Reversible phosphorylation of proteins is a post-translational modification that regulates diverse biological processes. The molecular mechanism underlying phosphoryl transfer catalyzed by enzymes, in particular the nature of transition state (TS), remains a subject of active debate. Structural evidence supports an associative TS, whereas physical organic studies point to a dissociative character. In this article, we briefly introduce our recent effort using the hybrid quantum mechanics/molecular mechanics (QM/MM) simulations to resolve the controversy. We perform QM/MM simulations for the reversible phosphorylation of phosphoserine phosphatase (PSP), which belongs to one of the largest phosphotransferase families characterized to data. Both phosphorylation and dephosphorylation reactions are investigated based on the two-dimensional energy surfaces along phosphoryl and proton transfer coordinates. The resultant structures of the active site at TS in both reactions have compact geometries but a less electron density of the phosphoryl group. This suggests that the TS of PSP has a geometrically associative yet electronically dissociative character and strongly depends on proton transfer being coupled with phosphoryl transfer. Structure and literature database searches on phosphotransferases suggest that such a hybrid TS is consistent with many structures and physical organic studies and likely holds for most enzymes catalyzing phosphoryl transfer.