Synthesis and Metabolism of Drugs by Means of Enzyme-Catalysed Reactions

Abstract

The usefulness of enzyme catalysed-reactions is exemplified by recent results from research at Roche.
Sequences of enzyme reactions, well organised in metabolic pathways of selected microorganisms, lead to secondary metabolites with innovative chemical structures. An example is the pancreas-lipase inhibitor lipstatin produced by Streptomyces toxytricini. Hydrogenation of lipstatin yields tetrahydrolipstatin, the active substance of the anti-obesity drug Xenical™. The biosynthetic pathway has been elucidated and an improved fermentation process for the production of lipstatin has been developed.
Intermediates of the primary metabolism can be valuable building blocks for the chemical synthesis of drugs. Examples are quinic acid and shikimic acid, which are both suitable starting materials for the synthesis of the neuraminidase inhibitor GS 4104. Metabolic engineering of Escherichia coli with the goal to overproduce these two substances is briefly described.
Microorganisms or enzymes derived thereof are used in drug synthesis to catalyse single, highly specific reaction steps (biotransformations). Three examples yielding chiral precursors of a protein-kinase inhibitor, a collagenase inhibitor, and an antifungal compound are discussed.
Recombinant Escherichia coli strains expressing human drug-metabolising enzymes are suited to mimic drug metabolism and to produce intermediates of human drug metabolism. The desired hydroxylated drug derivatives could be obtained after incubation of drug substances with strains coexpressing one specific human cytochrome P450 isozyme together with human reductase.