2AQB

Structure-activity relationships at the 5-position of thiolactomycin: an intact 5(R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherchia coli

Summary for 2AQB

• Entry DOI: 10.2210/pdb2aqb/pdb
• Related: 1FJ4 2AQ7
• Descriptor: 3-oxoacyl-[acyl-carrier-protein] synthase I, (5R)-5-[(1E)-BUTA-1,3-DIENYL]-4-HYDROXY-3,5-DIMETHYLTHIOPHEN-2(5H)-ONE (3 entities in total)
• Functional Keywords: fabb-ligand active-site complex, transferase
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P0A953
• Total number of polymer chains: 4
• Total formula weight: 171213.61

Authors

Kim, P.,Zhang, Y.M.,Shenoy, G.,Nguyen, Q.A.,Boshoff, H.I.,Manjunatha, U.H.,Goodwin, M.B.,Lonsdale, J.,Price, A.C.,Miller, D.J. (deposition date: 2005-08-17, release date: 2006-01-17, Last modification date: 2023-08-23)

Primary citation

Kim, P.,Zhang, Y.M.,Shenoy, G.,Nguyen, Q.A.,Boshoff, H.I.,Manjunatha, U.H.,Goodwin, M.B.,Lonsdale, J.,Price, A.C.,Miller, D.J.,Duncan, K.,White, S.W.,Rock, C.O.,Barry III, C.E.,Dowd, C.S.
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
J.Med.Chem., 49:159-171, 2006

PubMed Abstract: 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.

PubMed: 16392800
DOI: 10.1021/jm050825p

Experimental method

X-RAY DIFFRACTION (2.19 Å)