Purine auxotrophy: Possible applications beyond genetic marker

• Published in: Yeast (Chichester, England) England), 2019-11, Vol.36 (11), p.649-656
• Main Authors: Kokina, Agnese, Ozolina, Zane, Liepins, Janis
• Format: Article
• Language: English
• Subjects: Adenine; Auxotrophs; Auxotrophy; budding yeast; Cancer; Cell cycle; Cell proliferation; Drug development; Drug metabolism; Eukaryotes; evolution model; Genetic markers; Leishmaniasis; Malaria; Metabolism; Parasites; Protozoa; purine auxotrophy; Purines; Saccharomyces cerevisiae; Strains (organisms); Supplements; Toxoplasmosis; Tropical diseases
• ISSN: 0749-503X; 1097-0061
• DOI: 10.1002/yea.3434

Exploring new drug candidates or drug targets against many illnesses is necessary as “traditional” treatments lose their effectivity. Cancer and sicknesses caused by protozoan parasites are among these diseases. Cell purine metabolism is an important drug target. Theoretically, inhibiting purine metabolism could stop the proliferation of unwanted cells. Purine metabolism is similar across all eukaryotes. However, some medically important organisms or cell lines rely on their host purine metabolism. Protozoans causing malaria, leishmaniasis, or toxoplasmosis are purine auxotrophs. Some cancer forms have also lost the ability to synthesize purines de novo. Budding yeast can serve as an effective model for eukaryotic purine metabolism, and thus, purine auxotrophic strains could be an important tool. In this review, we present the common principles of purine metabolism in eukaryotes, effects of purine starvation in eukaryotic cells, and purine‐starved Saccharomyces cerevisiae as a model for purine depletion‐elicited metabolic states with applications in evolution studies and pharmacology. Purine auxotrophic yeast strains behave differently when growing in media with sufficient supplementation with adenine or in media depleted of adenine (starvation). In the latter, they undergo cell cycle arrest at G1/G0 and become stress resistant. Importantly, similar effects have also been observed among parasitic protozoans or cancer cells. We consider that studies on metabolic changes caused by purine auxotrophy could reveal new options for parasite or cancer therapy. Further, knowledge on phenotypic changes will improve the use of auxotrophic strains in high‐throughput screening for primary drug candidates. Purine de novo synthesis pathway in all eukaryotes is functionally similar. Some medically important organisms or cell lines do not synthesize purines; forms of relapsing cancer, protozoans causing malaria, leishmaniasis, or toxoplasmosis are notorious examples. Budding yeast purine auxotrophic strains is model for purine auxotrophy in eukaryotes and can be used to screen for new drugs against cancer, protozoan infections, or instrument to find out how purine auxotrophy has emerged in the past.