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Monoamine oxidases (MAOs) and the histone demthylase LSD1 are evolutionarily related enzymes that catalyze the oxidative deamination of their substrates. They represent a spectacular example of how similarities in the chemistry of the catalyzed reaction can constrain evolution, despite different biological functions and cellular localizations. MAOs bind the outer mitochondrial membrane and play a central role in the metabolism of neurotransmitters such as dopamine and serotonin. MAO’s rise to prominence in the biomedical community originated in the early fifties from Zeller’s finding that MAO was the target for hydrazine inhibition which could function in treating depression. Since then, a huge number of MAO inhibitors have been developed and several of them have been used for the treatment of Parkinson’s disease and depression. Our structural studies have shown that most of the known MAO inhibitors function through a mechanism-based mode that generates a covalent adduct with the FAD cofactor. LSD1 is a more recently discovered enzyme. It is responsible for the demethylation of Lys4 of histone H3. LSD1 is implicated in tumorigenesis and there are increasing efforts to identify LSD1 inhibitors. The crystal structure of LSD1 reveals a different substrate-binding site but similar catalytic machinery compared to those exhibited by MAO structures. This similarity is proving to be particularly insightful, prompting researchers to exploit the knowledge gained from MAO inhibition studies to develop effective LSD1 inhibitors. We shall present a comparative analysis of LSD1 and MAOs with a focus on the relevance of the structural investigations for understanding the mechanisms drug action and for the design of new inhibitor molecules targeting these amine oxidase enzymes.

CPADD (closest packing approach forde novodrug design) to inhibit VEGF/R and Notch/RBP/MAM systems