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.