Project 1. In Vivo Chemical Biology：Visualizing and controlling metabolism in molecular level
Our bodies are assemblies of molecules. Lives are sustained by a variety of molecules such as amino acids, vitamins, lipids, nucleic acids, and proteins. Those molecules constructs cells, cells constructs tissues, and then tissues constructs bodies, which are complexly functionalized. Our life-activities are attributed to number, structure, kinetics of the biomolecules, called “metabolism.” Although researches on genes and proteins have been dramatically proceeding recently, “activities of molecules in a body = metabolism” is a field remaining a lot of mysteries.
To this end, we are trying to develop molecular sensors visualizing metabolism and microenvironment in a body by molecular designs based on organic chemistry. In addition to disclosing unrevealed metabolic networks, we are aiming to develop molecular tools to control the metabolic networks, i.e. inhibitors and drugs.
Research 1. Imaging for metabolism and microenvironment
Among various imaging techniques, we are focusing on nuclear magnetic resonance/magnetic resonance imaging (NMR/MRI). This technique has a lot of advantages such as that “deep areas in a body are available” and “multiple molecules can be measured at once.” On the other hand, the sensitivity of NMR is too low for broad applications to bioimaging. We are challenging this problem by developing novel real-time-imaging methodologies with combination of newly created molecular probes and techniques enhancing NMR sensitivity such as dynamic nuclear polarization (DNP) and chemical exchange saturation transfer (CEST). [reference] Nat. Commun. 2013, 4, 2411. Angew. Chem.,Int. Ed. 2016, 55, 1765–1768. Angew. Chem., Int. Ed. 2016, 55, 10626–10629. Sci. Rep. 2017, 7, 40104. [collaborators] National Institutes for Quantum and Radiological Science and Technology National Institute of Health UT Southwestern Medical Center École polytechnique fédérale de Lausanne
Research 2. Development of molecular probes to visualize metabolism and exploration for inhibitors<
Serine hydroxymethyl transferase (SHMT) is an important enzyme which plays a core role in One Carbon Metabolism, which supplies carbon in metabolism networks. SHMT attracts a lot of interests as a significant target for therapeutics of cancers and malaria. In our group, a fluorescent molecular probe to detect the activity of SHMT has been developed. Furthermore, new SHMT inhibitors were found through high throughput screening using the developed probe. [reference] Nat. Commun. 2019, 10, 876. [collaborators] Tsumoto group, the University of Tokyo National Institutes of Biomedical Innovation, Health and Nutrition