ArticleThe Journal of biological chemistry2010
Prodrug activation by Cryptosporidium thymidine kinase.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Anti-Cryptosporidial Drug-Discovery Challenges and Existing Therapeutic Avenues: A "One-Health" Concern.Life (Basel, Switzerland) · 2024Review
- Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets.Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology · 2017Review
- A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis.PLoS neglected tropical diseases · 2017Article
- Parasitology: CRISPR for Cryptosporidium.Nature · 2015Article
- Structural and Kinetic Characterization of Thymidine Kinase from Leishmania major.PLoS neglected tropical diseases · 2015Article
- Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis.Antimicrobial agents and chemotherapy · 2014Article
- Expression of functional Plasmodium falciparum enzymes using a wheat germ cell-free system.Eukaryotic cell · 2013Article
- Inhibition of Mycoplasma pneumoniae growth by FDA-approved anticancer and antiviral nucleoside and nucleobase analogs.BMC microbiology · 2013Article
- Drug repurposing screen reveals FDA-approved inhibitors of human HMG-CoA reductase and isoprenoid synthesis that block Cryptosporidium parvum growth.Antimicrobial agents and chemotherapy · 2013Article
- Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum.Bioorganic & medicinal chemistry letters · 2013Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
Abstract
Cryptosporidium spp. cause acute gastrointestinal disease that can be fatal for immunocompromised individuals. These protozoan parasites are resistant to conventional antiparasitic chemotherapies and the currently available drugs to treat these infections are largely ineffective. Genomic studies suggest that, unlike other protozoan parasites, Cryptosporidium is incapable of de novo pyrimidine biosynthesis. Curiously, these parasites possess redundant pathways to produce dTMP, one involving thymidine kinase (TK) and the second via thymidylate synthase-dihydrofolate reductase. Here we report the expression and characterization of TK from C. parvum. Unlike other TKs, CpTK is a stable trimer in the presence and absence of substrates and the activator dCTP. Whereas the values of k(cat) = 0.28 s(-1) and K(m)(,ATP) = 140 microm are similar to those of human TK1, the value of K(m)(thymidine) = 48 microm is 100-fold greater, reflecting the abundance of thymidine in the gastrointestinal tract. Surprisingly, the antiparasitic nucleosides AraT, AraC, and IDC are not substrates for CpTK, indicating that Cryptosporidium possesses another deoxynucleoside kinase. Trifluoromethyl thymidine and 5-fluorodeoxyuridine are good substrates for CpTK, and both compounds inhibit parasite growth in an in vitro model of C. parvum infection. Trifluorothymidine is also effective in a mouse model of acute disease. These observations suggest that CpTK-activated pro-drugs may be an effective strategy for treating cryptosporidiosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.