| Sortase B | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 3.4.22.71 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| |||||||||
Sortases are membrane anchoredenzyme that sort these surfaceproteins onto the bacterial cell surface and anchor them to thepeptidoglycan.[1] There are different types ofsortases and each catalyse the anchoring of differentproteins tocell walls.[2]
It is very important forbacteria to acquire iron during infection,[3] Iron is perhaps the most importantmicronutrient required for bacteria to proliferate and cause disease. Sortase B, is a 246amino acids polypeptide with putative N-terminal membrane anchor and an active site cysteine located within the TLXTC signature motif of sortases.[4][5]
It appears these enzymes are dedicated to helping the bacteria acquire iron by anchoring iron acquisition proteins to the cell membrane[6][7] Sortase B recognises and cleaves the NPQTN motif.[8][9] It links IsDC to mature assemble peptidoglycan,[10] The enzyme catalyses acell wall sorting reaction in which a surface protein with a sorting signal containing a NXTN motif is cleaved.
This enzyme belongs to thepeptidase family C60.
SrtB overall structure is conserved in differentgram-positive bacteria. The overall structure of SrtB inS. aureus as shown in the figure, consists of a unique eight-stranded β-barrel core structure and a two-helix subdomain at the N-terminal end.
SrtB is similar in structure to SrtA with rmsd of 1.25Å but SrtB has more peripheral helices[6] It has an N-terminal helical bundle and anα-helix between β6 and β7. The N-terminal extension present in SrtB relative to SrtA is very significant. It is known to place the two termini on the same side of the protein. This is believed to result in a different orientation of the protein on the surface of the cell, potentially affecting substrate access.[6]
The sortase B enzyme catalyzes acell wall sorting reaction with a surface protein where a signal NXTN motif is cleaved. In the result, the C-end of the protein is covalently attached to a pentaglycine cross-bridge through an amide linkage, thus tethering the C-terminus ofprotein A to the cell wall.[11]
It cleaves the protein precursor molecule at the NPQTN motif. The peptide bond between T and N of the NPQTN sorting motif is cleaved to form a tetrahedral acyl intermediate. The amino groups of the pentaglycine cross-bridges linked to the lipid II peptidoglycan precursor molecules are thought to function as nucleophile resolving acyl intermediates and creating an amide bond between the surface protein and lipid II with subsequent incorporation of this intermediate into the cell wall envelope.
IsDC remains buried within the cell wall, not surface located like IsDA and IsDB anchored by Sortase A. This whole system work together to scavenge iron fromhaemoglobin.[9]
Surface proteins of Gram-positive bacteria play an important role in the pathogenesis of human infections such asClostridioides difficile infection.[7][1] These surface/adhesion proteins mediate the initial attachment of bacteria to host tissues. These proteins are covalently linked to the peptidoglycan of the bacterial cell wall. As more and more pathogens become resistant toantibiotics, inhibition of sortases may offer a novel strategy against gram-positive bacterial infections.[12]
SrtB, in particular, has gained much attention and is recognized as a promising target[13] and deletion of its gene ingram-positive bacteria will lead to serious virulence defects. Crystal structures of these SrtB enzymes from different species have been solved with ligands/inhibitors bound to their active site. With knowledge of the active site, the development of better therapeutics against these bacteria species can be done.
