Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1- phosphate uridyltransferase (GlmU)

Tran, A. T., Wen, D., West, N. P., Baker, E. N., Britton, W. J. and Payne, R. J. (2013) Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1- phosphate uridyltransferase (GlmU). Organic and Biomolecular Chemistry, 11 46: 8113-8126. doi:10.1039/c3ob41896k


Author Tran, A. T.
Wen, D.
West, N. P.
Baker, E. N.
Britton, W. J.
Payne, R. J.
Title Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1- phosphate uridyltransferase (GlmU)
Formatted title
Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1- phosphate uridyltransferase (GlmU)
Journal name Organic and Biomolecular Chemistry   Check publisher's open access policy
ISSN 1477-0520
1477-0539
Publication date 2013-12-14
Year available 2013
Sub-type Article (original research)
DOI 10.1039/c3ob41896k
Open Access Status Not Open Access
Volume 11
Issue 46
Start page 8113
End page 8126
Total pages 14
Place of publication Cambridge, United Kingdom
Publisher Royal Society of Chemistry
Language eng
Abstract Peptidoglycan is an essential component of the cell wall of bacteria, including Mycobacterium tuberculosis, that provides structural strength and rigidity to enable internal osmotic pressure to be withstood. The first committed step in the biosynthesis of peptidoglycan involves the formation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) from uridine triphosphate (UTP) and GlcNAc-1-phosphate. This reaction is catalysed by N-acetylglucosamine- 1-phosphate uridyltransferase (GlmU), a bifunctional enzyme with two independent active sites that possess acetyltransferase and uridyltransferase activities. Herein, we report the first inhibition study targeted against the uridyltransferase activity of M. tuberculosis GlmU. A number of potential inhibitors were initially prepared leading to the discovery of active aminoquinazoline-based compounds. The most potent inhibitor in this series exhibited an IC50 of 74 μM against GlmU uridyltransferase activity and serves as a promising starting point for the discovery of more potent inhibitors.
Formatted abstract
Peptidoglycan is an essential component of the cell wall of bacteria, including Mycobacterium tuberculosis, that provides structural strength and rigidity to enable internal osmotic pressure to be withstood. The first committed step in the biosynthesis of peptidoglycan involves the formation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) from uridine triphosphate (UTP) and GlcNAc-1-phosphate. This reaction is catalysed by N-acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme with two independent active sites that possess acetyltransferase and uridyltransferase activities. Herein, we report the first inhibition study targeted against the uridyltransferase activity of M. tuberculosis GlmU. A number of potential inhibitors were initially prepared leading to the discovery of active aminoquinazoline-based compounds. The most potent inhibitor in this series exhibited an IC50 of 74 μM against GlmU uridyltransferase activity and serves as a promising starting point for the discovery of more potent inhibitors.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Chemistry and Molecular Biosciences
 
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