Relation between Penicillin and N-acetylmuramic Acid in the Binding Site of LysozymeAuthor(s): J. CollinsSource: Proceedings of the Royal Society of London. Series B, Biological Sciences, Vol. 167, No.1009, A Discussion on the Structure and Function of Lysozyme (Apr. 18, 1967), pp. 441-442Published by: The Royal SocietyStable URL: http://www.jstor.org/stable/75687 .

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Relation between penicillin and iV-acetylmuramic acid

in the binding site of lysozyme

By J. Collins

Department of Molecular Biology, King's Buildings, West Mains Road, Edinburgh 9

It has been known for some time that penicillin exerts its antibiotic action by

inhibiting the synthesis of the cell wall mucopeptide polymer in sensitive bacteria.

Richmond and I, seeking an explanation for this specificity, suggested that there

was a structural similarity between penicillin and Af-acetylmuramic acid, one of

the components in the polymer, and that penicillin might inhibit one of the en?

zymes involved in the synthesis of the polymer because of this similarity (Collins & Richmond 1962). It is therefore very interesting to hear that phenoxymethyl- penicillin has a single binding site in the lysozyme molecule, which is also the

binding site for a-benzyl-A^-acetylmuramic acid (the site number 5, in Dr Phillips's notation). With the data from the 6 A resolution picture of these enzyme complexes obtained by Dr Johnson, it is not possible to determine which groups are involved in interactions between lysozyme and the bound molecules of penicillin and a-

benzyl-iV-acetylmuramic acid. Examination of the lysozyme model in the region where these molecules are bound shows some groups which may be involved in

hydrophobic interactions, but few polar groups. This weakens the possibility that the similarity suggested by Richmond and me underlies the interaction between the molecules in these complexes, since we found the maximum similarity to lie in the disposition of polar groups in penicillin and in JV-acetylmuramic acid.

Briefly, we drew an analogy between the carboxyl groups, between the ring nitrogen atom in penicillin and the ether oxygen atom in the lactyl side-chain of

A'-acetylmuramic acid, and between the carbonyl groups in the amide links in the two molecules.

Since both penicillin and a-benzyl-if-acetylmuramic acid are excluded from the sites believed by Dr Phillips to bind the lysozyme substrate (which contains

i^-acetylmuramic acid residues) the large hydrophobic phenyl group common to these molecules may play a significant part in the complex formation. If there

proves to be analogous binding of the phenyl groups of phenoxymethylpenicillin and of a-benzyl-jV-acetylmuramie acid in their complexes with lysozymes there can hardly be much similarity of interaction with the polar groups. When the

structure of these complexes is known in greater detail it may be found that the coincidence of the sites of binding for these two rather dissimilar molecules is fortuitous for this reason. It has recently been suggested that penicillin inhibits the reaction which cross-links the mucopeptide chains through glycine bridges in the normal bacterial cell wall, and that no similarity between penicillin and N-

acetylmuramic acid is involved in the explanation of the antibiotic activity of

penicillin (Tipper & Strominger 1965). Structural similarities were suggested be-

[ 441 ]

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442 J. Collins (Discussion Meeting)

tween penicillin and the D-alanyl-D-alanine group in the substrate in the cross-

linking reaction, but it is clear that much remains to be explained about the mode of action of penicillin. It will be remarkable if penicillin, which inhibits some

enzyme involved in the formation of the mucopeptide polymer, binds simply by chance to the enzyme whose sole catalytic function is the hydrolysis of this

polymer.

References (Collins)

Collins, J. F. & Richmond, M. H. 1962 Nature, Lond. 195, 142. Tipper, D. J. & Strominger, J. L. 1965 Proc. Natl. Acad. Sci. Wash. 54, 1133.

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