Why has GTP energy been used in the development and evolution of life? What functions did life acquire and evolution become possible by using ATP and GTP differently? What are the mechanisms that support the dynamically fluctuating GTP energy metabolism and what are the implications of these fluctuations? We are trying to unravel the fundamental mechanisms of these biological systems one by one.
The discovery of the GTP sensor PI5P4Kβ was an indication that a new use of GTP energy was born in the process of evolution. However, how, when, and why PI5P4Kβ became a GTP sensor is still shrouded in mystery. Our analysis of cells and mice expressing PI5P4Kβ lacking the GTP sensor function has shown that PI5P4Kβ is involved in cancer and metabolic diseases, as well as in the regulation of brain function from embryonic development. We are currently developing a specific inhibitor for PI5P4Kβ, which we believe will be very powerful as a tool compound. Thanks to the infrastructure of the Keio Institute for Advanced Biosciences, which is one of our major strengths, multi-layered omics analysis from cells to organs is now underway.
Comparison of wild-type PI5P4Kβ and PI5P4Kβ without GTP sensor function in cancer cells. In wild-type PI5P4Kβ, cancer cells proliferated and formed tumors (left, red arrow), and in PI5P4Kβ without GTP sensor function, cancer cells did not proliferate (right).
In addition, a finding reported in Nature Cell Biology in 2019 shows that malignant brain tumors hijack GTP metabolism to enhance their proliferative effects. This switch in GTP metabolism in malignant brain tumors was triggered by increased expression of inosinate dehydrogenase (IMPDH), a molecule in the GTP metabolic pathway, and the increased levels of GTP produced by IMPDH signaled the formation of ribosomes, a protein synthesis factory in the nucleolus (also known as the nucleolus). At the same time, GTP synthesized by IMPDH was incorporated into the ribosome as a component of the ribosome. Thus, the increased capacity for protein production by IMPDH supported the explosive growth of the cancer. This discovery solved the 100-year mystery of nucleolar enlargement in cancer, and was covered by various media including NHK World. Importantly, this discovery revealed a part of the system that controls the GTP energy balance in cells and organs. We are now discovering that IMPDH is indeed a very cleverly regulated system, and we are working on drug discovery to exploit this system.
In this way, we at GTP-GEEKS are able to understand the biological phenomena governed by GTP by integrating various fields such as new analysis tools of GTP biology by drug discovery science, drugs for disease treatment, big data analysis, evolutionary biology, and trans-scale biology that captures the structure from protein to tissue. This is the essence of GTP-GEEKS. We expect to create therapies targeting GTP energy changes in pathological conditions such as cancer, obesity/metabolic diseases, and immune diseases.