Year: 2025
Type: review
Abstract: . The PI5P4K family consists of three isozymes in mammals-PI5P4Kα, β, and γ-which notably utilize both GTP and ATP as phosphodonors. Unlike the other two isozymes, which can utilize both ATP and GTP, PI5P4Kβ exhibits a marked preference for GTP over ATP, acting as an intracellular GTP sensor that alters its kinase activity in response to physiological changes in GTP concentration. Knockout studies have demonstrated a critical role for PI5P4Kα and β in tumorigenesis, while PI5P4Kγ has been implicated in regulating immune and neural systems. Pharmacological targeting of PI5P4K holds promise for the development of new therapeutic approaches against cancer, immune dysfunction, and neurodegenerative diseases. Although several PI5P4K inhibitors have already been developed, challenges remain in PI5P4K inhibitor development, including a discrepancy between in vitro and cellular efficacy. This discrepancy is attributable to mainly three factors. (a) Most PI5P4K inhibitors were developed at low ATP levels, where these enzymes exhibit minimal activity. (b) Non-catalytic functions of PI5P4K require careful interpretation of PI5P4K depletion studies, as their scaffolding roles suppress class I PI3K signaling. (c) The lack of pharmacodynamic markers for in vivo assessment complicates efficacy assessment. To address these issues and promote the development of effective and targeted therapeutic strategies, this review provides an analytical overview of the distinct roles of individual isozymes and recent developments in PI5P4K inhibitors, emphasizing structural insights and the importance of pharmacodynamic marker identification.
Source: FEBS Journal
DOI: 10.1111/febs.17393
Authors: Koh Takeuchi, Lisa Nagase, Shun Kageyama, Hirotaka Kanoh, Masashi Oshima, Aki Ogawa‐Iio, Yoshiki Ikeda, Yuki Fujii, Sei Kondo, Natsuki Osaka, Takeshi Masuda, Tsukasa Ishihara, Yoshikazu Nakamura, Yoshihisa Hirota, Takehiko Sasaki, Toshiya Senda, Atsuo T. Sasaki
Institutions: National Institute of Advanced Industrial Science and Technology, The University of Tokyo, High Energy Accelerator Research Organization, Institute of Materials Structure Science, Institute for Advanced Biosciences, Keio University, University of Cincinnati, University of Cincinnati Medical Center, Shibaura Institute of Technology, Kyoto University, Institute for Integrated Cell-Material Sciences, Kyoto University, Tokyo University of Science, Institute of Science Tokyo, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo, University of Tsukuba, The Graduate University for Advanced Studies, SOKENDAI, Hiroshima University Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: Naito Foundation, Takeda Science Foundation, Japan Agency for Medical Research and Development, Human Frontier Science Program, Keio University, Astellas Pharma, Astellas Foundation for Research on Metabolic Disorders, National Institutes of Health, Japan Society for the Promotion of Science, Japan Science and Technology Agency, National Institute of General Medical Sciences, Center for Scientific Review, Core Research for Evolutional Science and Technology
Awards: G1443609199, G146485245, Exploring the molecular mechanism of GTP-driven stress response system, G2521286739, G2576085165, G2720596666, 新規計測技術による腫瘍制御性リン脂質代謝系の解明, 腎糸球体ポドサイトのGTP代謝に着目した新規蛋白尿治療法の開発, G5151590897, G5514976981, Therapeutic Potential of Vitamin K and Its Derivatives in Alzheimer's Disease Treatment: A Novel Approach to Inhibit Ferroptosis, G6360993976, G6498760175, G6718509927, in cell structure-guided drug development by NMR, 細胞膜脂質の変化から紐解く細胞老化制御機構, G7606810250, Exploratory research on the unveiling of new mechanisms for energy homeostasis in multicellular organisms, Analysis of metabolic reprogramming mechanisms in response to changes in nutritional status, G8894390220, G9000042673
OpenAlex ID: W4406593511