Aldehyde Oxidase (AOX) is a molybdenum enzyme with toxicological importance since, along with cytochrome P450 (CYP450), it metabolizes different classes of xenobiotics being one of the principal drug-metabolizing enzymes in the liver. AOX oxidizes and inactivates a large number of drug molecules and has been responsible for a number of drug failures in clinical trials. The problem became more serious when efforts from the industry to reduce CYP450 metabolic liability led to chemical structures (azaheterocycles) for new drugs that turned to be good substrates of AOX. One important goal of our research plan will be defining the molecular basis for the mechanism of the AOX-dependent oxidation of target molecules.
From all this data we expect at the end of this project to be able to (1) unravel the catalytic and inhibition mechanisms of hAOX1 and related bacterial enzymes (DgAOR, EcPaoABC); (2) elucidate the role of AOX in the metabolism of drugs and xenobiotics; (3) define an in silico method to predict the susceptibility of a certain molecule to be a substrate of AO, allowing to design AOX-stable putative drugs; (4) discover and identify the endogenous substrate(s) of human and mouse AOXs.