Degenerative Disease Research: Structural basis of kynurenine 3-monooxygenase inhibition eInterview: Professor Nigel S. Scrutton ScD FRSC FSB

Director Manchester Institute of Biotechnology
EPSRC Established Career Fellow |Faculty of Life Sciences | Manchester Institute of Biotechnology | University of Manchester | Manchester | M1 7DN | UK | What are the main findings of your study?

Dr. Scrutton: A major breakthrough has been made by our team of researchers seeking treatments for degenerative illnesses such as Parkinson’s Disease.

We have detailed how an enzyme in the brain interacts with a drug-like lead compound directed against Huntington’s Disease (but also with major implications for Alzheimer’s and Parkinson’s diseases) to inhibit its activity. The work – which solved the molecular structure of a crucial brain enzyme called kynurenine 3-monooxygenase – opens the door to effective treatment for neurodegenerative diseases such as Huntington’s, Alzheimer’s and Parkinson’s. The main findings not only describe the molecular details of the enzyme, but also how it interacts with a lead drug compound that inhibits the natural activity of the enzyme.

The work shows that the compound (called UPF648) binds in the ‘reaction centre’ of the enzyme where it prevents the natural activity of the enzyme. This prevents formation of brain metabolites that are implicated in brain damage and the onset of neurodegenerative disease.

The discovery offers real hope for clinicians and patients as it opens up major new opportunities to find therapeutic molecules that can inhibit kynurenine 3-monooxygenase. The current lead molecule (UPF648) is not brain permeable (it doesn’t readily get through the blood-brain barrier), and the next challenge is to find related molecules that can be readily transported into the brain.  This will now be the major focus of future research programs to find exciting and novel therapies for a variety of neurodegenerative diseases.


Structural basis of kynurenine 3-monooxygenase inhibition

Marta Amaral, Colin Levy, Derren J. Heyes, Pierre Lafite, Tiago F. Outeiro, Flaviano Giorgini, David Leys & Nigel S. Scrutton
Nature (2013) doi:10.1038/nature12039 Published online10 April 2013

Last Updated on December 5, 2013 by Marie Benz MD FAAD