Objective
Monoamine oxidase (MAO; EC1.4.3.4) is a key enzyme involved into catabolism of major monoamine neurtransmitters. It exists in two isoforms, denominated as MAO A and MAO B. Altered MAO activity has been recognised in numerous neuro-psychiatric conditions and MAO A inhibitors are effective antidepressants whereas MAO B inhibitor deprenyl is widely used for the treatment of Parkinson's disease.
MAO is a hydrophobic protein, which readily aggregates after purification and extraction of detergents. This seriously complicates enzyme crystallisation and therefore characterisation of the active site of this enzyme. Molecular biology manipulations, constructing various chimeric proteins can only partially explain differences between MAO A and MAO B with respect to very limited number of selective substrates and inhibitors. Tertiary structure of either isoform remains unknown and so active site structure still requires further characterisation using other approaches.
. In this project we intend:
(a) To evaluate spatial characteristics of active sites of monoamine oxidase A and B using few sets of flexible and rigid competitive inhibitors of MAO;
(b)To determine the role of flavin cofactor and active site thiols in the MAO interaction with these inhibitors;
(c)To develop a model of human MAO A and MAO B;
(d)To develop the new generation of competitive reversible inhibitors with equal efficacy with respect to both type of MAO (MAO A and MAO B).
The results of this research will provide a clearer explanation for basic differences in the substrate specificity and inhibitor selectivity of MAO A and B. Elucidation of fundamental principles for design of new generation of reversible inhibitors with equal efficacy with respect to both MAOs will allow to develop new much more potent drugs for the treatment of neurological disorders. In addition, the information will provide the wisdom necessary to avoid unwanted MAO inhibitory activity in other drugs.
All research teams have constant reliable contacts for at least 3-5 years. They are interested in various aspects of monoamine oxidase and approached employed by each team are complementary to each other. This will promote successful solution of the problem announced in the proposal.
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Programme(s)
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Coordinator
5000 Namur
Belgium
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