The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00475942" target="_blank" >RIV/61388963:_____/17:00475942 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388971:_____/17:00475942 RIV/68407700:21230/17:00315473

Výsledek na webu

<a href="https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx157" target="_blank" >https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx157</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/nar/gkx157" target="_blank" >10.1093/nar/gkx157</a>

Jazyk výsledku

angličtina

Název v původním jazyce

The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine

Popis výsledku v původním jazyce

The excision of 8-oxoguanine (oxoG) by the human 8-oxoguanine DNA glycosylase 1 (hOGG1) base-excision repair enzyme was studied by using the QM/MM (M06-2X/6-31G(d,p): OPLS2005) calculation method and nuclear magnetic resonance (NMR) spectroscopy. The calculated glycosylase reaction included excision of the oxoG base, formation of Lys249-ribose enzyme-substrate covalent adduct and formation of a Schiff base. The formation of a Schiff base with Delta G(#) = 17.7 kcal/mol was the rate-limiting step of the reaction. The excision of the oxoG base with Delta G(#) = 16.1 kcal/mol proceeded via substitution of the C1'-N9 N-glycosidic bond with an H-N9 bond where the negative charge on the oxoG base and the positive charge on the ribose were compensated in a concerted manner by NH3+(Lys249) and CO2- (Asp268), respectively. The effect of Asp268 on the oxoG excision was demonstrated with H-1 NMR for WT hOGG1 and the hOGG1(D268N) mutant: the excision of oxoG was notably suppressed when Asp268 was mutated to Asn. The loss of the base-excision function was rationalized with QM/MM calculations and Asp268 was confirmed as the electrostatic stabilizer of ribose oxocarbenium through the initial base-excision step of DNA repair. The NMR experiments and QM/MM calculations consistently illustrated the base-excision reaction operated by hOGG1.

Název v anglickém jazyce

The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine

Popis výsledku anglicky

The excision of 8-oxoguanine (oxoG) by the human 8-oxoguanine DNA glycosylase 1 (hOGG1) base-excision repair enzyme was studied by using the QM/MM (M06-2X/6-31G(d,p): OPLS2005) calculation method and nuclear magnetic resonance (NMR) spectroscopy. The calculated glycosylase reaction included excision of the oxoG base, formation of Lys249-ribose enzyme-substrate covalent adduct and formation of a Schiff base. The formation of a Schiff base with Delta G(#) = 17.7 kcal/mol was the rate-limiting step of the reaction. The excision of the oxoG base with Delta G(#) = 16.1 kcal/mol proceeded via substitution of the C1'-N9 N-glycosidic bond with an H-N9 bond where the negative charge on the oxoG base and the positive charge on the ribose were compensated in a concerted manner by NH3+(Lys249) and CO2- (Asp268), respectively. The effect of Asp268 on the oxoG excision was demonstrated with H-1 NMR for WT hOGG1 and the hOGG1(D268N) mutant: the excision of oxoG was notably suppressed when Asp268 was mutated to Asn. The loss of the base-excision function was rationalized with QM/MM calculations and Asp268 was confirmed as the electrostatic stabilizer of ribose oxocarbenium through the initial base-excision step of DNA repair. The NMR experiments and QM/MM calculations consistently illustrated the base-excision reaction operated by hOGG1.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

<a href="/cs/project/GA13-27676S" target="_blank" >GA13-27676S: Pyramidalizace glykosidického dusíku v nukleových kyselinách; efekt pyramidalizace na chemii štěpení glykosidické vazby</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nucleic Acids Research

ISSN

0305-1048

e-ISSN

—

Svazek periodika

45

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

12

Strana od-do

5231-5242

Kód UT WoS článku

000402064200028

EID výsledku v databázi Scopus

2-s2.0-85027274090