Research

Our research aims are 1) develop chemical methods to introducing artificial or hitherto unknown
post-translational modifications (neo-PTMs) into proteins, 2) detect change of endogenous
chemical network driven by the neo-PTMs, and 3) understand their biological outputs.

What is neo-PTMs?

Life emerges from chemical networks intervening in biomolecules in cells. Protein post-translational modifications (PTMs) of proteins represent the chemical reactions in cells, and they regulate cellular functions in multiple ways. Our question is “what happens if the life comes to have new-to-nature PTMs?” We named the new-to-nature PTMs “neo-PTMs”, which are hitherto unknown modifications or those exogenously introduced by chemical ways.

Purpose of research

First, we develop chemical methods to introducing the neo-PTMs in cells. Second, we develop chemical/biochemical methods to detect the changes of in-cell chemical network driven by the neo-PTMs. Lastly, we understand biological meaning and outputs of the neo-PTMs. This interdisciplinary research project will contribute to biology and medicines through finding a new way to regulate cellular functions.

Project Outline

Chemical catalysts to introduce neo-PTMs

One of the most important PTMs is those of histone proteins, which associate with DNA in the cellular nucleus. The histone PTM network regulates chromatin structure/functions to control gene expression. The team of Dr. Yamatsugu (A01) will develop chemical catalysts to introduce neo-PTMs into histone in live cells, and try to understand the newly created in-cell chemical network.

Synergistic effects induced by neo-PTMs

Cells employ multiple levels of regulation, including modifications of genome (DNA), transcriptome (RNA), proteome (proteins), and metabolome (metabolites). Many of these hierarchical networks are synergistically regulated by enzyme-catalyzed reactions, and disrupting the network is closely associated with diseases. Although many of small molecule drugs enable to control the specific post-transcriptional modification of interest, understanding how the small molecules influence the complex network has been largely unclear. The team of Dr. Sohtome (A02) will develop the chemical methodology to analyze the synergistic changes of the chemical modifications induced by small molecules (endogenous cofactor mimics and enzyme inhibitors).

Biological outcomes of neo-PTMs

Current research has focused on deepening our understanding of PTMs that organisms have in nature, and thus remain to be uncovered about the biological functions of neo-PTMs that do not exist in nature. Therefore, the team of Dr. Shimazu (A03) will focus on neo-PTMs that can be introduced chemically (A01) or enzymatically (A02), and investigate new functions of neo-PTMs in cells and animals. The team aims to comprehensively understand various life functions from biochemistry, cell biology, and molecular biology perspectives.

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