Summary: Penicillin binding protein transpeptidase domain
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Penicillin binding proteins Edit Wikipedia article
|Penicillin-binding protein, transpeptidase|
|Penicillin-binding protein, dimerisation domain|
Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics (except for tabtoxinine-β-lactam, which inhibits glutamine synthetase) bind to PBPs, which are essential for bacterial cell wall biogenesis.
There are a large number of PBPs, usually several in each organism, and they are found as both membrane-bound and cytoplasmic proteins. For example, Spratt (1977) reports that six different PBPs are routinely detected in all strains of E. coli ranging in molecular weight from 40,000 to 91,000. The different PBPs occur in different numbers per cell and have varied affinities for penicillin (see appendix). The PBPs are usually broadly classified into high-molecular-weight (HMW) and low-molecular-weight (LMW) categories. Proteins that have evolved from PBPs occur in many higher organisms and include the mammalian LACTB protein.
PBPs are all involved in the final stages of the synthesis of peptidoglycan, which is the major component of bacterial cell walls. Bacterial cell wall synthesis is essential to growth, cell division (thus reproduction) and maintaining the cellular structure in bacteria. Inhibition of PBPs leads to irregularities in cell wall structure such as elongation, lesions, loss of selective permeability, and eventual cell death and lysis.
PBPs have been shown to catalyze a number of reactions involved in the process of synthesizing cross-linked peptidoglycan from lipid intermediates and mediating the removal of D-alanine from the precursor of peptidoglycan. Purified enzymes have been shown to catalyze the following reactions: D-alanine carboxypeptidase, peptidoglycan transpeptidase, and peptidoglycan endopeptidase. In all bacteria that have been studied, enzymes have been shown to catalyze more than one of the above reactions. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (involved in formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (involved in cross-linking of the peptide subunits) and the serine at the active site is conserved in all members of the PBP family.
PBPs bind β-lactam antibiotics because they are similar in chemical structure to the modular pieces that form the peptidoglycan. When they bind to penicillin, the β-lactam amide bond is ruptured to form a covalent bond with the catalytic serine residue at the PBPs active site. This is an irreversible reaction and inactivates the enzyme.
There has been a great deal of research into PBPs because of their role in antibiotics and resistance. Bacterial cell wall synthesis and the role of PBPs in its synthesis is a very good target for drugs of selective toxicity because the metabolic pathways and enzymes are unique to bacteria. Resistance to antibiotics has come about through overproduction of PBPs and formation of PBPs that have low affinity for penicillins (among other mechanisms such as lactamase production). Research on PBPs has led to the discovery of new semi-synthetic β-lactams, wherein altering the side-chains on the original penicillin molecule has increased the affinity of PBPs for penicillin, and, thus, increased effectiveness in bacteria with developing resistance.
The β-lactam ring is a structure common to all β-lactam antibiotics.
- Sainsbury, S., Bird, L., Rao, V., Shepherd, S.M., Stuart, D.I., Hunter, W.N., Owens, R.J., and Ren, J. (2011). "Crystal Structures of Penicillin-Binding Protein 3 from Pseudomonas aeruginosa: Comparison of Native and Antibiotic-Bound Forms". J.Mol.Biol. 405: 173–184. doi:10.1016/j.jmb.2010.10.024.
- Spratt BG (1977). "Properties of the penicillin-binding proteins of Escherichia coli K12,.". Eur J Biochem 72 (2): 341–52. doi:10.1111/j.1432-1033.1977.tb11258.x. PMID 319999.
- Basu J, Chattopadhyay R, Kundu M, Chakrabarti P (1992). "Purification and partial characterization of a penicillin-binding protein from Mycobacterium smegmatis.". J Bacteriol 174 (14): 4829–32. PMC 206282. PMID 1624470.
- Peitsaro N, Polianskyte Z, Tuimala J, Pörn-Ares I, Liobikas J, Speer O, Lindholm D, Thompson J, Eriksson O (2008). "Evolution of a family of metazoan active-site-serine enzymes from penicillin-binding proteins: a novel facet of the bacterial legacy". MBC Evolutionary Biology 8: 16. doi:10.1186/1471-2148-8-26. PMC 2266909. PMID 18226203.
- Nguyen-Distèche M, Leyh-Bouille M, Ghuysen JM (1982). "Isolation of the membrane-bound 26 000-Mr penicillin-binding protein of Streptomyces strain K15 in the form of a penicillin-sensitive D-alanyl-D-alanine-cleaving transpeptidase.". Biochem J 207 (1): 109–15. PMC 1153830. PMID 7181854.
- Chambers HF (1999). "Penicillin-binding protein-mediated resistance in pneumococci and staphylococci.". J Infect Dis. 179 Suppl 2: S353–9. doi:10.1086/513854. PMID 10081507.
Penicillin binding protein transpeptidase domain Provide feedback
The active site serine (residue 337 in P14677) is conserved in all members of this family.
Pares S, Mouz N, Petillot Y, Hakenbeck R, Dideberg O , Nat Struct Biol 1996;3:284-289.: X-ray structure of Streptococcus pneumoniae PBP2x, a primary penicillin target enzyme. PUBMED:8605631 EPMC:8605631
Internal database links
|Similarity to PfamA using HHSearch:||Peptidase_S11 Beta-lactamase2|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001460
This signature identifies a large group of proteins, which include:
- Beta-lactamase precursor (EC, penicillinase)
- Peptidoglycan synthetase ftsI (EC, peptidoglycan glycosyltransferase 3)
- Methicillin resistance mecR1 protein
- Methicillin resistance blaR1 protein
The large number of penicillin binding proteins, which are represented in this group of sequences, are responsible for the final stages of peptidoglycan biosynthesis for cell wall formation. The proteins synthesise cross-linked peptidoglycan from lipid intermediates, and contain a penicillin-sensitive transpeptidase carboxy-terminal domain. The active site serine (residue 337 in SWISSPROT) is conserved in all members of this family [PUBMED:8605631].
MecR1 and BlaR1 are metallopeptidases belonging to MEROPS peptidase family M56, clan M-. BlaR1 and MecR1 cleave their cognate transcriptional repressors BlaI and MecI, respectively, activating the synthesis of MecA.
MecR1 is present in Staphylococcus aureus and Staphylococcus sciuri, whereas BlaR1 (also known as BlaR, PenR1, or PenJ) has been found in Bacillus licheniformis, Staphylococcus epidermidis, Staphylococcus haemolyticus, and several S. aureus strains. These proteins are either plasmid-encoded, chromosomal, or transposon-mediated. MecR1/BlaR1 proteins are made up by homologous N-terminal 330-residue transmembrane metallopeptidase domains linked to extracellular 260-residue homologous PBP-like penicillin sensor moieties.
|Molecular function||penicillin binding (GO:0008658)|
|Biological process||peptidoglycan-based cell wall biogenesis (GO:0009273)|
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This superfamily contains proteins that have a beta-lactamase fold. This includes beta-lactamases as well as Dala-Dala carboxypeptidases and glutaminases.
The clan contains the following 7 members:Beta-lactamase Beta-lactamase2 DAP_B Glutaminase Peptidase_S11 Peptidase_S13 Transpeptidase
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Curation and family details
|Seed source:||Bateman A & Pfam-B_726 (Release 8.0)|
|Author:||Bateman A, Finn RD|
|Number in seed:||42|
|Number in full:||25088|
|Average length of the domain:||286.30 aa|
|Average identity of full alignment:||21 %|
|Average coverage of the sequence by the domain:||43.58 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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There are 4 interactions for this family. More...
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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 Transpeptidase domain has been found. There are 218 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 seqence.
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