In recent years, it has emerged that methylation is a major intracellular post‑translational modification (PTM) of proteins and modulator of protein‑protein interactions (PPIs). In yeast, over twenty protein methyltransferases (MTases) have been identified. Their substrates include RNA processing proteins, the translation machinery and histone proteins, on which dozens of lysine and arginine methylation sites have been mapped. The regulation of protein MTases, however, is poorly understood. To investigate whether protein MTases could be subject to post‑translational regulation, we overexpressed and purified the following S. cerevisiae protein MTases from their native host: Hmt1, Set5, Rkm1, Rkm4 and Efm4. This set of MTases includes both lysine and arginine methyltransferases, and encompasses the different types of MTases present in yeast in regards to structure and function. Then, we fully characterised these MTases using a multi‑protease, multi‑fragmentation mass spectrometry workflow. Briefly, the purified MTases were digested with trypsin, LysargiNase or Asp‑N, then each sample was analysed by LC‑HCD‑MS/MS and LC‑ETD-MS/MS. With this approach, we identified several novel phosphorylation, acetylation and methylation sites on these enzymes. By projecting each PTM to structural models of the MTases, potential regulatory PTM sites and PTM hotspots were revealed. In particular, some PTMs fell on the same interface as the catalytic pockets of Rkm1 and Efm4, suggesting a potential role for these PTMs in mediating the enzyme‑substrate interaction. Other PTMs fell in predicted disordered regions of Hmt1, Set5 and Rkm4, which is a common feature of regulatory PTMs. Altogether, these results reveal that protein MTases are highly modified enzymes and suggest several of these PTMs have regulatory functions, opening the venue to further research on the regulation of protein methylation.