The 5′-triphosphates of 3′-azido-3′-deoxythymidine and 2′, 3′-dideoxynucleosides inhibit DNA polymerase γ by different mechanisms

Izuta, Shunji; Saneyoshi, Mineo; Sakurai, Takeshi; Suzuki, Motoshi; Kojima, Kiyohide; Yoshida, Shonen

doi:10.1016/0006-291x(91)91884-f

Cited by 74 publications

(39 citation statements)

References 16 publications

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“…However, the interference of the shift in gel mobility by ddTTP did not occur (data not shown), indicating that the action modes of ddTTP and solanapyrone A on pol ␤ differed from each other. The ddTTP data were in agreement with those of a previous study (45), indicating that the inhibition mode of pol ␤ by ddTTP was noncompetitive with the DNA template-primer.…”

Section: ͼ100supporting

confidence: 82%

“…ddTTP inhibited the pol ␤ activity by competing with TTP (45). In contrast, the inhibition of pol ␤ by solanapyrone A was competitive with the DNA template (Fig.…”

Section: ͼ100mentioning

confidence: 90%

“…The inhibition of pol ␤ by ddTTP was non-competitive with activated DNA as a DNA template-primer and competitive with respect to the dNTP substrate (45). ddTTP inhibited the pol ␤ activity by competing with TTP (45).…”

Section: ͼ100mentioning

confidence: 97%

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A Plant Phytotoxin, Solanapyrone A, Is an Inhibitor of DNA Polymerase β and λ

Mizushina¹,

Kamisuki²,

Kasai³

et al. 2002

Journal of Biological Chemistry

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Eukaryotic cells reportedly contain three replicative DNAdirected DNA polymerases (EC 2.7.7.7) (pol ␣, ␦, and ⑀), 1 mitochondrial DNA polymerase (pol ␥), and at least nine repair types of DNA polymerase (pol ␤, ␦, ⑀, , , , , , and ) (1-8), and we have screened for natural compounds that selectively inhibit each of these eukaryotic DNA polymerases and found several inhibitors (9 -15). The purpose was to use the compounds as tools and molecular probes to distinguish DNA polymerases and to clarify their biological and in vivo functions. In this study, we found an interesting fungus-produced compound that selectively inhibits the activities of pol ␤ and pol . Interestingly, the compound was found to be a plant phytotoxin, solanapyrone A, isolated from the causal fungus of early blight disease in potato. To our knowledge, such specific natural compounds have not been reported with the exception of the pol ␤-inhibitor, prunasin, which we reported previously (13). The compound was a stronger pol ␤-inhibitor than prunasin, and no pol -inhibitors have been reported.Pol ␤ is the lowest molecular mass (39 kDa) DNA polymerase lacking such intrinsic accessory activities as 3Ј-or 5Ј-exonuclease, endonuclease, dNMP turnover, or pyrophosphorolysis (16). Pol ␤ consists of an independently folded N-terminal 8-kDa domain and C-terminal 31-kDa domain (17,18). The N-terminal domain was originally characterized as a single-stranded DNA (ssDNA)-binding domain. It was then found to possess binding specificity for the 5Ј-phosphate in gapped DNA (19 -21) and a helix-hairpin-helix motif found in several other DNA repair enzymes (22,23). Recently, Matsumoto and Kim (24) demonstrated that pol ␤ catalyzes the removal of dRP from the AP endonuclease-incised AP site via ␤-elimination as opposed to hydrolysis, and that this dRP lyase activity resides in the 8-kDa domain of pol ␤. According to recent studies (7, 25), moreover, pol ␤ is known to have another family polymerase, pol . Pol ␤ has been present in all tissues examined and is generally expressed at a low level as are a number of other so-called constitutive "house-keeping" enzymes. Although the in vivo function of the family enzyme, pol , is unclear as yet, pol appears to work in a similar manner to pol ␤ (7). As to why a plant phytotoxin is a pol ␤-family-specific inhibitor, we presently are analyzing the structure and function of pol ␤ and pol using the inhibitor from two different view-points to understand the precise role of each of the polymerases in vivo and to develop a drug design strategy for cancer chemotherapy agents. We previously reported the three-dimensional structure of pol ␤ and the N-terminal 8-kDa domain (the DNA template-binding domain) with or without long chain fatty acids to further clarify the structure and function of pol ␤ (26). Because at least pol ␤ is an essential enzyme for nucleotide excision repair (1, 2), the plant phytotoxin may lead to blockage of the DNA repair systems of rescue cancer cells under clinical radiation-therapy or chemotherapy. The plan...

