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Antimicrobial Agents and Chemotherapy, March 2001, p. 660-663, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.660-663.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Standard Numbering Scheme for Class
B 
-Lactamases
-Lactamase Working
Group
Centre d'Ingénierie des Protéines, Université de Liège, B-4000 Liège, Belgium1; Dipartimento di Biologia Molecolare, Sezione di Microbiologia, Università di Siena, I-53100 Siena, Italy2; Division of Protein Structure, NIMR, London NW7 1AA, United Kingdom3; and Laboratoire de Cristallographie Macromoleculaire, Institut de Biologie Structurale Jean-Pierre Ebel (CNRS-CEA), F-38027 Grenoble, France4
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Appendix
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Metallo--lactamases
constitute the molecular class B of Ambler (1) and group 3 according to the Bush-Jacoby-Medeiros functional classification
(6). In recent years, many new enzymes of this class have
been described and the sequences of the corresponding genes have been
determined. Their clinical importance is highlighted by the fact that
they hydrolyze carbapenems, compounds which most often escape the
activity of active-site serine -lactamases. Moreover, most
metallo--lactamases are broad-spectrum enzymes which also hydrolyze
a variety of penicillins and cephalosporins (13, 21, 22,
26). On the basis of the known sequences, three different
lineages, identified as subclasses B1, B2, and B3, can be
characterized. Subclass B1 contains most known metallo--lactamases, including the -lactamase II (BcII) proteins from Bacillus
cereus or other Bacillus spp. (15, 16, 19)
and Bacillus sp. strain 170 (16), the CcrA
(24) (also named CfiA [29]) proteins of
Bacteroides fragilis, the BlaB proteins from
Chryseobacterium meningosepticum (2, 26, 34),
the IND-1 enzyme from Chryseobacterium indologenes
(3), the IMP proteins found in some clinical isolates of
Pseudomonas aeruginosa (17, 28), Serratia
marcescens (21), Klebsiella pneumoniae
(GenBank EMBL accession no. D29636), and Acinetobacter
baumannii (25), and the VIM proteins found in some
P. aeruginosa clinical isolates (18, 22).
Subclass B2 includes the enzymes produced by various species of
Aeromonas (CphA [20], ImiS
[33], and CphA2 [23]) and the Sfh-I
-lactamase (GenBank accession no. AF197943) from Serratia
fonticola. Finally, subclass B3 includes the L1 proteins from
Stenotrophomonas maltophilia (27, 32), the GOB
proteins from C. meningosepticum (2), the FEZ-1
enzyme from Legionella gormanii (5), and
the THIN-B -lactamase produced by Janthinobacterium
lividum (25a).
The three-dimensional structures of several B1 (BcII [7, 9,
12], CcrA [8, 10], and IMP-1
[11]) enzymes and one B3 (L1 [31]) enzyme
have been solved by X-ray crystallography. Despite a very low degree of
sequence similarity between the two subclasses, the general structures
and the relative positions of the secondary structure elements are
similar. Surprisingly, the L1 enzyme is a tetramer (4,
31), whereas the B1, B2, and other B3 (FEZ-1 [5; P. S. Mercuri, F. Bouillenne, L. Boschi, J. Lamotte-Brasseur, G. Amicosante,
B. Devreese, J. van Beeumen, J. M. Frère, G. M. Rossolini, and M. Galleni, unpublished data] and GOB-1
[2]) -lactamases so far studied are monomers.
There are, however, no doubts that the proteins are homologous and the sequences of representatives of the three subclasses can be easily aligned. Indeed, in addition to the expected differences at the N and C termini, several insertions and deletions are necessary to allow the alignment of the few conserved residues acting, for instance, as ligands of the two zinc ions which can bind at the active site. Thus, homologous residues from the different class B sequences which are known to play a relevant role in the structure and function often differ in their numbering, even within each subclass.
In order to facilitate the comparative analysis of the structures and
of the catalytic mechanisms, we would like to propose a standard
numbering scheme for the class B -lactamases, the BBL numbering, by
analogy with the ABL numbering which has been widely accepted for class
A -lactamases. For the class B enzymes, the task was complicated by
insertions and deletions and by the generally low degree of similarity
but facilitated by the availability of some three-dimensional
structures, which allowed the identification of homologous secondary
structure elements, even when the sequence similarity was not obvious.
