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Changing the R-group side chain gives penicillins different properties and activities against different bacteria. There is, however, a slight problem in altering this R-group as the b-lactam ring is very labile and strained. To remove the R-group of benzyl penicillin [Penicillin G], the side chain amide bond [shown in green below] must be hydrolysed so that a new group can be attached. However, as the b-lactam ring is more reactive, the b-lactam ring amide bond [shown in blue] hydrolyses first, giving benzyl penicilloic acid.
One way to overcome this problem is to use an enzyme called penicillin acylase from Escherichia coli, which selectively hydrolyses the side chain amide bond and does not affect the b-lactam amide bond. This reaction produces 6-amino penicillanic acid, or 6-APA, and this is used as the building block for manufacturing semi-synthetic penicillins. The reaction scheme below shows the production of amoxicillin using this method.12
The image below shows the enzyme penicillin acylase from E. coli with benzyl penicillin in the active site. This is where it hydrolyses benzyl penicillin to 6-APA.13
[Adapted from 1FXV.pdb, available to download from www.rcsb.org/pdb/]
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