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Edited by Lily Yeh Jan, University of California, San Francisco, CA, and approved October 26, 2020 (received for review May 3, 2020)
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.
Abstract
The antimalarial artemisinins have also been implicated in the regulation of various cellular pathways including immunomodulation of cancers and regulation of pancreatic cell signaling in mammals. 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 postsynaptic 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 also interfere presynaptically with GABAergic signaling. Our data provide a comprehensive picture of artemisinin-induced effects on inhibitory signaling in the brain.
Footnotes
↵1V.B.K. and A.P.M. contributed equally to this work.
↵2Present address: Neurobiology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
- ↵3To whom correspondence may be addressed. Email: vkasaragod{at}mrc-lmb.cam.ac.uk or hermann.schindelin{at}virchow.uni-wuerzburg.de.
Author contributions: V.B.K., A.P.M., N.S., F.Z., C.A., C.V., and H.S. designed research; V.B.K., A.P.M., N.S., F.Z., N.B., and C.V. performed research; V.B.K., A.P.M., N.S., F.Z., N.B., C.V., and H.S. analyzed data; and V.B.K., C.A., C.V., and H.S. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2008695117/-/DCSupplemental.
Data Availability.
The coordinates of mPDXK-apo, mPDXK-ATPγS, and mPDXK-ATPγS–artesunate structures have been deposited in the PDB with accession codes 6YJZ, 6YK0, and 6YK1, respectively.
Published under the PNAS license.
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Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission
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