Words similar to metallo-β-lactamases
Example sentences for: metallo-β-lactamases
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There are over 300 distinct β-lactamases known, and these enzymes have been grouped by a number of classification schemes [ 8 9 10 11 12 13 14 15 ] . For example, Bush has developed a scheme, based on the enzymes' molecular properties, that has four distinct β-lactamase groups [ 10 15 ] . One of the more alarming groups are the Bush group 3 enzymes, which are Zn(II) dependent enzymes that hydrolyze nearly all known β-lactam containing antibiotics and for which there are no or very few known clinical inhibitors [ 9 14 16 17 18 19 ] . The metallo-β-lactamases have been further divided by Bush into subgroups based on amino acid sequence identity: the Ba enzymes share a >23% sequence identity, require 2 Zn(II) ions for full activity, prefer penicillins and cephalosporins as substrates, and are represented by metallo-β-lactamase CcrA from Bacteroides fragilis, the Bb enzymes share a 11% sequence identity with the Ba enzymes, require only 1 Zn(II) ion for full activity, prefer carbapenems as substrates, and are represented by the metallo-β-lactamase imiS from Aeromonas sobria, and the Bc enzymes have only 9 conserved residues with the other metallo-β-lactamases, require 2 Zn(II) ions for activity, contain a different metal binding motif than the other metallo-β-lactamases, prefer penicillins as substrates, and are represented by the metallo-β-lactamase L1 from Stenotrophomonas maltophilia [ 9 ] . A similar grouping scheme (B1, B2, and B3) based on structural properties of the metallo-β-lactamases has recently been offered [ 41 ] . The diversity of the group 3 β-lactamases is best exemplified by the enzymes' vastly differing efficacies towards non-clinical inhibitors; these differences predict that one inhibitor may not inhibit all metallo-β-lactamases [ 18 20 21 22 23 24 25 26 27 28 29 ] . To combat this problem, we are characterizing a metallo-β-lactamase from each of the subgroups in an effort to identify a common structural or mechanistic aspect of the enzymes that can be targeted for the generation of an inhibitor.
Instead, we predict that the insertion of an aspartic acid into the active site at position 224 results in a change in the hydrogen bonding network in L1; this hydrogen bonding network is extensive in all metallo-β-lactamases that have been characterized crystallographically [ 37 42 44 45 48 49 62 63 ] . The N233D mutant also exhibited greatly reduced k cat values for biapenem and meropenem but not for imipenem or any of the other substrates tested.
Efforts to solve the crystal structure of one of the metallo-β-lactamases with a bound substrate molecule have failed, most likely due to the high activity of the enzymes towards all β-lactam containing antibiotics [ 37 54 ] . Therefore, computational studies have been used extensively to study substrate binding, the role of the Zn(II) ions in catalysis, the protonation state of the active site, and inhibitor binding [ 37 42 55 56 57 58 59 ] . All of the substrate binding models have made assumptions before the substrate was docked into the active site [ 37 42 ] , and some of these assumptions have been shown to be invalid for certain substrates [ 43 ] . With L1, two key assumptions were made: (1) the bridging hydroxide functions as the nucleophile during catalysis and (2) Zn 1 coordinates the β-lactam carbonyl [ 37 ] . With these assumptions and after energy minimizations, Ser224 was predicted to hydrogen bond to the substrate carboxylate [ 37 ] , reminiscent of the role predicted for Lys224 in CcrA [ 42 ] . Ullah et al.
The substrate-binding model showed that Tyr228 in L1 was position-conserved with Asn233 in the other crystallographically characterized metallo-β-lactamases [ 37 42 44 45 46 ] . Spencer and coworkers postulated that Tyr228 is part of an oxyanion hole that interacts with the β-lactam carbonyl on substrate and helps to stabilize the putative tetrahedral intermediate formed during substrate turnover [ 37 ] . To test this hypothesis, Tyr228 was changed to an alanine and to a phenylalanine to afford the Y228A and Y228F mutants, respectively.
All sequenced subclass Ba and Bb metallo-β-lactamases (except VIM-1) have a lysine residue at position 224 [ 41 ] , and all computational models for substrate binding to the metallo-β-lactamases assume that the invariant carboxylate on substrates forms an electrostatic interaction with this lysine.
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