Giardia intestinalis thymidine kinase is a high-affinity enzyme crucial for DNA synthesis and an exploitable target for drug discovery

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Giardia intestinalis thymidine kinase is a high-affinity enzyme crucial for DNA synthesis and an exploitable target for drug discovery

Krakovka, Sascha (author): Uppsala universitet,Mikrobiologi och immunologi

Ranjbarian, Farahnaz (author): Umeå universitet,Institutionen för medicinsk kemi och biofysik,Umeå Univ, Dept Med Biochem & Biophys, Umeå, Sweden.

Luján, Lucas A. (author): Centro de Investigación y Desarrollo en Immunología y Enfermedades Infecciosas (CIDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)/Universidad Católica de Córdoba (UCC), Cordoba, Argentina,Univ Catolica Cordoba UCC, Ctr Invest & Desarrollo Immunol & Enfermedades In, Consejo Nacl Invest Cient & Tecn CONICET, Cordoba, Argentina.

Saura, Alicia (author): Centro de Investigación y Desarrollo en Immunología y Enfermedades Infecciosas (CIDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)/Universidad Católica de Córdoba (UCC), Cordoba, Argentina,Univ Catolica Cordoba UCC, Ctr Invest & Desarrollo Immunol & Enfermedades In, Consejo Nacl Invest Cient & Tecn CONICET, Cordoba, Argentina.

Larsen, Nicolai B. (author): Statens Serum Institut, København S, Denmark,Statens Serum Inst, Copenhagen S, Denmark.

Jimenez-Gonzalez, Alejandro (author): Uppsala universitet,Molekylär evolution

Reggenti, Anna (author): Umeå universitet,Institutionen för medicinsk kemi och biofysik,Umeå Univ, Dept Med Biochem & Biophys, Umeå, Sweden.

Luján, Hugo D. (author): Centro de Investigación y Desarrollo en Immunología y Enfermedades Infecciosas (CIDIE), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)/Universidad Católica de Córdoba (UCC), Cordoba, Argentina,Univ Catolica Cordoba UCC, Ctr Invest & Desarrollo Immunol & Enfermedades In, Consejo Nacl Invest Cient & Tecn CONICET, Cordoba, Argentina.

Svärd, Staffan (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Mikrobiologi och immunologi

Hofer, Anders (author): Umeå universitet,Institutionen för medicinsk kemi och biofysik,Umeå Univ, Dept Med Biochem & Biophys, Umeå, Sweden.

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American Society for Biochemistry and Molecular Biology, 2022
2022
English.
In: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 298:6

Related links:: https://doi.org/10.1...; show more...; https://umu.diva-por... (primary) (Raw object); https://uu.diva-port... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; https://urn.kb.se/re...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

Giardiasis is a diarrheal disease caused by the unicellular parasite Giardia intestinalis, for which metronidazole is the main treatment option. The parasite is dependent on exogenous deoxyribonucleosides for DNA replication and thus is also potentially vulnerable to deoxyribonucleoside analogs. Here, we characterized the G. intestinalis thymidine kinase, a divergent member of the thymidine kinase 1 family that consists of two weakly homologous parts within one polypeptide. We found that the recombinantly expressed enzyme is monomeric, with 100-fold higher catalytic efficiency for thymidine compared to its second-best substrate, deoxyuridine, and is furthermore subject to feedback inhibition by dTTP. This efficient substrate discrimination is in line with the lack of thymidylate synthase and dUTPase in the parasite, which makes deoxy-UMP a dead-end product that is potentially harmful if converted to deoxy-UTP. We also found that the antiretroviral drug azidothymidine (AZT) was an equally good substrate as thymidine and was active against WT as well as metronidazole-resistant G. intestinalis trophozoites. This drug inhibited DNA synthesis in the parasite and efficiently decreased cyst production in vitro, which suggests that it could reduce infectivity. AZT also showed a good effect in G. intestinalis–infected gerbils, reducing both the number of trophozoites in the small intestine and the number of viable cysts in the stool. Taken together, these results suggest that the absolute dependency of the parasite on thymidine kinase for its DNA synthesis can be exploited by AZT, which has promise as a future medication effective against metronidazole-refractory giardiasis.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

azidothymidine
deoxynucleoside kinase
deoxynucleoside salvage
deoxyribonucleoside kinase
deoxyribonucleoside salvage
Giardia duodenum
Giardia intestinalis
Giardia lamblia
thymidine kinase
zidovudine

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By the author/editor: Krakovka, Sascha; Ranjbarian, Fara ...; Luján, Lucas A.; Saura, Alicia; Larsen, Nicolai ...; Jimenez-Gonzalez ...; show more...; Reggenti, Anna; Luján, Hugo D.; Svärd, Staffan; Hofer, Anders; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

Articles in the publication: Journal of Biolo ...

By the university: Umeå University; Uppsala University

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