Words similar to carbapenems
Example sentences for: carbapenems
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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.
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.
L1's preference for penicillins and carbapenems over cephalosporins, as exemplified by the k cat values, is in agreement with previous studies and supports L1's placement in the β-lactamase 3c family [ 9 ] .
Three carbapenems were also used as substrates for L1, and biapenem, imipenem, and meropenem exhibited K m values of 32 ± 1 μM, 57 ± 7 μM, and 15 ± 4 μM and k cat values of 134 ± 4 s -1, 370 ± 5 s -1, and 157 ± 9 s -1, respectively (Table 5).
The Tyr228 mutants exhibited increased K m values for 8 of the 9 substrates tested, with the smallest changes in K m observed when the carbapenems were used as the substrate.
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