Summary: Metallo-beta-lactamase superfamily
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Metallo-beta-lactamase protein fold Edit Wikipedia article
|SCOP2||1bmc / SCOPe / SUPFAM|
The metallo-Î²-lactamase (MBL) superfamily constitutes a group of proteins found in all domains of life that share a characteristic Î±Î²Î²Î± fold with the ability to bind transition metal ions. Such metal binding sites may have divalent transition metal ions like Zn(II), Fe(II)/Fe(III) and Mn(II), and are located at the bottom of a wide cleft able to accommodate diverse substrates. The name was adopted after the first members of the superfamily to be studied experimentally: a group of zinc-dependent hydrolytic enzymes conferring bacterial resistance to Î²-lactam antibiotics. These zinc-Î²-lactamases (ZBLs) inactivate Î²-lactam antibiotics through hydrolysis of the Î²-lactam ring. Early studies on MBLs were conducted on the enzyme Î²LII isolated from strain 569/H/9 of Bacillus cereus. It was named Î²LII because it was the second Î²-lactamase shown to be produced by the bacterium; the first one, Î²LI, was a non-metallic Î²-lactamase, i.e., insensitive to inhibition with EDTA (Î²LII was renamed BcII over time).
Low-resolution X-ray crystallographic analyses published in 1995, disclosed the new Î±Î²Î²Î± fold that would become the hallmark of the MBL superfamily, along with a single Zn(II) ion bound to a three-histidine motif, resembling the active site typical of carbonic anhydrases. Thus, BcII and ZBLs in general were thought to use a single Zn(II) ion to activate a water molecule for hydrolysis, analogous to the mechanism by which carbonic anhydrases hydrate carbon dioxide into bicarbonate. This belief was soon debunked when the structure of Bacteroides fragilis ZBL, CcrA, was published, showing an additional Zn(II) ion next to the previous one. The second zinc was coordinated to nearby Asp, Cys and His residues. Besides, the second metal ion was later found in Bacillus cereus ZBL too, starting a decade-long controversy regarding the role of each zinc ion. Later on, it was found that monometallic ZBLs are rather exceptional and the antibiotic inactivation reaction requires two Zn(II) ions.
Metallo-beta-lactamases are important enzymes because they are involved in the breakdown of antibiotics by antibiotic-resistant bacteria. It is unclear whether metallo-beta-lactamase activity evolved once or twice within the superfamily; if twice, this would suggest structural exaptation. Proteins belonging to the MBL superfamily usually combine at least one MBL domain with additional domains that provide different functions, such as substrate recognition or binding to other polypeptides, in a modular fashion. Thus, MBL superfamily members grasp the metal-assisted water-activation ability of the MBL domain in order to perform a wide variety of hydrolytic reactions. Such diversity is often expanded by mutations around the metal-binding site in order to bind different metal ions. Indeed, those MBLs that bind Fe(II)/Fe(III) are often redox active due to the ability to perform one-electron redox reactions.
Early attempts to systematically classify all members of the MBL superfamily were conducted in 1999 by Aravind, who showed that many other proteins display the Î±Î²Î²Î± typical of MBLs. These observations were updated in 2001 by Daiyasu et al. who defined at least 16 families within the MBL superfamily. These proteins include thiolesterases, members of the glyoxalase II family, that catalyse the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid and a competence protein that is essential for natural transformation in Neisseria gonorrhoeae and could be a transporter involved in DNA uptake. Except for the competence protein these proteins bind two zinc ions per molecule as cofactor. Currently, at least one hundred proteins have been shown to contain an Î±Î²Î²Î± domain using X-ray crystallography, whereas the whole MBL superfamily includes about half a million members.
- GonzÃ¡lez, JM (2021). "Visualizing the superfamily of metallo-Î²-lactamases through sequence similarity network neighborhood connectivity analysis". Heliyon. 7 (1): e05867. doi:10.1016/j.heliyon.2020.e05867. PMCÂ 7785958. PMIDÂ 33426353.
- Carfi A, Pares S, DuÃ©e E, Galleni M, Duez C, FrÃ¨re JM, Dideberg O (1995). "The 3-D structure of a zinc metallo-beta-lactamase from Bacillus cereus reveals a new type of protein fold". EMBO Journal. 14 (20): 4914â€“21. doi:10.1002/j.1460-2075.1995.tb00174.x. PMCÂ 394593. PMIDÂ 7588620.
