Publication details

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

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JANOŠ Pavel KOZMON Stanislav TVAROŠKA Igor KOČA Jaroslav

Year of publication 2018
Type Article in Periodical
Magazine / Source Chemistry - A European Journal
MU Faculty or unit

Central European Institute of Technology

Keywords enzyme catalysis; glycosyltransferases; molecular modeling; reaction mechanisms; tuberculosis
Description 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.
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