Elucidation of a new action mechanism of immunosuppressants

December 14, 2022

FKBP12 suppresses fungal isoleucine biosynthetic enzyme

Tacrolimus (FK506) and rapamycin, which are produced by actinomycetes, are used as immunosuppressants and drugs for refractory lymphatic diseases. They are known to bind to the intracellular protein FKBP12 to demonstrate functions. FKBP12 is widely conserved in eukaryotes, but its original functions in cells were not well understood. The University of Tokyo, in collaboration with the RIKEN CSRS and Kyoto University, has shown that in fission yeast, FKBP12 suppresses the function of Tda1 protein, which catalyzes the deamination of threonine, an amino acid, and thereby inhibits isoleucine biosynthesis. Although the isoleucine biosynthetic pathway is known to be regulated by various factors, the inhibition by FKBP12 was previously unknown. This finding indicates that FKBP12 plays a role in regulating the activity of isoleucine biosynthetic enzymes. The results of this study are expected to lead to the development of new antifungal agents, since humans do not have the isoleucine biosynthetic pathway, which is important for fungi.

Original article
iScience doi:10.1016/j.isci.2022.105659
M. Sasaki, S. Nishimura, Y. Yashiroda, A. Matsuyama, H. Kakeya, M. Yoshida,
"FK506 binding protein, FKBP12, promotes serine utilization and negatively regulates threonine deaminase in fission yeast".
Minoru Yoshida; Group Director
Chemical Genomics Research Group
Yoko Yashiroda; Deputy Team Leader
Molecular Ligand Target Research Team