title: A head-to-head comparison of eneamide and epoxyamide inhibitors of glucosamine-6-phosphate synthase from the dapdiamide biosynthetic pathway.
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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Hollenhorst
authors.forename: Ioanna
authors.initials: I
authors.lastname: Ntai
authors.forename: Bernard
authors.initials: B
authors.lastname: Badet
authors.forename: Neil L
authors.initials: NL
authors.lastname: Kelleher
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Walsh
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D001427:Bacterial Toxins / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000096:biosynthesis / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry* / Q000494:pharmacology; D044084:Erwinia amylovora / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D048168:Escherichia coli K12 / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry*; D020636:Pantoea / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013237:Stereoisomerism
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004151:Dipeptides; D004852:Epoxy Compounds; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); C000731191:component S, glutamate mutase protein, Bacteria