Saturday, 1 March 2014

Penicillin: molecule for the month of March

Penicillin is one of the most well known of biological molecules, although I suspect that most people who know the name, don't know the molecule! The structure of penicillin shown left. The compound comes in a number of slight variations which are generated by changing the chemistry at the R position (top left). (The use of the letter R is common in chemistry and biochemistry for indication a range of functional groups). The effect of the drug was famously discovered by Sir Alexander Fleming in 1928 (for which he later shared the Nobel Prize with Florey and Chain). The square shaped "ring" structure at the core of the molecule is called a beta lactam, which is fused to a five-membered thiazolidine ring, which gives rise to the term penam, and hence the name penicillin. 

The compound was first extracted from the mould, Penicillium, thanks to the tenacity mainly of the Biochemist Ernst Chain (it would be Florey who pioneered its application for the treatment of clinical infections, although my colleague at Sheffield, Milton Wainwright has I believe, produced the definitive Penicillin history). It acts on the enzymes responsible for the completion of the biosynthesis of the bacterial cell wall. The polymers that give the stiffness to bacterial cell walls are a mixture of carbohydrate and amino acids and are called peptidoglycans. The drug prevents these polymers from forming cross-links, which give the bacteria an outer netting. 

Penicillin looks unusual as most biological molecules go and it is in fact synthesised by an interesting class of enzymes that form the basis of the Y12 synthetic biology project. The compound is formed by joining three amino acids together Amino Adipic Acid (not an amino acid found in proteins) and the two proteogenic (protein generating) amino acids Cysteine and Valine. The enzyme name is ACV synthetase. It is one of a group of enzymes that assembles amino acids into short peptides, giving rise to the term non-ribosomal peptide synthesis (since most proteins are made by the ribosome). The molecule is then further modified by a group of enzymes, to produce slightly different forms (the image left is one such enzyme). 

Penicillin remains a major drug for treating infections, and is often used in conjunction with other antibiotics if infections are persistent. Except for the 1% who are allergic to it! The problem of resistance to penicillin is also a major problem. Here the target for the drug has picked up a mutation, and is no longer inhibited, allowing cell wall biosynthesis to continue unhindered. The careful and responsible use of antibiotics is a hot topic at the moment, and the search for new ones, should, in my view be a greater priority.  

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