2aq7
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(New page: 200px<br /><applet load="2aq7" size="450" color="white" frame="true" align="right" spinBox="true" caption="2aq7, resolution 2.30Å" /> '''Structure-activity r...)
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Revision as of 06:10, 21 November 2007
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Structure-activity relationships at the 5-posiiton of thiolactomycin: an intact 5(R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli
Overview
Thiolactomycin inhibits bacterial cell growth through inhibition of the, beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The, effect of modifications of the 5-position isoprenoid side chain on both, IC(50) and MIC were determined. Synthesis and screening of a structurally, diverse set of 5-position analogues revealed very little tolerance for, substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as, reducing one or both double bonds of the diene were not tolerated. The, only permissible structural modifications were removal of the isoprene, methyl group or addition of a methyl group to the terminus., Cocrystallization of these two inhibitors with the condensing enzyme from, Escherichia coli revealed that they retained the TLM binding mode at the, active site with reduced affinity. These results suggest a strict, requirement for a conjugated, planar side chain inserting within the, condensing enzyme active site.
About this Structure
2AQ7 is a Single protein structure of sequence from Escherichia coli with TL5 as ligand. Active as Beta-ketoacyl-acyl-carrier-protein synthase I, with EC number 2.3.1.41 Full crystallographic information is available from OCA.
Reference
Structure-activity relationships at the 5-position of thiolactomycin: an intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli., Kim P, Zhang YM, Shenoy G, Nguyen QA, Boshoff HI, Manjunatha UH, Goodwin MB, Lonsdale J, Price AC, Miller DJ, Duncan K, White SW, Rock CO, Barry CE 3rd, Dowd CS, J Med Chem. 2006 Jan 12;49(1):159-71. PMID:16392800
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