气候变化领域集成服务门户(CCPortal): Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission

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DOI	10.1073/PNAS.2008695117
	Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission
	Kasaragod V.B.; Pacios-Michelena A.; Schaefer N.; Zheng F.; Bader N.; Alzheimer C.; Villmann C.; Schindelin H.
发表日期	2021
ISSN	00278424
起始页码	33235
结束页码	33245
卷号	117 期号:52
英文摘要	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. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Artemisinins; GABA biosynthesis; Inhibitory neurotransmission; Pyridoxal kinase; Pyridoxal phosphate (PLP)
语种	英语
scopus关键词	4 aminobutyric acid; artemisinin derivative; artesunate; gephyrin; glutamate decarboxylase; pyridoxal kinase; pyridoxine; scaffold protein; 4 aminobutyric acid; 4 aminobutyric acid receptor; adenosine 5'-O-(3-thiotriphosphate); adenosine triphosphate; artemisinin derivative; glutamate decarboxylase; protein kinase inhibitor; pyridoxal kinase; Article; controlled study; crystal structure; down regulation; drug protein binding; enzyme active site; enzyme inhibition; enzyme structure; GABAergic transmission; hippocampal slice; in vitro study; mouse; nervous system electrophysiology; neuromodulation; nonhuman; presynaptic inhibition; priority journal; protein analysis; signal transduction; animal; binding site; biological model; biosynthesis; C57BL mouse; chemistry; drug effect; electrophysiology; female; male; metabolism; molecular model; nerve cell inhibition; synapse; synaptic transmission; Adenosine Triphosphate; Animals; Artemisinins; Binding Sites; Down-Regulation; Electrophysiological Phenomena; Female; GABAergic Neurons; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Male; Mice, Inbred C57BL; Models, Biological; Models, Molecular; Neural Inhibition; Protein Kinase Inhibitors; Pyridoxal Kinase; Synapses; Synaptic Transmission
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179639
作者单位	Institute of Structural Biology, Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, 97080, Germany; Institute for Clinical Neurobiology, University of Würzburg, Würzburg, 97078, Germany; Institute of Physiology and Pathophysiology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, 91054, Germany; Neurobiology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom
推荐引用方式 GB/T 7714	Kasaragod V.B.,Pacios-Michelena A.,Schaefer N.,et al. Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission[J],2021,117(52).
APA	Kasaragod V.B..,Pacios-Michelena A..,Schaefer N..,Zheng F..,Bader N..,...&Schindelin H..(2021).Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission.Proceedings of the National Academy of Sciences of the United States of America,117(52).
MLA	Kasaragod V.B.,et al."Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021).