GSBS Student Publications

Title

New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Pharmacology and Molecular Toxicology

Date

1-1-1997

Document Type

Article

Medical Subject Headings

Animals; Drug Resistance; Folic Acid Antagonists; Leishmania; Leishmaniasis; Methotrexate; Oxidoreductases; Pteridines

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Leishmania and other trypanosomatid protozoa require reduced pteridines (pterins and folates) for growth, suggesting that inhibition of these pathways could be targeted for effective chemotherapy. This goal has not yet been realized, indicating that pteridine metabolism may be unusual in this lower eukaryote. We have investigated this possibility using both wild type and laboratory-selected antifolate-resistant strains, and with defined genetic knockouts of several pteridine metabolic genes. In Leishmania, resistance to the antifolate methotrexate is mediated through several mechanisms singly or in combination, including alterations in transport leading to reduced drug influx, overproduction (R-region amplification) or point mutation of dihydrofolate reductase-thymidylate synthase (DHFR-TS), and amplification of a novel pteridine reductase (PTR1, encoded by the H-region). All of the proteins involved are potential targets for antifolate chemotherapy. Notably, parasites in which the gene encoding dihydrofolate reductase (DHFR) has been deleted (dhfr-ts- knockouts) do not survive in animal models, validating this enzyme as a target for effective chemotherapy. However, the properties of pteridine reductase 1 (PTR1) suggest a reason why antifolate chemotherapy has so far not been successful in trypanosomatids. PTR1, by its ability to provide reduced pterins and folates, has the potential to act as a by-pass and/or modulator of DHFR inhibition under physiological conditions. Moreover, PTR1 is less sensitive to many antifolates targeted primarily against DHFR. These findings suggest that successful antifolate chemotherapy in Leishmania will have to target simultaneously both DHFR and PTR1.

Rights and Permissions

Citation: Parasitology. 1997;114 Suppl:S101-10.

Related Resources

Link to article in PubMed

Journal Title

Parasitology

PubMed ID

9309772