National Academy of Sciences, Proceedings of the National Academy of Sciences, 52(117), p. 33235-33245, 2020
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Significance Information processing in the central nervous system relies on chemical synapses where neurotransmitters such as the inhibitory neurotransmitter γ-aminobutyric acid (GABA) are released at presynaptic nerve endings. GABA is synthesized by glutamic acid decarboxylase (GAD), an enzyme requiring pyridoxal 5'-phosphate (PLP or vitamin B6) as cofactor, the latter being synthesized by pyridoxal kinase (PDXK). Here, we show that the antimalarial drug artemisinin inhibits PDXK and describe the structural basis of this inhibition. The decrease in PLP production reduces the amount of GABA being produced, which, in turn, impacts the efficacy of GABAergic transmission. This study combined with our previous data sheds light on how artemisinins can influence inhibitory synaptic transmissions both presynaptically, as described here, and postsynaptically.