Words similar to metallo-β-lactamases
Example sentences for: metallo-β-lactamases
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However, MJ0301 has been shown to belong to the metallo-β-lactamase superfamily of enzymes and, in the evolutionary classification of metallo-β-lactamases, belongs to an archaea-specific family (Figure 2; COG1237) [ 28].
To combat these enzymes, β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam have been given in combination with a β-lactam containing antibiotic to treat bacterial infections [ 52 ] . One class of β-lactamases that are particularly unaffected by the known β-lactamase inhibitors and have been shown to hydrolyze almost all known β-lactam containing antibiotics including late generation carbapenems at high rates are the metallo-β-lactamases [ 14 15 16 17 18 19 ] . Although there are no reports of metallo-β-lactamases isolated from major pathogens [ 51 53 ] , these enzymes are produced by pathogens such as B. fragilis, S. maltophilia, and P. aeruginosa.
All crystallographically characterized metallo-β-lactamases have a flexible amino acid chain that extends over the active site [ 37 42 44 45 46 47 48 49 ] . Previous NMR studies on CcrA have shown that this loop "clamps down" on substrate or inhibitor upon binding, and there is speculation that the distortion of substrate upon clamping down of the loop may drive catalysis [ 50 ] . The crystal structure of L1 showed that there is a large loop that extends over the active site, and modeling studies have predicted that two residues, Ile164 and Phe158, make significant contacts with large, hydrophobic substituents at the 2' or 6' positions on penicillins, cephalosporins, or carbapenems [ 37 ] . To test this prediction, Ile 164 and Phe158 were changed from large, hydrophobic residues to alanines to afford the I164A and F158A mutants.
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.
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