- Concha NO, Rasmussen BA, Bush K, Herzberg O (1996). "Crystal structure of the wide-spectrum binuclear zinc beta-lactamase from Bacteroides fragilis". Structure. 4 (7): 823â€“36. doi:10.1016/s0969-2126(96)00089-5. PMIDÂ 8805566.
- Orellano EG, Girardini JE, Cricco JA, Ceccarelli EA, Vila AJ (1998). "Spectroscopic characterization of a binuclear metal site in Bacillus cereus beta-lactamase II". Biochemistry. 37 (28): 10137â€“80. doi:10.1021/bi980309j. PMIDÂ 9665723.
- GonzÃ¡lez JM, Meini MR, Tomatis PE, Medrano MartÃn FJ, Cricco JA, Vila AJ (2012). "Metallo-Î²-lactamases withstand low Zn(II) conditions by tuning metal-ligand interactions". Nature Chemical Biology. 8 (8): 698â€“700. doi:10.1038/nchembio.1005. PMCÂ 3470787. PMIDÂ 22729148.
- Shaw, Robert W; Kim, Sung-kun (November 2008). "Inhibition of metallo-Î²-lactamase". 7456274.
- Alderson R, Barker D, Mitchell JB (2014). "One origin for metallo-beta-lactamase activity, or two? An investigation assessing a diverse set of reconstructed ancestral sequences based on a sample of phylogenetic trees". J. Mol. Evol. 79 (3â€“4): 117â€“29. Bibcode:2014JMolE..79..117A. doi:10.1007/s00239-014-9639-7. PMCÂ 4185109. PMIDÂ 25185655.
- Aravind, L (1999). "An evolutionary classification of the metallo-beta-lactamase fold proteins". In Silico Biology. 1 (2): 69â€“91. PMIDÂ 11471246.
- Daiyasu H, Osaka K, Ishino Y, Toh H (2001). "Expansion of the zinc metallo-hydrolase family of the beta-lactamase fold". FEBS Letters. 503 (1): 1â€“6. doi:10.1016/s0014-5793(01)02686-2. PMIDÂ 11513844. S2CIDÂ 83777351.
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Metallo-beta-lactamase superfamily Provide feedback
No Pfam abstract.
Carfi A, Pares S, Duee E, Galleni M, Duez C, Frere JM, Dideberg O; , EMBO J 1995;14:4914-4921.: The 3-D structure of a zinc metallo-beta-lactamase from Bacillus cereus reveals a new type of protein fold. PUBMED:7588620 EPMC:7588620
Internal database links
|SCOOP:||Beta-Casp Beta_lactamase3 BLACT_WH HAGH_C Lactamase_B_2 Lactamase_B_3 Lactamase_B_4 Lactamase_B_5 Lactamase_B_6 ODP PDEase_II|
|Similarity to PfamA using HHSearch:||Lactamase_B_2 Lactamase_B_3 Lactamase_B_6 ODP|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001279
Metallo beta lactamases exhibit low sequence identity between enzymes but they are structurally similar. They have a characteristic alpha-beta/beta-alpha sandwich fold in which the active site is at the interface between domains. Apart from the beta-lactamases and metallo-beta-lactamases, a number of other proteins contain this domain and share the same fold type [ PUBMED:7588620 , PUBMED:23163348 ]. These proteins include thiolesterases, members of the glyoxalase II family, that catalyse the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid and a competence protein that is essential for natural transformation in Neisseria gonorrhoeae and could be a transporter involved in DNA uptake. Except for the competence protein these proteins bind two zinc ions per molecule as cofactor.
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This superfamily of enzymes including beta-lactamases, thiolesterases, members of the glyoxalase II family that catalyse the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid all bind two ions of zinc. An additional family of competence proteins essential for natural transformation do not appear to bind zinc, and might be a transporter involved in DNA uptake.
The clan contains the following 10 members:Beta_lactamase3 HAGH_C Lactamase_B Lactamase_B_2 Lactamase_B_3 Lactamase_B_4 Lactamase_B_5 Lactamase_B_6 ODP PDEase_II
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|Author:||Ponting CP , Bateman A|
|Number in seed:||123|
|Number in full:||81739|
|Average length of the domain:||183.20 aa|
|Average identity of full alignment:||14 %|
|Average coverage of the sequence by the domain:||50.47 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||30|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Lactamase_B domain has been found. There are 950 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.