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Tryptophan Deficiency May Underlie Side Effects of Malaria Treatment

Working in a yeast system, researchers have obtained evidence that the anti-malaria drug quinine might cause many of its adverse side effects by blocking a cell’s ability to take up the essential amino acid tryptophan. If confirmed, these findings would suggest that dietary tryptophan supplements could be a simple and inexpensive way to improve the performance of this important drug. Quinine is a very commonly used anti-malaria drug, yet, to this day, the principal mode of quinine action against the malaria parasite is largely unclear, as is the basis for adverse reactions like nausea, headaches, and blurred vision. In a screen of yeast mutants, the researchers found that strains unable to make tryptophan were extremely susceptible to quinine poisoning, which led the scientists to identify a tryptophan transporter as a key quinine target (yeast that cannot make their own tryptophan have to rely exclusively on external sources, and thus die if tryptophan transport is blocked). This discovery fits in well with evidence that, in humans, quinine reactions are more severe in malnourished individuals. Unlike yeast, humans cannot make their own tryptophan and thus require dietary tryptophan, which is abundant in meat but limited in yams, a staple food crop in the tropics where malaria is prevalent. If quinine severely reduces tryptophan uptake, then it follows that people with preexisting tryptophan deficiencies would be especially at risk from this drug. The authors also noted that tryptophan is important as a precursor for the brain chemical serotonin, so the enhanced tryptophan deficiency induced by quinine might explain why many of quinine's side effects are localized to the head region. This work was published online on June 26 in the Journal of Biological Chemistry. [Press release] [JBC abstract]