Tautomycetin, Protein Phosphatase 1 Specific Inhibitor, opened the Door for understanding the Role of PP1 in Minkowski Space

When the structure of tautomycin (TM) was determined, it was pointed out that the molecule must have potent inhibitory effects against protein phosphatases (PPs). The hint was brought from the structure of okadaic acid (OA), which was just disclosed to be a potent inhibitor of PPs. Protein phosphatase type 2A (PP2A) was the primary molecular target of OA, while TM was found to be a dual inhibitor for protein phosphatase type 1 (PP1) and PP2A, with partial selectivity to PP1. The rigid structure of OA, however, exhibited the biological activity as a tumor promoter, whereas the flexible structure of TM did not induce any tumor promotion in vivo. Tautomycetin (TC), having very similar structure to TM, was found to be the only inhibitor specific to PP1 at low concentrations, and the discovery opened the door to therapeutic strategies for immune disorders, cancer or neurological disorders involving PP1 and to understanding the distinguishable roles of PP1 and PP2A, two major Ser/Thr PPs in human cells. Sephin1, a selective inhibitor of PP1 holoenzyme containing growth arrest and DNA damage-inducible protein (GADD34), attenuated expression of stressinducible gene products. The approach was one of the several challenges for developing PP1-targeted therapeutics for neurological disorders to which circadian rhythm would be related. Thus appropriately modulating PP1 activity could lead to new treatments for neurological disorders in Minkowski space, a combination of threedimensional space and one dimension of time.

Keywords: Anti-cancer agents, Circadian clock, Immunosuppressant, Okadaic acid (OA), PP1/PP2A balance, PP1-target therapeutics, Protein phosphatase type 1 (PP1), Protein phosphatase type 2A (PP2A), Tautomycetin (TC), Tautomycin (TM), Tumor promoter.