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The class A beta-lactamase PER-1, which displays 26% identity with the TEM-type extended-spectrum beta-lactamases (ESBLs), catalyses the hydrolysis of oxyimino-beta-lactams such as cefotaxime (CTX), ceftazidime (CAZ) and aztreonam (AZT). Molecular modelling was used to identify in PER-1 the amino acid residues corresponding to those found at positions 104, 164, 238 and 240 in the TEM-type ESBLs, which are critical for hydrolysis of oxyimino-beta-lactams. The function of these residues in PER-1 was assessed by site-directed mutagenesis. In this enzyme, residue 104 could be either a glutamine, an asparagine or a threonine. The Gln--&gt;Gly mutation did not significantly affect the catalytic efficiency, while Asn--&gt;Gly and Thr--&gt;Glu resulted in a marked decrease in catalytic activity, probably due to the alteration of a hydrogen bond network connecting the putative Asn-104 residue to Asn-132 and Glu-166. Replacement of Ala-164 by Arg in PER-1 resulted in a mutant with no detectable activity, thus suggesting that Ala-164 is important for catalysis and stability of PER-1. Conversely, Ser-238--&gt;Gly and Gly-240--&gt;Glu had little effect on kcat and Km values. Finally, the replacement of the catalytic residue Glu-166 by an alanine resulted in a complete loss of activity for CTX and a marked decrease of kcat for CAZ and AZT. These results suggest that Glu-166 is an important residue in PER-1. However, residues other than Glu-166 could contribute in maintaining residual activity towards oxyimino-beta-lactams in the Ala-166 mutant.

Role of residues 104, 164, 166, 238 and 240 in the substrate profile of PER-1 β-lactamase hydrolysing third-generation cephalosporins