6yjz › Citations

Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission.

Kasaragod VB, Pacios-Michelena A, Schaefer N, Zheng F, Bader N, Alzheimer C, Villmann C, Schindelin H
Proc Natl Acad Sci U S A 117 33235-33245 (2020)
Related entries: 6yk0, 6yk1

Cited: 7 times
EuropePMC logo PMID: 33318193

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.

Reviews citing this publication (3)

  1. Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity. Hadtstein F, Vrolijk M. Adv Nutr 12 1911-1929 (2021)
  2. Targeting Nutrient Dependency in Cancer Treatment. Fan K, Liu Z, Gao M, Tu K, Xu Q, Zhang Y. Front Oncol 12 820173 (2022)
  3. Another Use for a Proven Drug: Experimental Evidence for the Potential of Artemisinin and Its Derivatives to Treat Alzheimer's Disease. Kiss E, Kins S, Gorgas K, Venczel Szakács KH, Kirsch J, Kuhse J. Int J Mol Sci 25 4165 (2024)

Articles citing this publication (4)

  1. Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response. Zhu L, van der Pluijm RW, Kucharski M, Nayak S, Tripathi J, White NJ, Day NPJ, Faiz A, Phyo AP, Amaratunga C, Lek D, Ashley EA, Nosten F, Smithuis F, Ginsburg H, von Seidlein L, Lin K, Imwong M, Chotivanich K, Mayxay M, Dhorda M, Nguyen HC, Nguyen TNT, Miotto O, Newton PN, Jittamala P, Tripura R, Pukrittayakamee S, Peto TJ, Hien TT, Dondorp AM, Bozdech Z. Commun Biol 5 274 (2022)
  2. Scientific opinion on the tolerable upper intake level for vitamin B6. EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Bohn T, Castenmiller J, de Henauw S, Hirsch-Ernst KI, Knutsen HK, Maciuk A, Mangelsdorf I, McArdle HJ, Pelaez C, Pentieva K, Siani A, Thies F, Tsabouri S, Vinceti M, Fairweather-Tait S, Vrolijk M, Fabiani L, Titz A, Naska A. EFSA J 21 e08006 (2023)
  3. Loss of Extrasynaptic Inhibitory Glycine Receptors in the Hippocampus of an AD Mouse Model Is Restored by Treatment with Artesunate. Kuhse J, Groeneweg F, Kins S, Gorgas K, Nawrotzki R, Kirsch J, Kiss E. Int J Mol Sci 24 4623 (2023)
  4. Artesunate Therapy Alleviates Fracture-Associated Chronic Pain After Orthopedic Surgery by Suppressing CCL21-Dependent TREM2/DAP12 Inflammatory Signaling in Mice. Zhang L, Li N, Zhang H, Wang Y, Gao T, Zhao Y, Wang G, Yu Y, Wang C, Li Y. Front Pharmacol 13 894963 (2022)


Quick links