Effects of exogenous polyamine and trypanocides on the DNA polymerase activities from Trypanosoma brucei brucei, mouse thymus and murine leukemia virus

Marcus, Stuart L.; Kopelman, Rebecca; Koll, Brian; Bacchi, Cyrus J.

doi:10.1016/0166-6851(82)90032-9

Cited by 15 publications

(5 citation statements)

References 16 publications

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“…Its analogue homidiurn has been considered to act primarily by inhibiting DNA synthesis (Newton, 1957) because of its binding to DNA by intercalation between the base pairs (Waring, 1965;Le Pecq & Paoletti, 1967). Similarly, ISMM has been shown to be capable of binding to DNA (Wagner, 1971;Kinabo & Bogan, 1987) and inhibiting RNA polymerase (Richardson, 1973), DNA polymerase (Marcus et al, 1982) and the incorporation of nucleic acid precursors into DNA and RNA (Lantz & Van Dyke, 1972). These findings suggest that the primary action of ISMM is blockade of nucleic acid synthesis.…”

Section: Mode Of Actionmentioning

confidence: 99%

“…However, this mechanism does not explain the basis of selective toxicity of ISMM. Marcus et al (1982) found that both mammalian and trypanosomal DNA polymerases were inhibited by ISMM. It is probable that interaction of the drug with certain biochemical systems of trypanosomes such as glycosomes, kinetoplast DNA (Opperdoes, 1 985), glycoprotein biosynthesis (Casero et al, 1982), lipid metabolism (Dixon et al, 1971;Macadam & Williamson, 1974;Kinabo & Bogan, 1987) and membrane transport systems (Girgis-Takla & James, 1974) may constitute part of the overall mode of action of the drug and thus provide a basis for its selective toxicity.…”

Section: Mode Of Actionmentioning

confidence: 99%

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The pharmacology of isometamidium

Kinabo¹,

Bogan²

1988

Vet Pharm & Therapeutics

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Section: Mode Of Actionmentioning

confidence: 99%

Section: Mode Of Actionmentioning

confidence: 99%

The pharmacology of isometamidium

Kinabo¹,

Bogan²

1988

Vet Pharm & Therapeutics

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“…Isometamidium chloride (ISM; Samorin) is a very powerful trypanocide with curative and prophylactic activity in husbandry animals (Kirkby 1964). The toxic eects of ISM on trypanosomes pathogenic for domestic animals that have been observed include intercalation of ISM between DNA base pairs (Wagner 1971) and inhibition of DNA polymerase (Marcus et al 1982). The kinetoplast is the cell organelle in which ISM-induced changes ®rst become obvious, and ISM disrupts kinetoplastic DNA but not nuclear DNA (Newton 1974).…”

mentioning

confidence: 99%

Susceptibility of dyskinetoplastic Trypanosoma evansi and T. equiperdum to isometamidium chloride

Kaminsky

Schmid

Lun

1997

Parasitology Research

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Isometamidium chloride (ISM) is an effective trypanocide with curative and prophylactive activity in husbandry animals. The mode of action of ISM against pathogenic trypanosomes is not fully understood, but there is evidence in the literature that kinetoplastic topoisomerase type II is selectively inhibited by the drug. This prompted the hypothesis that dyskinetoplastic trypanosomes would express a reduced level of susceptibility to ISM. From parental Trypanosoma evansi and T. equiperdum populations we generated clones containing only dyskinetoplastic organisms and clones containing organisms with kinetoplasts. The susceptibility of these clones to ISM was quantified by in vitro assays. The susceptibility of all clones was in the same range. Minor differences in drug susceptibility found between the clones showed that the dyskinetoplastic T. evansi and T. equiperdum clones were even more susceptible to ISM than their kinetoplastic counterparts. Thus, the hypothesis that the dyskinetoplastic trypanosomes would be less susceptible to or tolerant of ISM was clearly disproved. The previously demonstrated inhibition of kinetoplastic topoisomerase type II by ISM cannot be the primary toxic effect of the drug on trypanosomes, and the mode of action of ISM needs to be reassessed.

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“…Earlier biochemical studies in T. cruzi epimastigotes have led to the characterization of different DNA polymerase fractions with different properties to those found in mammalian cells [21][22][23]. Interestingly, some of these were similar to other DNA polymerase activities found in other trypanosomatids and in the algae Chlorella [24][25][26][27]. Later, a third and major DNA polymerase activity was described in epimastigotes, which was different from those described earlier [28].…”

Section: Introductionmentioning

confidence: 93%

In Vitro Identification of Phosphorylation Sites on TcPolβ by Protein Kinases TcCK1, TcCK2, TcAUK1, and TcPKC1 and Effect of Phorbol Ester on Activation by TcPKC of TcPolβ in Trypanosoma cruzi Epimastigotes

Maldonado,

Canobra,

Oyarce

et al. 2024

Microorganisms

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Chagas disease is caused by the single-flagellated protozoan Trypanosoma cruzi, which affects several million people worldwide. Understanding the signal transduction pathways involved in this parasite’s growth, adaptation, and differentiation is crucial. Understanding the basic mechanisms of signal transduction in T. cruzi could help to develop new drugs to treat the disease caused by these protozoa. In the present work, we have demonstrated that Fetal Calf Serum (FCS) can quickly increase the levels of both phosphorylated and unphosphorylated forms of T. cruzi DNA polymerase beta (TcPolβ) in tissue-cultured trypomastigotes. The in vitro phosphorylation sites on TcPolβ by protein kinases TcCK1, TcCK2, TcAUK1, and TcPKC1 have been identified by Mass Spectrometry (MS) analysis and with antibodies against phosphor Ser-Thr-Tyr. MS analysis indicated that these protein kinases can phosphorylate Ser and Thr residues on several sites on TcPolβ. Unexpectedly, it was found that TcCK1 and TcPKC1 can phosphorylate a different Tyr residue on TcPolβ. By using a specific anti-phosphor Tyr monoclonal antibody, it was determined that TcCK1 can be in vitro autophosphorylated on Tyr residues. In vitro and in vivo studies showed that phorbol 12-myristate 13-acetate (PMA) can activate the PKC to stimulate the TcPolβ phosphorylation and enzymatic activity in T. cruzi epimastigotes.

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Effects of exogenous polyamine and trypanocides on the DNA polymerase activities from Trypanosoma brucei brucei, mouse thymus and murine leukemia virus

Cited by 15 publications

References 16 publications

The pharmacology of isometamidium

The pharmacology of isometamidium

Susceptibility of dyskinetoplastic Trypanosoma evansi and T. equiperdum to isometamidium chloride

In Vitro Identification of Phosphorylation Sites on TcPolβ by Protein Kinases TcCK1, TcCK2, TcAUK1, and TcPKC1 and Effect of Phorbol Ester on Activation by TcPKC of TcPolβ in Trypanosoma cruzi Epimastigotes

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