7a5z | pdb_00007a5z

Structure of VIM-2 metallo-beta-lactamase with hydrolysed Faropenem imine product

spinqualitylabelsall models 7a5z, resolution 1.29Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7a5z is a 1 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.29Å Ligands: CL, MG, NA, QZH, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9K2N0_PSEAI Publication Abstract from PubMed Penems have demonstrated potential as antibacterials and beta-lactamase inhibitors; however, their clinical use has been limited, especially in comparison with the structurally related carbapenems. Faropenem is an orally active antibiotic with a C-2 tetrahydrofuran (THF) ring, which is resistant to hydrolysis by some beta-lactamases. We report studies on the reactions of faropenem with carbapenem-hydrolysing beta-lactamases, focusing on the class A serine beta-lactamase KPC-2 and the metallo beta-lactamases (MBLs) VIM-2 (a subclass B1 MBL) and L1 (a B3 MBL). Kinetic studies show that faropenem is a substrate for all three beta-lactamases, though it is less efficiently hydrolysed by KPC-2. Crystallographic analyses on faropenem-derived complexes reveal opening of the beta-lactam ring with formation of an imine with KPC-2, VIM-2, and L1. In the cases of the KPC-2 and VIM-2 structures, the THF ring is opened to give an alkene, but with L1 the THF ring remains intact. Solution state studies, employing NMR, were performed on L1, KPC-2, VIM-2, VIM-1, NDM-1, OXA-23, OXA-10, and OXA-48. The solution results reveal, in all cases, formation of imine products in which the THF ring is opened; formation of a THF ring-closed imine product was only observed with VIM-1 and VIM-2. An enamine product with a closed THF ring was also observed in all cases, at varying levels. Combined with previous reports, the results exemplify the potential for different outcomes in the reactions of penems with MBLs and SBLs and imply further structure-activity relationship studies are worthwhile to optimise the interactions of penems with beta-lactamases. They also exemplify how crystal structures of beta-lactamase substrate/inhibitor complexes do not always reflect reaction outcomes in solution. Faropenem reacts with serine and metallo-beta-lactamases to give multiple products.,Lucic A, Hinchliffe P, Malla TR, Tooke CL, Brem J, Calvopina K, Lohans CT, Rabe P, McDonough MA, Armistead T, Orville AM, Spencer J, Schofield CJ Eur J Med Chem. 2021 Feb 9;215:113257. doi: 10.1016/j.ejmech.2021.113257. PMID:33618159 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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