The Ambler Classification Scheme for ß-lactamases

The most widely used classification of ß-lactamases is the Ambler classification (Ambler, Philos Trans R Soc Lond B Biol Sci 289: 321-331, 1980) that divides ß-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 ß-lactamases and Class B, the metallo-ß-lactamases that require a bivalent metal ion, usually Zn++, for activity. When a new group of serine ß-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 ß-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 ß-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 ß-lactamases show no structural homology with the Class B metallo-ß-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-ß-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 ß-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 ß-lactamases: the Serine ß-lactamases (S) and the Metallo-ß-lactamases (M). To reduce the confusion that can arise when a classification scheme is revised, the Serine ß-lactamases could be divided into three classes, SA, SC, and SD, corresponding to the current A, C, and D. the metallo-ß-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 ß-lactamases, and would also facilitate the addition of additional classes should new ß-lactamases be discovered that exhibit no sequence homology with any of the existing classes.