Section 1.3.4.5. Drug manufacturing and crystallography

The development of drugs is a major undertaking and one of the hallmarks of modern societies. However, once a safe and effective therapeutic agent has been fully tested and approved, manufacturing the compound on a large scale is often the next major challenge. Truly massive quantities of penicillin and cephalosporin are produced worldwide, ranging from 2000 to 7000 tons annually (Conlon et al., 1995). In the production of semi-synthetic penicillins, the enzyme penicillin acylase plays a very significant role. This enzyme catalyses the hydrolysis of penicillin into 6-aminopenicillanic acid. Its crystal structure has been elucidated (Duggleby et al., 1995) and may now be used for protein-engineering studies to improve its properties for the biotechnology industry. The production of cephalosporins could benefit in a similar way from knowing the structure of cephalosporin acylase (CA), since the properties of this enzyme are not optimal for use in production plants. Therefore, the crystal structure determination of CA could provide a basis for improving the substrate specificity of CA by subsequent protein-engineering techniques. Fortunately, a first CA structure has been solved recently (Kim et al., 2000), with many other structures expected to be solved essentially simultaneously. Clearly, crystallography can be not only a major player in the design and optimization of therapeutic drugs, but also in their manufacture.