Publication details

Theoretical QM/MM Study of the inverting ppGalNAcT2 Glycosyltransferase Reaction Mechanism

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KOZMON Stanislav TRNKA Tomáš TVAROŠKA Igor KOČA Jaroslav

Year of publication 2012
Type Conference abstract
MU Faculty or unit

Central European Institute of Technology

Description 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 because knowledge of transition state structures would enable targeted design of selective inhibitors usable as potential drugs. A retaining glycosyltransferase – polypeptide UDP-GalNAc transferase (ppGalNAcT) 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.
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