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Section: ͼ100supporting

confidence: 82%

“…ddTTP inhibited the pol ␤ activity by competing with TTP (45). In contrast, the inhibition of pol ␤ by solanapyrone A was competitive with the DNA template (Fig.…”

Section: ͼ100mentioning

confidence: 90%

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A Plant Phytotoxin, Solanapyrone A, Is an Inhibitor of DNA Polymerase β and λ

Mizushina¹,

Kamisuki²,

Kasai³

et al. 2002

Journal of Biological Chemistry

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“…[The following references were cited only in Table 1: Barile et al, 1994Barile et al, , 1997Benbrik et al, 1997;Browne et al, 1993;Chen and Cheng, 1992;Cherrington et al, 1995;Corcuera et al, 1996;Cui et al, 1997;Dalakas et al, 1990;Elimadi et al, 1997. The following references were cited only in Table 1: Feldman and Anderson, 1994;Feldman et al, 1992;Hart et al, 1992;Hertzberg et al, 1992;Hobbs et al, 1992Hobbs et al, , 1995; Institute of Medicine (US) Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials, 1995;Izuta et al, 1991. The following references were cited only in Table 1: Modica-Napolitano, 1993;Nusbaum and Joseph, 1996;Parker et al, 1991;Pereira et al, 1998;Richardson et al, 1994;Schroder et al, 1996;Stevenson et al, 1995;Tsai et al, 1994.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Lewis

Copeland

Day

2001

Laboratory Investigation

159

111

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“…In contrast to dideoxynucleotides, we did not detect any incorporation of AZT-TP into the primer terminus by polymerase y, although this enzyme is to some extent sensitive to AZT-TP (Cherrington et al, Antiviral Chemistry & Chemotherapy 8(3) Nucleotideincorporationby host DNApolymerases 1995). Based on these data, the unproductive binding of AZT-TP into the dNTP-binding site can be considered as the predominant mechanism of inhibition of this enzyme (Izuta et al, 1991). Conflicting results have been reported regarding the incorporation of AZT-TP by polymerase ex.…”

Section: Discussionmentioning

confidence: 99%

Incorporation of Selected Nucleoside Phosphonates and Anti-Human Immunodeficiency Virus Nucleotide Analogues into DNA by Human DNA Polymerases α, β and γ

Cihlář

Chen

1997

Antivir Chem Chemother

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SummaryIncorporation of selected diphosphates of nucleoside phosphonates and friphosphotes of currently approved anti-human immunodeficiency virus nucleoside analogues into DNA by human DNA polymerases a,~and y was studied. All three polymerases were able to incorporate diphosphates of 9-(2-phosphonomethoxyethyl)adenine (PMEApp), 9-(2-phosphonomethoxyethyl)guanine (PMEGpp), (R)-9-(2-phosphonomethoxypropyl)adenine (PMPApp), (R)-9-(2-phosphononomethoxypropyl)-2,6-diaminopurine (PMPDAPpp) and (2R,5R)-9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine (D4APpp) into primer/template DNA of defined sequence. After incorporation, these nucleoside phosphonates acted as terminators of primer extension. Kinetic constants of their incorporation were determined and compared with those for incorporation of ddATP, ddCTP, (-)-2'-deoxy-3'-thiacytidine triphosphate (3TC-TP),~',3'-dide hydro-3'-deoxythymidine triphosphate (d4T-TP) and 3'-azido-3'-deoxythymidine triphosphate (AZT-TP).Relative efficiencies of incorporation (percentage of the incorporation efficiency for the corresponding natural deoxynucleoside triphosphate) by DNA polymerase a ranged from 0.05% for 3TC-TP to 51% for PMEGpp. DNA polymerase~catalysed the incorporation with relative efficiencies ranging from 0.014% for AZT-TP to 125% for ddCTP, and efficiencies of incorporation by DNA polymerase y varied between 0.13% for 3TC-TP and 25% for ddCTP. Generally, the lowest incorporation efficiencies with all three polymerases were found for PMPApp (0.06-1 .4%) and PMPDAPpp (0.075-2.2%).

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The 5′-triphosphates of 3′-azido-3′-deoxythymidine and 2′, 3′-dideoxynucleosides inhibit DNA polymerase γ by different mechanisms

Cited by 74 publications

References 16 publications

A Plant Phytotoxin, Solanapyrone A, Is an Inhibitor of DNA Polymerase β and λ

A Plant Phytotoxin, Solanapyrone A, Is an Inhibitor of DNA Polymerase β and λ

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Incorporation of Selected Nucleoside Phosphonates and Anti-Human Immunodeficiency Virus Nucleotide Analogues into DNA by Human DNA Polymerases α, β and γ

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