The Sound of Evolution
Tacrolimus
Mechanism of action:
Tacrolimus is a calcineurin inhibitor and a macrolide immunosuppressant. After entering T cells, tacrolimus first binds to the intracellular protein FKBP12 (FK506-binding protein 12), forming a tacrolimus-FKBP12 complex. This complex inhibits calcineurin activity. Under normal conditions, calcineurin dephosphorylates NFAT (nuclear factor of activated T cells), allowing it to enter the nucleus and initiate gene transcription. When calcineurin is inhibited by tacrolimus, NFAT cannot be dephosphorylated and therefore cannot enter the nucleus, leading to reduced transcription of cytokines such as IL-2, IL-4, IFN-g, and TNF-a.
Reference(s):
1. Kino T et al. (1987). FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo).
2. Pritchard DI et al. (2005). Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today.
3. Liu J et al. (1991). Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell.