How Mycobacterium tuberculosis Galactofuranosyl Transferase2 (GlfT2) Generates Alternating beta-(1-6) and beta-(1-5) Linkages: AQM/MM Molecular Dynamics Study of the Chemical Steps

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F18%3A00102716" target="_blank" >RIV/00216224:14740/18:00102716 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1002/chem.201800558" target="_blank" >http://dx.doi.org/10.1002/chem.201800558</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/chem.201800558" target="_blank" >10.1002/chem.201800558</a>

Jazyk výsledku

angličtina

Název v původním jazyce

How Mycobacterium tuberculosis Galactofuranosyl Transferase2 (GlfT2) Generates Alternating beta-(1-6) and beta-(1-5) Linkages: AQM/MM Molecular Dynamics Study of the Chemical Steps

Popis výsledku v původním jazyce

Mycobacterium tuberculosis features a unique cell wall that protects the bacterium from the external environment. Disruption of the cell wall assembly is a promising direction for novel anti-tuberculotic drugs. A key component of the cell wall is galactan, a polysaccharide chain composed of galactofuranose (Galf) units connected by alternating beta-(1–5) and beta-(1–6) linkages. The majority of the galactan chain is biosynthesized by a bifunctional enzyme—galactofuranosyl transferase 2 (GlfT2). GlfT2 catalyzes two reactions: the formation of beta-(1–5) and beta-(1–6) linkages. It was suggested that the enzyme acts through a processive mechanism until it adds 30–35 Galf units in a single active site. We applied a QM/MM string method coupled with ab initio molecular dynamics simulations to study the two reactions catalyzed by GlfT2. We showed that both reactions proceed very similarly and feature similar transition-state structures. We also present novel information about the ring puckering behavior of the five-membered furanose ring during the glycosyltransferase reaction and a calculated transition-state structure with galactose in a furanose form that may be used as a guide for the rational design of very specific and extremely potent inhibitors, that is, transition-state analogues, for GlfT2. Due to the absence of a furanose form of galactose in humans, transition-state-analogous inhibitors represent an attractive scaffold for the development of novel antibacterial drugs.

Název v anglickém jazyce

How Mycobacterium tuberculosis Galactofuranosyl Transferase2 (GlfT2) Generates Alternating beta-(1-6) and beta-(1-5) Linkages: AQM/MM Molecular Dynamics Study of the Chemical Steps

Popis výsledku anglicky

Mycobacterium tuberculosis features a unique cell wall that protects the bacterium from the external environment. Disruption of the cell wall assembly is a promising direction for novel anti-tuberculotic drugs. A key component of the cell wall is galactan, a polysaccharide chain composed of galactofuranose (Galf) units connected by alternating beta-(1–5) and beta-(1–6) linkages. The majority of the galactan chain is biosynthesized by a bifunctional enzyme—galactofuranosyl transferase 2 (GlfT2). GlfT2 catalyzes two reactions: the formation of beta-(1–5) and beta-(1–6) linkages. It was suggested that the enzyme acts through a processive mechanism until it adds 30–35 Galf units in a single active site. We applied a QM/MM string method coupled with ab initio molecular dynamics simulations to study the two reactions catalyzed by GlfT2. We showed that both reactions proceed very similarly and feature similar transition-state structures. We also present novel information about the ring puckering behavior of the five-membered furanose ring during the glycosyltransferase reaction and a calculated transition-state structure with galactose in a furanose form that may be used as a guide for the rational design of very specific and extremely potent inhibitors, that is, transition-state analogues, for GlfT2. Due to the absence of a furanose form of galactose in humans, transition-state-analogous inhibitors represent an attractive scaffold for the development of novel antibacterial drugs.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10402 - Inorganic and nuclear chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

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

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Chemistry - A European Journal

ISSN

0947-6539

e-ISSN

—

Svazek periodika

24

Číslo periodika v rámci svazku

27

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

9

Strana od-do

7051-7059

Kód UT WoS článku

000431975000022

EID výsledku v databázi Scopus

2-s2.0-85046095834