
fatcat:t4bvo2v7p5cfjbaph4pblpamuq
Mechanistic Crosstalk between DNA/RNA Polymerase Enzyme Kinetics and Nucleotide Substrate Availability in Cells: Implications for Polymerase Inhibitor Discovery
2020
Journal of Biological Chemistry
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Enzyme kinetic analysis reveals a dynamic relationship between enzymes and their substrates. ...
Polymerases are commonly targeted by nucleotide analogue inhibitors for the treatments of various human diseases such as cancers and viral pathogens. ...
Acknowledgments This review manuscript was supported by NIH AI136581 (to B.K.), AI150451 (to B.K.), and MH116695 (to R.F.S.). ...
doi:10.1074/jbc.rev120.013746
pmid:32737197
pmcid:PMC7521635
fatcat:75trz64ig5b73c3uiqy4gzumge
Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates
1999
FEBS Letters
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The results demonstrate a broad substrate specificity and complex kinetics, and suggest a role for TK2 in the activation of chemotherapeutic nucleoside analogues. z 1999 Federation of European Biochemical ...
Based on amino acid sequence information from purified mitochondrial thymidine kinase (TK2), a cDNA of 1930 bp was cloned, containing an open reading frame encoding 232 amino acid residues starting with ...
Acknowledgements: This work was supported by grants from the Swedish Medical Research Council, the Swedish Cancer Society (Project 1806) and grants from the European Community (BM44-CT96-0479; BIO4-CT97 ...
doi:10.1016/s0014-5793(98)01711-6
pmid:9989599
fatcat:mym2t35jgffzdedqevz2fheyka
Reverse transcription of the HIV-1 pandemic
2007
The FASEB Journal
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In this review, we provide a brief history of HIV/AIDS, followed by analysis of one therapeutic target of HIV-1: its reverse transcriptase (RT). ...
Reverse transcription of the HIV-1 pandemic. FASEB J. 21, 3795-3808 (2007) ...
REVERSE TRANSCRIPTION Because HIV was found to be a retrovirus, it must encode an enzyme (RT) in order to copy the genomic RNA to integrate into the host's DNA. ...
doi:10.1096/fj.07-8697rev
pmid:17639073
fatcat:c73xkn3ji5cqxgl4eaxv7fwlge
Enzyme Kinetics of the Mitochondrial Deoxyribonucleoside Salvage Pathway Are Not Sufficient to Support Rapid mtDNA Replication
2011
PLoS Computational Biology
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We find that an external source of deoxyribonucleoside diphosphates or triphosphates (dNTPs), in addition to those supplied by mitochondrial salvage, is essential for the replication of mitochondrial DNA ...
Our analysis of the enzyme kinetics also revealed that the majority of enzymes of this pathway prefer substrates that are not precursors (canonical deoxyribonucleosides and deoxyribonucleotides) for mitochondrial ...
For the knockin mouse [62] , a compensatory mechanism involving increased mtDNA transcription through suppression of MTERF3 (mitochondrial transcription termination factor 3) expression was implicated ...
doi:10.1371/journal.pcbi.1002078
pmid:21829339
pmcid:PMC3150320
fatcat:mzskscrrxbcz3iuzehj6fd426e
A mechanistic view of human mitochondrial DNA polymerase γ: Providing insight into drug toxicity and mitochondrial disease
2010
Biochimica et Biophysica Acta - Proteins and Proteomics
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Mitochondrial DNA polymerase gamma (Pol γ) is the sole polymerase responsible for replication of the mitochondrial genome. ...
This review will provide a brief history on the discovery and characterization of human mitochondrial DNA polymerase γ, focusing on kinetic analyses of the polymerase and mechanistic data illustrating ...
Acknowledgments This work was supported by NIH GM49551 to KSA ...
doi:10.1016/j.bbapap.2010.01.007
pmid:20083238
pmcid:PMC2846211
fatcat:rj2spfofdnbkto77seji254tv4
Differential Incorporation and Removal of Antiviral Deoxynucleotides by Human DNA Polymerase γ
2001
Journal of Biological Chemistry
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We evaluated the ability of such analogs to inhibit DNA synthesis by the human mitochondrial DNA polymerase (pol ␥) by comparing the insertion and exonucleolytic removal of six antiviral nucleotide analogs ...
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. ...
Acknowledgments-We thank Susan Danehower (GlaxoWellcome) for 3TC-TP and CBV-TP. We thank Dr. K. Bebenek (NIEHS, National Institutes of Health, Research Triangle Park, NC) for purified HIV-RT enzyme. ...
doi:10.1074/jbc.m101114200
pmid:11319228
fatcat:eq43uud2nzdmna4fz2bktcj32e
Selective Inhibition of HIV-1 Reverse Transcriptase by an Antiviral Inhibitor, (R)-9-(2-Phosphonylmethoxypropyl)adenine
1998
Journal of Biological Chemistry
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type 1 (HIV-1) reverse transcriptase, an exonuclease-deficient T7 DNA polymerase (T7 exo ؊ ), and wild-type rat DNA polymerase  in order to evaluate the selectivity of PMPA as an antiviral inhibitor. ...
By using presteady state kinetic methods, we examined the incorporation of the diphosphate of PMPA, 2,3-dideoxyadenosine 5-triphosphate (ddATP), and dATP catalyzed by wild-type human immunodeficiency virus ...
