Protein glycosylation is thought to be main means of cell recognition. Misregulation of the cascade of glycosyltransferases is related to many diseases with the most prominent example being cancer. There is thus significant scientific interest in the reaction mechanisms of glycosyltransferases. However, reaction mechanism of the configuration-retaining group of glycosyltransferases hasn't been explained yet. For his reason we have chosen a retaining glycosyltransferase – polypeptide UDP-GalNAc transferase (ppGalNAcT) – as the subject of our quantum-chemical study. This enzyme catalyses the transfer of N-acetylgalactosamine moiety onto protein serine or threonine hydroxyls, forming the first bond of the so-called O-linked glycosylation pathway. Increased activity of this enzyme has been found to enable metastasis of breast and colorectal cancer.Thanks to the availability of high-resolution X-ray structures of three members of the ppGalNAcT family (human transferases 2 and 10, murine transferase 1) we have been able to successfully mount a quantum chemistry study of the human ppGalNAcT2, leveraging information on substrate positioning in active site from the ppGalNAcT10. We are using a hybrid quantum mechanics/molecular mechanics approach using density functional theory on the BP86/TZP level for the important part of the active site. Structures in reactant and product energy minima have been successfully obtained, enabling a potential energy surface scan to find the locations of transition state candidates. Results clearly show that proton transfer between the acceptor hydroxyl moiety and the donor phosphate plays a crucial role in enabling the reaction to take place. The 2D energy map suggests that the reaction proceeds via a two-step mechanism with formation of a carbocation intermediate and its subsequent nucleophilic trapping by the acceptor oxygen. However, exact location of the transition states is yet necessary to prove this conclusively.