Abstract
Thiolactomycin (TLM) is a natural product inhibitor of KasA, the β-ketoacyl synthase A from Mycobacterium tuberculosis. To improve the affinity of TLM for KasA, a series of TLM analogs have been synthesized based on interligand NOEs between TLM and a pantetheine analog when both are bound simultaneously to the enzyme. Kinetic binding data reveal that position 3 of the thiolactone ring is a suitable position for elaboration of the TLM scaffold, and the structure-activity relationship studies provide information on the molecular features that govern time-dependent inhibition in this enzyme system. These experiments also exemplify the utility of transient one-dimensional NOE spectroscopy for obtaining interligand NOEs compared with traditional steady state two-dimensional NOESY spectroscopy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / genetics
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Mycobacterium smegmatis / enzymology
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Mycobacterium smegmatis / genetics
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Mycobacterium tuberculosis / enzymology*
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Mycobacterium tuberculosis / genetics
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Protein Binding
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
Substances
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Bacterial Proteins
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Enzyme Inhibitors
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Thiophenes
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thiolactomycin
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase