期刊
ACS CHEMICAL BIOLOGY
卷 8, 期 2, 页码 387-396出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb300426u
关键词
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资金
- European Community's Seventh Framework Programme (Aeropath) [223461]
- Scottish Universities Life Science Alliance
- Royal Society
- Biotechnology and Biological Sciences Research Council [BBS/E/J/000C0618] Funding Source: researchfish
- BBSRC [BBS/E/J/000C0618] Funding Source: UKRI
Glucose-1-phosphate thymidylyltransferase (RmlA) catalyzes the condensation of glucose-1-phosphate (G1P) with deoxy-thymidine triphosphate (dTTP) to yield dTDP-D-glucose and pyrophosphate. This is the first step in the L-rhamnose biosynthetic pathway. L-Rhamnose is an important component of the cell wall of many microorganisms, including Mycobacterium tuberculosis and Pseudomonas aeruginosa. Here we describe the first nanomolar inhibitors of P. aeruginosa RmlA. These thymine analogues were identified by high-throughput screening and subsequently optimized by a combination of protein crystallography, in silico screening, and synthetic chemistry. Some of the inhibitors show inhibitory activity against M. tuberculosis, The inhibitors do not bind at the active site of RmlA but bind at a second site active site. Despite this, the compounds act as competitive inhibitors of G1P but with high cooperativity. This novel behavior was probed by structural analysis, which suggests that the inhibitors work by preventing RmlA from undergoing the conformational change key to its ordered bi-bi mechanism.
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