a 2012

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

TRNKA, Tomáš, Stanislav KOZMON, Igor TVAROŠKA and Jaroslav KOČA

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

Language

English

Type of outcome

Konferenční abstrakt

Field of Study

10403 Physical chemistry

Country of publisher

Czech Republic

Confidentiality degree

není předmětem státního či obchodního tajemství

RIV identification code

RIV/00216224:14740/12:00064663

Organization unit

Central European Institute of Technology

Keywords in English

glycosyltransferases reaction mechanism qm/mm
Změněno: 5/4/2013 15:13, Olga Křížová

Abstract

V originále

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