Figure 1 shows the proposed alignment and
the derived numbering. The observed (B1 and B3) and expected (B2)
secondary structure elements are indicated.
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The following comments can be made. (i) Not all the known sequences are shown. When variants of an enzyme are known and the amino acid alignment exhibits more than 80% sequence identity, only the first described sequence is included in the alignment.
(ii) Alignments at the N and C termini are rather uncertain, due to a high variability even within each subclass. As is done for the class A enzymes, residue no. 1 is the first residue of the leader peptide sequence of the S. maltophilia L1 protein (32). Since they are highly divergent and irrelevant to the functional structure, the other leader sequences have not been included unless the site of action of the signal peptidase has not been verified (Sfh-I [GenBank accession no. AF197943], IND-1 [3], and THIN-B [25a]).
(iii) This is only a numbering scheme. The fact that residues in different proteins have been assigned the same number does not imply that they occupy exactly the same relative spatial position. Indeed, if the Zn ions and their ligands are superimposed, the G232N233 dyad of BcII is more than 3 Å away from the corresponding residues in the S. maltophilia enzyme.
(iv) The loop which can close the active site of B1 enzymes extends between residues BBL 61 and 65 (11, 14, 30). It is absent in subclass B3 (31) and probably in B2.
(v) Any insert in a newly discovered enzyme can be characterized by small letters following the number of the last residue of the consensus sequence. Accordingly, residues N140G141 of THIN-B are defined as BBL 150a and -b and residues I198EQG201 of Sfh-I are defined as BBL 252a, -b, -c and -d, respectively.
(vi) Table 1 shows a cross-reference of
the BBL numbering of the residues identified as or suspected to be the
Zn1 and Zn2 ligands and that used for the individual enzymes up to the
present time. Note that in subgroup B3, one of the Zn2 ligands (H121) originates with a very different part of the polypeptide chain compared
to subgroup B1. Similarly, in subclass B2 and for the B3 GOB-1 enzyme,
the sequence alignments unambiguously point to residues H118, H196, and
N116 (B2) or Q116 (B3), but such a function is rather unusual for
asparagine and glutamine side chains.
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APPENDIX |
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Appendix
References
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The metallo--lactamase group also includes the following: G. Amicosante and N. Franceschini, Dipartimento di Scienze e Tecnologie Biomediche, Università di L'Aquila, I-67100 Coppito, L'Aquila, Italy; K. Bush, The R. W. Johnson Pharmaceutical Research
Institute, Raritan, NJ 08869; N. O. Concha, Department of
Structural Biology, SmithKline Beecham Pharmaceuticals, King of
Prussia, PA 19406; O. Herzberg, Center for Advanced Research in
Biotechnology, University of Maryland Biotechnology Institute,
Rockville, MD 20850; D. M. Livermore, Antibiotic Resistance
Monitoring and Reference Laboratory, Central Public Health Laboratory,
London NW9 5HT, United Kingdom; P. Nordmann, Service de
Bactériologie-Virologie, Hopital de Bicêtre, Faculté
de Médecine Paris-Sud, 94275 Le Kremlin-Bicêtre, France; B. A. Rasmussen, Wyeth-Ayerst Research, Pearl River, NY 10965; J. Rodrigues and M. J. Saavedra, Department of Animal Health, University of Trás-os-Montes e Alto Douro, 5000-911 Vila Real, Portugal; B. Sutton and S. M. Fabiane, The Randall Centre, King's College London, London SE1 1UL, United Kingdom; and J. H. Toney, Department of Biochemistry, Merck Research Laboratories, Rahway, NJ
07065-0900.
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ACKNOWLEDGMENTS |
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This work was supported in part by a grant from the European Union (grant ERB3512-IC15-CT98-0914) as part of the training and mobility of researchers program and by the Belgian Program Pôles d'Attraction Interuniversitaire initiated by the Belgian state, prime minister's office, Services Fédéraux des Affaires Economiques, Techniques et Culturelles (PAI P4/03).
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FOOTNOTES |
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* Corresponding author. Mailing address: Centre for Protein Engineering, B6 Sart Tilman, University of Liège, B4000 Liège, Belgium. Phone: 32-043663419. Fax: 32-043663364. E-mail: mgalleni{at}ulg.ac.be.
Members are listed in the Appendix.
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