Identification and Drug Development of an Intracellular GTP Sensor for Metabolism and Tumorigenesis

Introduction: High energy metabolites such as ATP and GTP is indispensable to drive numerous enzymatic reactions in cells. Concentrations of the high energy metabolites are varied by tissue type, environment, and pathological conditions. As for ATP, it has been shown that the changes in cellular ATP concentrations are detected by ATP molecular sensors, such as, and these ATP-sensors convert ATP concentration cue into signaling for metabolic adaptations. While GTP is driving molecule for protein synthesis and its concentrations change independent from ATP, whether it serves as a metabolic cue for biological signaling like ATP remains elusive due to the lack of GTP sensors.

Results and Discussion: Here we report that PI5P4Kβ, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentrations and converts them into lipid second messenger signaling. PI5P4Kβ was identified as GTP binding protein by whole cell proteome screening, and follow up biochemical analyses showed that PI5P4Kβ preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation. Its activity is sensitive to the changes in physiological GTP concentrations and structure-based development of the GTP-insensitive mutant of PI5P4Kβ revealed its indispensable role in metabolic adaptation. Furthermore, the GTP-sensing activity of PI5P4Kβ is critical for tumorigenesis, which motivated us to the development of PI5P4Kβ inhibitors as an anti-cancer drug. So far we have identified several compounds that are specific to PI5P4Kβ.

Conclusions: PI5P4Kβ is a missing GTP sensor and GTP concentrations function as a metabolic cue via PI5P4Kβ. The dependence of cancer on the GTP-sensing activity of PI5P4Kβ makes this lipid kinase as a new target for cancer therapy.