title: Insights into the Zinc-Dependent Deacetylase LpxC: Biochemical Properties and Inhibitor Design.
abstract: The bacterial enzyme UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC), catalyzing the first committed step of lipid A biosynthesis, represents a promising target in the development of novel antibiotics against Gram-negative bacteria. Structure, catalytic reaction mechanism and regulation of the Zn2+-dependent metalloamidase have been intensively investigated. The enzyme is required for growth and viability of Gram-negative bacteria, displays no sequence homology with any mammalian protein, but is highly conserved in Gram-negative bacteria, thus permitting the development of Gram-negative selective antibacterial agents with limited off-target effects. Several smallmolecule LpxC inhibitors have been developed, like the substrate analog TU-514 (12a), the aryloxazoline L-161,240 (13w), the sulfonamide BB-78485 (23a), the N-aroyl-L-threonine derivative CHIR-090 (24a), the sulfone-containing pyridone LpxC-3 (43e), and the uridine-based inhibitor 1-68A (47a), displaying diverse inhibitory and antibacterial activities. Most of these compounds share a Zn2+-binding hydroxamate moiety attached to a structural element addressing the hydrophobic tunnel or the UDP binding site. The butadiynyl derivative ACHN-975 (28) is the first LpxC inhibitor entering clinical trials.
authors.forename: Dmitrii V
authors.initials: DV
authors.lastname: Kalinin
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfalischen Wilhelms-Universitat Munster, Corrensstr. 48, D-48149 Münster, Germany. hollr@uni-muenster.de.
authors.forename: Ralph
authors.initials: R
authors.lastname: Holl
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism* / Q000494:pharmacology; D000595:Amino Acid Sequence; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D015032:Zinc / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C514484:LpxC deacetylase, Pseudomonas; D015032:Zinc