STUDY OF THE PPGALNACT2 GLYCOSYLTRANSFERASE CATALYTIC MECHANISM BY QM/MM METHODS

TRNKA, Tomáš, Stanislav KOZMON, Igor TVAROŠKA and Jaroslav KOČA. STUDY OF THE PPGALNACT2 GLYCOSYLTRANSFERASE CATALYTIC MECHANISM BY QM/MM METHODS. In XXIII. biochemický sjezd. 2012.

Basic information

• Original name: STUDY OF THE PPGALNACT2 GLYCOSYLTRANSFERASE CATALYTIC MECHANISM BY QM/MM METHODS
• Authors: TRNKA, Tomáš (203 Czech Republic, belonging to the institution), Stanislav KOZMON (703 Slovakia, belonging to the institution), Igor TVAROŠKA (703 Slovakia) and Jaroslav KOČA (203 Czech Republic, guarantor, belonging to the institution).
• Edition: XXIII. biochemický sjezd, 2012.

Other information

• Original language: English
• Type of outcome: Conference abstract
• Field of Study: 10403 Physical chemistry
• Country of publisher: Czech Republic
• Confidentiality degree: is not subject to a state or trade secret
• RIV identification code: RIV/00216224:14740/12:00064663
• Organization unit: Central European Institute of Technology
• Keywords in English: glycosyltransferases reaction mechanism qm/mm

Abstract

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.

Links

• ED1.1.00/02.0068, research and development project: Name: CEITEC - central european institute of technology
• 2SGA2747, interní kód MU: Name: Saccharide - protein dispersion interactions involved in the bacterial recognition processes (Acronym: SaProDI)

Investor: South-Moravian Region, Incoming grants

• 286154, interní kód MU: Name: SYLICA - Synergies of Life and Material Sciences to Create a New Future (Acronym: SYLICA)

Investor: European Union, Capacities