Aldehyde Oxidases as Enzymes in Phase I Drug Metabolism

This chapter discusses the significance of aldehyde oxidases for the design and development of new drugs, and discusses associated problems. Aldehyde oxidases are a group of enzymes with important functions in the context of drug and xenobiotic metabolism. Aldehyde oxidases (AOXs) and xanthine oxidoreductases (XORs) are structurally and evolutionarily linked molybdoflavoproteins. AOXs and XORs are widely distributed throughout all kingdoms of life, homologous proteins have been identified in many eukaryotic and prokaryotic organisms. The C-terminal domain III is binding the molybdenum cofactor (Moco) in its sulfido-containing form. At the catalytic site, the Moco adopts an approximately square pyramidal geometry. Heterologous expression systems for mammalian AOXs, including the human enzyme, in Escherichia coli have been developed, allowing site directed mutagenesis approaches to the role of distinct amino acid residues at the active site. The identification and characterization of genetic variants of enzymes involved in drug metabolism is highly relevant for the definition of the effectiveness and toxicity of pharmaceutical treatments.