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

a 2012

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

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

Základní údaje

Originální název

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

Autoři

KOZMON, Stanislav (703 Slovensko, domácí), Tomáš TRNKA (203 Česká republika, domácí), Igor TVAROŠKA (703 Slovensko) a Jaroslav KOČA (203 Česká republika, garant, domácí)

Vydání

8th International Symosium on Glycosyltransferases, 2012

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

10403 Physical chemistry

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Kód RIV

RIV/00216224:14740/12:00064661

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

glycosyltransferase reaction mechanism qm/mm

Změněno: 5. 4. 2013 15:14, Olga Křížová

Anotace

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.

Návaznosti

ED1.1.00/02.0068, projekt VaV

Název: CEITEC - central european institute of technology

2SGA2747, interní kód MU

Název: Saccharide - protein dispersion interactions involved in the bacterial recognition processes (Akronym: SaProDI)

Investor: Jihomoravský kraj, Saccharide - protein dispersion interactions involved in the bacterial recognition processes, Granty pro zahraniční vědce

Citovat

KOZMON, Stanislav, Tomáš TRNKA, Igor TVAROŠKA a Jaroslav KOČA. Theoretical QM/MM Study of the inverting ppGalNAcT2 Glycosyltransferase Reaction Mechanism. In 8th International Symosium on Glycosyltransferases. 2012.

@proceedings{1094630,
   author = {Kozmon, Stanislav and Trnka, Tomáš and Tvaroška, Igor and Koča, Jaroslav},
   booktitle = {8th International Symosium on Glycosyltransferases},
   keywords = {glycosyltransferase reaction mechanism qm/mm},
   language = {eng},
   title = {Theoretical QM/MM Study of the inverting ppGalNAcT2 Glycosyltransferase Reaction Mechanism},
   year = {2012}
}

TY  - CONF
ID  - 1094630
AU  - Kozmon, Stanislav - Trnka, Tomáš - Tvaroška, Igor - Koča, Jaroslav
PY  - 2012
TI  - Theoretical QM/MM Study of the inverting ppGalNAcT2 Glycosyltransferase Reaction Mechanism
KW  - glycosyltransferase reaction mechanism qm/mm
N2  - 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.
ER  -

KOZMON, Stanislav, Tomáš TRNKA, Igor TVAROŠKA a Jaroslav KOČA. Theoretical QM/MM Study of the inverting ppGalNAcT2 Glycosyltransferase Reaction Mechanism. In \textit{8th International Symosium on Glycosyltransferases}. 2012.

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