RT Journal Article SR Electronic T1 Pyridoxal Kinase Inhibition by Artemisinins Downregulates Inhibitory Neurotransmission JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.05.026310 DO 10.1101/2020.04.05.026310 A1 Kasaragod, Vikram Babu A1 Pacios-Michelena, Anabel A1 Schaefer, Natascha A1 Zheng, Fang A1 Bader, Nicole A1 Alzheimer, Christian A1 Villmann, Carmen A1 Schindelin, Hermann YR 2020 UL http://biorxiv.org/content/early/2020/04/05/2020.04.05.026310.abstract AB The anti-malarial artemisinins have also been implicated in the regulation of various other cellular pathways. Despite their widespread application, the cellular specificities and molecular mechanisms of target recognition by artemisinins remain poorly characterized. We recently demonstrated how these drugs modulate inhibitory postsynaptic signaling by direct binding to the scaffolding protein gephyrin. Here, we report the crystal structure of the central metabolic enzyme pyridoxal kinase (PDXK), which catalyzes the production of the active form of vitamin-B6 (also known as pyridoxal 5’-phosphate, PLP), in complex with artesunate at 2.4-Å resolution. Partially overlapping binding of artemisinins with the substrate pyridoxal inhibits PLP biosynthesis as demonstrated by kinetic measurements. Electrophysiological recordings from hippocampal slices and activity measurements of glutamic acid decarboxylase (GAD), a PLP-dependent enzyme synthesizing the neurotransmitter γ-aminobutyric acid (GABA), define how artemisinins interfere presynaptically with GABAergic signaling. Our data provide a comprehensive picture of artemisinin-induced effects on inhibitory signaling in the brain.