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Metallo Beta Lactamase Class E Phylogeny

The phylogeny includes both functional Class E metallo-β-lactamases, those enzymes that can hydrolyze β-lactam antibiotics (in boldface and thick lines), and Class E homologs, proteins that have have not been shown to hydrolyze β-lactam antibiotics or that have been shown to lack that activity (light face and thin lines). β-lactam hydrolyzing activity arose independently in the Class B and Class E groups

Class E = Subclass B3 in the Ambler classification scheme

Class E

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The Ambler Classification Scheme for β-lactamases

The most widely used classification of β-lactamases is the Ambler classification (Ambler, Philos Trans R Soc Lond B Biol Sci 289: 321-331, 1980) that divides β-lactamases into four classes (A, B, C, and D) based upon their amino acid sequences. Ambler originally specified two classes: Class A, the active-site serine β-lactamases and Class B, the metallo-β-lactamases that require a bivalent metal ion, usually Zn++, for activity. When a new group of serine β-lactamases was discovered to lack sequence homology either with Class A or Class B enzymes it was designated Class C (Jaurin, et al., Proc Natl Acad Sci U S A 78: 4897-4901, 1981). A few years later other serine β-lactamases were found that exhibited no sequence homology with any of the existing classes, and were designated Class D (Ouellette, et al., Proc Natl Acad Sci U S A 84: 7378-7382, 1987). That classification scheme remains in effect today.

Not only do the three classes of serine β-lactamases share a common catalytic mechanism, they share sufficient homology at the protein structure level that we can be confident that they descended from a common ancestor (Hall and Barlow, Drug Resistance Updates 7:111-123, 2004). In contrast, the serine β-lactamases show no structural homology with the Class B metallo-β-lactamases (Carfi, Acta Cryst. D54: 313-323, 1998).
Class B has been divided into three subgroups, B1, B2, and B3, on the basis of sequence similarity (Rasmussen and Bush, Antimicrob. Agents Chemother. 41:223-232, 1997), but phylogenetic analysis (Hall et al, J. Mol. Evol. 57: 249-254, 2003) has shown that subgroup B3 lacks detectable sequence homology with subgroups B1 & B2.

Thus for the metallo-β-lactamases the relationship between subgroup B1+B2 and subgroup B3 is exactly the same as the relationship among Class A, C, and D of the serine β-lactamases.

The picture presented by the current implementation of the Ambler scheme is a false one as is shown in this diagram.

It would be useful to revise the Ambler scheme to define two major groups of β-lactamases: the Serine β-lactamases (S) and the Metallo-β-lactamases (M). To reduce the confusion that can arise when a classification scheme is revised, the Serine β-lactamases could be divided into three classes, SA, SC, and SD, corresponding to the current A, C, and D. the metallo-β-lactamases could similarly be divided into two classes, MB and ME, corresponding to Class B subclasses B1+B2, and Class B subclass B3. The revised scheme would accurately reflect the relationships among the various groups of β-lactamases, and would also facilitate the addition of additional classes should new β-lactamases be discovered that exhibit no sequence homology with any of the existing classes.