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<StructureSection load= size=550 side='right' scene='37/372728/Transpeptidase_in_rainbow/ | <StructureSection load= size=550 side='right' scene='37/372728/Transpeptidase_in_rainbow/2'> | ||
==='''Introduction'''=== | ==='''Introduction'''=== | ||
Peptidoglycan transpeptidase (TP) also known as penicillin-binding proteins (PBP), are essential for bacterial cell wall synthesis and catalyze the cross-linking of peptidoglycan polymers during bacterial wall synthesis.[http://en.wikipedia.org/wiki/Beta-lactam_antibiotic Beta-lactam antibiotic], which includes the penicillins,cephalosporins,carbapenems, and the monobactam aztreonam | Peptidoglycan transpeptidase (TP) also known as penicillin-binding proteins (PBP), are essential for bacterial cell wall synthesis and catalyze the cross-linking of peptidoglycan polymers during bacterial wall synthesis.[http://en.wikipedia.org/wiki/Beta-lactam_antibiotic Beta-lactam antibiotic], which includes the penicillins,cephalosporins,carbapenems, and the monobactam aztreonam (figure 1); bind and irreversibly inhibit the active site of TP. The overuse and misuse of b-lactam antibiotics has led to strains of ''Staphylococcus aureus (S.aureus)'' that are resistant to all currently available b-lactams and are often susceptible to so-called "last resort antibiotics", such as vancomycin. | ||
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==='''Structure of PBP2a, a B-Lactam Resistant Transpeptidase'''=== | ==='''Structure of PBP2a, a B-Lactam Resistant Transpeptidase'''=== | ||
Isolates of methicillin-resistant S. aureus (MRSA) are resistant to almost all currently available B-lactams because they have acquired an alternative PBP, PBP2A (encoded by the mecA gene) that is neither bound nor inhibited by B-lactams. PBP2a is composed of two domains: a non-penicillin binding domain <scene name='37/372728/Npb_domain/1'>(NPB)</scene> and a <scene name='37/372728/Tp_domain/1'>TP</scene>-binding domain. The NBP domain of PBP2a is anchored in the cell membrane, while the TP domain residues in the periplasm with its active site facing the inner surface of the cell wall. The active site contains <scene name='37/372724/Serine403label/2'> a serine residue at position 403 (Ser403)</scene>, which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links. | Isolates of methicillin-resistant S. aureus (MRSA) are resistant to almost all currently available B-lactams because they have acquired an alternative PBP, PBP2A (encoded by the mecA gene) that is neither bound nor inhibited by B-lactams. PBP2a is composed of two domains: <font color='orangered'><b>a non-penicillin binding domain </b><scene name='37/372728/Npb_domain/1'>(NPB)</scene></font> and a <font color='dodgerblue'>'''transpeptidase'''<scene name='37/372728/Tp_domain/1'>TP</scene>'''-binding domain'''</font>. The NBP domain of PBP2a is anchored in the cell membrane, while the TP domain residues in the periplasm with its active site facing the inner surface of the cell wall. The active site contains <scene name='37/372724/Serine403label/2'> a serine residue at position 403 (Ser403)</scene>, which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links. | ||
==='''B-Lactams that Inhibit PBP2a'''=== | ==='''B-Lactams that Inhibit PBP2a'''=== | ||
MRSA becomes resistant to almost all B-Lactams by acquiring an alternative TP, PBP2a, that is neither bound nor inhibited by B-Lactams. Recently, two cephlosporins- <scene name=' | MRSA becomes resistant to almost all B-Lactams by acquiring an alternative TP, PBP2a, that is neither bound nor inhibited by B-Lactams. Recently, two cephlosporins- <scene name='36/365380/Ceftobiprole/28'>ceftobiprole</scene> and ceftaroline- that have anti-MRSA activity have been developed. Ceftobiprole is able to inhibit PBP2a because additional chemical groups at the <scene name='36/365380/Ceftobiprole/29'>R2</scene> position of ceftobiprole are able to interact with additional amino acid residues in PBP2a; specifically <scene name='37/372728/Tyr446_met641_interaction/4'>Tyr446 and Met641, and increase the association of ceftobiprole with PBP2a</scene>. As such, ceftobiprole is (shown as colors of the atom types [[CPK]]) is able to more efficiently react with Ser403 and therefore inhibit the activity of PBP2a. | ||
<scene name='37/372728/Tyr446_met641_interaction/4'>Tyr446 and Met641, and increase the association of ceftobiprole with PBP2a</scene>. | |||
As such, ceftobiprole is (shown as colors of the atom types [[CPK]]) is able to more efficiently react with Ser403 and therefore inhibit the activity of PBP2a. | |||
=='''PBP2a and Ceftaroline'''== | |||
<scene name='36/365380/3zfz_1/19'>PBP2a in complex with Ceftaroline</scene> (PDB:3ZFZ) | |||
In addition to TP domain of PBP2a, there is an allosteric domain,highlighted orange, in which the distance between <scene name='36/365380/3zfz_1/20'>the active site and the allosteric site</scene> is 60Å. | |||
Allosteric site serves as a binding site for the substrate <scene name='36/365380/3zfz_1/25'>peptidoglycan</scene>. When the substrate binds to the <scene name='36/365380/3zfz_1/21'>allosteric site</scene> (Tyr105, Asn146, Asp295, Tyr297), a conformational change occurs at the active site, opening it and allowing catalytic action to occur. | |||
The medicine, <scene name='37/372728/Ceftaroline/2'>ceftaroline</scene>, mimics the substrate at the <scene name='37/372728/3zfz_allosteric_site/2'>allosteric site</scene> opening the active site, allowing <scene name='36/365380/3zfz_1/22'>ceftaroline</scene> to <scene name='36/365380/3zfz_1/23'>enter and bind noncovalently</scene>. | |||