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DOI	10.1073/pnas.2112986118
	Molecular mechanism of glycolytic flux control intrinsic to human phosphoglycerate kinase
	Yagi H.; Kasai T.; Rioual E.; Ikeya T.; Kigawa T.
发表日期	2021
ISSN	1091-6490
卷号	118 期号:50
英文摘要	Glycolysis plays a fundamental role in energy production and metabolic homeostasis. The intracellular [adenosine triphosphate]/[adenosine diphosphate] ([ATP]/[ADP]) ratio controls glycolytic flux; however, the regulatory mechanism underlying reactions catalyzed by individual glycolytic enzymes enabling flux adaptation remains incompletely understood. Phosphoglycerate kinase (PGK) catalyzes the reversible phosphotransfer reaction, which directly produces ATP in a near-equilibrium step of glycolysis. Despite extensive studies on the transcriptional regulation of PGK expression, the mechanism in response to changes in the [ATP]/[ADP] ratio remains obscure. Here, we report a protein-level regulation of human PGK (hPGK) by utilizing the switching ligand-binding cooperativities between adenine nucleotides and 3-phosphoglycerate (3PG). This was revealed by nuclear magnetic resonance (NMR) spectroscopy at physiological salt concentrations. MgADP and 3PG bind to hPGK with negative cooperativity, whereas MgAMPPNP (a nonhydrolyzable ATP analog) and 3PG bind to hPGK with positive cooperativity. These opposite cooperativities enable a shift between different ligand-bound states depending on the intracellular [ATP]/[ADP] ratio. Based on these findings, we present an atomic-scale description of the reaction scheme for hPGK under physiological conditions. Our results indicate that hPGK intrinsically modulates its function via ligand-binding cooperativities that are finely tuned to respond to changes in the [ATP]/[ADP] ratio. The alteration of ligand-binding cooperativities could be one of the self-regulatory mechanisms for enzymes in bidirectional pathways, which enables rapid adaptation to changes in the intracellular environment.
英文关键词	enzyme regulation; glycolysis; in-cell NMR; ligand-binding cooperativity; solution NMR
语种	英语
scopus关键词	3-phosphoglycerate; adenosine diphosphate; adenosine triphosphate; glyceric acid; phosphoglycerate kinase; protein binding; catalysis; enzyme active site; Escherichia coli; gene expression regulation; genetics; glycolysis; human; metabolism; molecular model; physiology; protein conformation; Adenosine Diphosphate; Adenosine Triphosphate; Catalysis; Catalytic Domain; Escherichia coli; Gene Expression Regulation, Enzymologic; Glyceric Acids; Glycolysis; Humans; Models, Molecular; Phosphoglycerate Kinase; Protein Binding; Protein Conformation
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/250926
作者单位	RIKEN Center for Biosystems Dynamics Research, Laboratory for Cellular Structural Biology, Yokohama, 230-0045, Japan; Department of Chemistry, Graduate School of Science, Tokyo Metropolitan UniversityTokyo 192-0397, Japan; RIKEN Center for Biosystems Dynamics Research, Laboratory for Cellular Structural Biology, Yokohama 230-0045, Japan
推荐引用方式 GB/T 7714	Yagi H.,Kasai T.,Rioual E.,et al. Molecular mechanism of glycolytic flux control intrinsic to human phosphoglycerate kinase[J],2021,118(50).
APA	Yagi H.,Kasai T.,Rioual E.,Ikeya T.,&Kigawa T..(2021).Molecular mechanism of glycolytic flux control intrinsic to human phosphoglycerate kinase.Proceedings of the National Academy of Sciences of the United States of America,118(50).
MLA	Yagi H.,et al."Molecular mechanism of glycolytic flux control intrinsic to human phosphoglycerate kinase".Proceedings of the National Academy of Sciences of the United States of America 118.50(2021).