During replication, virally encoded reverse transcriptase (RT) copies the single-stranded viral RNA genome into a minus strand of DNA and then uses the resultant cDNA to synthesize a plus strand DNA to ...
doi:10.1074/jbc.273.42.27250
pmid:9765248
fatcat:yv2ctgjggjcrlcf5cgzfzkhngu
Enzymatic Therapeutic Index of Acyclovir
2007
Journal of Biological Chemistry
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We have examined the kinetics of incorporation of acyclovir triphosphate by the herpes simplex virus-1 DNA polymerase holoenzyme (Pol-UL42) and the human mitochondrial DNA polymerase using transient kinetic ...
For each enzyme, we compared the kinetic parameters for acyclovir to those governing incorporation of dGTP. ...
Most of the toxic side effects caused by nucleoside reverse transcriptase inhibitors (NRTIs) used for the treatment of human immunodeficiency virus (HIV) infection are a result of mitochondrial dysfunction ...
doi:10.1074/jbc.m703972200
pmid:17573351
fatcat:yl746gyrq5gxvdqtdq2hg3pgxu
Mitochondrial DNA Replication in Health and Disease
[chapter]
2011
DNA Replication-Current Advances
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The authors thank Brian Normanly for his English language editing. ...
The study was supported by grants PI081325 and PI070091 from "Fondo de Investigacion Sanitaria", and ACOMP2010/207 y PROMETEO/2010/060 from Generalitat Valenciana, Spain. ...
It involves the use of one or two NRTI and one Non-Nucleoside Analogue Reverse Inhibitor (NNRTI) or one protease inhibitor (Zolopa, 2010) . ...
doi:10.5772/19162
fatcat:rod2knbvjzc3jodcivp4aqhivq
Mechanisms of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription
1996
Antimicrobial Agents and Chemotherapy
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ACKNOWLEDGMENT Work performed in our laboratory was supported by the Medical Research Council of Canada and the National Health Research and Development Program. ...
None of the latter kinetic analyses of ddNMP or dNMP incorporation during DNA synthesis catalyzed by HIV-1 RT have employed an RNA primer-RNA template [to initiate synthesis of (Ϫ) DNA] or an RNA primer-DNA ...
HU is an inhibitor of ribonucleotide reductase, a rate-limiting enzyme responsible for the conversion of ribonucleosides to deoxyribonucleosides, and has been shown to be necessary for cellular DNA synthesis ...
pmid:8851566
pmcid:PMC163153
fatcat:n563vm4vxjgb5hukrbopsyb6vq
Mechanisms of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription
1996
Antimicrobial Agents and Chemotherapy
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ACKNOWLEDGMENT Work performed in our laboratory was supported by the Medical Research Council of Canada and the National Health Research and Development Program. ...
Model for incorporation of ddNMP by HIV-1 RT and subsequent chain termination during reverse transcription. ...
None of the latter kinetic analyses of ddNMP or dNMP incorporation during DNA synthesis catalyzed by HIV-1 RT have employed an RNA primer-RNA template [to initiate synthesis of (Ϫ) DNA] or an RNA primer-DNA ...
doi:10.1128/aac.40.3.527
fatcat:hhb6rfscv5bxzcpqeoydv3gzo4
Effects of 3'-deoxynucleoside 5'-triphosphate concentrations on chain termination by nucleoside analogs during human immunodeficiency virus type 1 reverse transcription of minus-strand strong-stop DNA
1996
Journal of Virology
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Pausing of HIV-1 reverse transcriptase during reverse transcription, altered by dNTP concentrations, may be a mechanism that controls the position and extent of incorporation of nucleoside analogs. ...
or a deoxyoligonucleotide as primer was used to monitor chain termi-nation mediated by 2',3'-dideoxynucleoside triphosphates (ddNTPs) during synthesis of minus-strand strong-stop DNA. ...
Research in the laboratory of S.F.J.L. was supported by NIH grant AI 36219 and by the core support facilities of the Center for AIDS Research grant at Case Western Reserve University. ...
pmid:8551607
pmcid:PMC189871
fatcat:vdmciso6rnbevg3uvjunzfmi64
Effects of 3'-deoxynucleoside 5'-triphosphate concentrations on chain termination by nucleoside analogs during human immunodeficiency virus type 1 reverse transcription of minus-strand strong-stop DNA
1996
Journal of Virology
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3 Lys or a deoxyoligonucleotide as primer was used to monitor chain termi-nation mediated by 2,3-dideoxynucleoside triphosphates (ddNTPs) during synthesis of minus-strand strong-stop DNA. ...
with those of their triphosphorylated derivatives in cell-free HIV-1 reverse transcription assays. ...
Research in the laboratory of S.F.J.L. was supported by NIH grant AI 36219 and by the core support facilities of the Center for AIDS Research grant at Case Western Reserve University. ...
doi:10.1128/jvi.70.2.712-720.1996
fatcat:d3w6xp4mzbbw3k6i3zxqevobta
Inhibition of Hepatitis B Virus DNA Polymerase by Thymidine Triphosphate Analogues in vitro
1991
Antiviral Chemistry & Chemotherapy
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Summers, J., and Mason, W.S. (1982) Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 29: 403-415. ...
Human HBV is characterized by its partially double- stranded circular DNA genome and its unusual replication mechanism encompassing reverse _ transcription (Summers and Mason, 1982). ...
doi:10.1177/095632029100200406
fatcat:33ewkixlvbhsncw3z2oer4f7qm
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