hAOX1

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The team integrates two RLabs and two young supervisors from the SMB group, with complimentary expertise in structural biology. The research aims to mechanistically characterize hAOX1 at the structural level (X-ray crystallography) and study its interactions with potential ligands (NMR). These goals are aligned with UCIBIO TL1 “Biological & Biomolecular Interactions”.
 

| Given the importance of hAOX1, the expected research will impact drug development programs and help understanding drug-metabolizing enzymes, towards the prevention of drug failure.

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Human Aldehyde oxidase (hAOX1) is a phase-I drug/xenobiotic metabolizing enzyme, responsible for unexpected drug-metabolism. It promotes drug interactions, affects drug efficacy and ultimately, is responsible for failures in clinical trials [1]. This Mo/FeS/FAD – enzyme is able to oxidize a wide range of commercial drugs but surprisingly, also perform reduction and hydrolysis reactions. However, these reactions are poorly characterized and the reduction active site is still unknown.

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The goal of this project is to unravel the reduction reactions of hAOX1 and find oxidation/reduction inhibitors by combining X-ray crystallography and Nuclear Magnetic Resonance methodologies. The atomic details obtained will disclose the reaction mechanism and the molecular determinants for ligand binding/recognition and allow predicting the likelihood of metabolism by hAOX1, thus, pushing lead optimization towards new, safer and better drugs.

The research is divided into 3 main tasks:

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Task1 – hAOX1 expression, purification and characterization

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Task2 – Characterization of hAOX1-ligand interactions

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Task3 – Structural determination and Time-Resolved (TR) studies 

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