PMID:21520904
| Citation |
Hollenhorst, MA, Ntai, I, Badet, B, Kelleher, NL and Walsh, CT (2011) A head-to-head comparison of eneamide and epoxyamide inhibitors of glucosamine-6-phosphate synthase from the dapdiamide biosynthetic pathway. Biochemistry 50:3859-61 |
|---|---|
| Abstract |
The dapdiamides make up a family of antibiotics that have been presumed to be cleaved in the target cell to enzyme-inhibitory N-acyl-2,3-diaminopropionate (DAP) warheads containing two alternative electrophilic moieties. Our prior biosynthetic studies revealed that an eneamide warhead is made first and converted to an epoxyamide via a three-enzyme branch pathway. Here we provide a rationale for this logic. We report that the R,R-epoxyamide warhead is a more efficient covalent inactivator of glucosamine-6-phosphate synthase by 1 order of magnitude versus the eneamide, and this difference correlates with a >10-fold difference in antibiotic activity for the corresponding acyl-DAP dipeptides. |
| Links |
PubMed PMC3097904 Online version:10.1021/bi2004735 |
| Keywords |
Amides/chemistry; Amides/pharmacology; Anti-Bacterial Agents/biosynthesis; Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/pharmacology; Bacterial Proteins/antagonists & inhibitors; Bacterial Proteins/chemistry; Bacterial Toxins/biosynthesis; Bacterial Toxins/chemistry; Bacterial Toxins/pharmacology; Dipeptides/biosynthesis; Dipeptides/chemistry; Epoxy Compounds/chemistry; Epoxy Compounds/pharmacology; Erwinia amylovora/drug effects; Erwinia amylovora/enzymology; Erwinia amylovora/growth & development; Escherichia coli K12/drug effects; Escherichia coli K12/enzymology; Escherichia coli K12/growth & development; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/antagonists & inhibitors; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/biosynthesis; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/chemistry; Pantoea/drug effects; Pantoea/enzymology; Pantoea/growth & development; Stereoisomerism |
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