What is it about?
Pyrimidines are one of the building blocks of the nucleic acids RNA and DNA. The parasite causing African sleeping sickness can either make pyrimidines themselves or obtain them from the external culture medium. Removing the last step in the biosynthetic pathway by deleting a gene for UMP synthase makes the parasite absolutely dependant on external pyrimidines added to the culture medium for growth. Levels of pyrimidines in plasma are too low in mice to sustain an infection and therefore these genetically modified parasites lack virulence. With time, however, the parasites increase the flow of metabolites through the pathway, excreting an intermediate called orotic acid. In animals this is converted in the liver to uridine, resulting in increased uridine in the plasma which the parasites can take up.
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Why is it important?
This study suggests that UMP synthase, the last enzyme in the synthesis of the pyrimdine, uridine, may not be a good target for drug development for extracellular parasites and pathogens. Enymes earlier in the pathway may be better target.
Perspectives
Our intitially contradictory findings that freshly prepared parasites lacked virulence, but long term cultured parasites regained virulence were rationalised when we discovered that adaptation had taken place with increased secretion of orotic acid.
Professor Alan H Fairlamb
University of Dundee
Read the Original
This page is a summary of: Trypanosoma brucei (UMP synthase null mutants) are avirulent in mice, but recover virulence upon prolonged culture in vitro while retaining pyrimidine auxotrophy, Molecular Microbiology, September 2013, Wiley,
DOI: 10.1111/mmi.12376.
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