Monoamine oxidases (MAO B and MAO A) are well-known targets for antidepressant drugs and for drugs used to treat neurological disorders and diseases of aging, such as Parkinson’s disease and Alzheimers disease. MAO A and MAO B are attached to the outer membrane of the mitochondria — the energy powerhouses of cells and function to oxidize amine neurotransmitters such as dopamine and serotonin. Through their model of the enzyme’s structure, the Emory and Pavia scientists revealed the architecture of the enzyme’s active site, which is responsible for its catalytic properties. They also described sites on the enzyme responsible for its binding to the membrane.
Pharmacologists have designed a number of drugs, both reversible and irreversible, that inhibit MAO B and are used to treat neurological disorders. For example, the MAO B inhibitor deprenyl is administered to increase the effectiveness of L-dopa therapy in the treatment of Parkinson’s disease and to provide neuroprotective effects in patients with pre-Parkinson’s syndrome. Recent studies have also demonstrated that MAO B is inhibited by compounds present in tobacco smoke, which may contribute to the addictive properties of tobacco use. Scientific and clinical interest in these enzymes has been ongoing for more that 40 years and has resulted in more than 15,000 papers published on their biological properties.
"Although scientists already have made considerable progress in the development of MAO B inhibitors to treat neurodegenerative and psychiatric disorders, we are very optimistic that our new knowledge about the three-dimensional structure of the enzyme will facilitate additional improvements in drug design which will lead to increased specificity and fewer side effects," said Dale Edmondson, Ph.D., professor of biochemistry, Emory University School of Medicine, and co-principal investigator of the project .
Other authors included co-principal investigator Andrea Mattevi, Department of Genetics and Microbiology, University of Pavia and postdoctorals Claudia Binda, Paige Newton-Vinson and Frantisek Hubalek.
MAO B has been shown to be elevated more than three fold in the brain tissue of elderly individuals. Recent studies have shown that elevated levels of MAO B in neurons and kidney cells can lead to cell death (apoptosis). Clinical trials currently are underway in several centers to target increased levels of MAO B that have been identified in astrocytes (a type of brain cell) in Alzheimer’s patients.
"The structural insights will provide us with a new framework to explore the catalytic mechanism of the enzyme, to understand the differences between the A and B forms, and to design specific new inhibitors to treat and prevent age-related disorders," Dr. Edmondson said. "It also will help us understand the role of these enzymes in the clearance of amine-containing drugs either in development or in clinical use for the treatment of other disorders."
"This finding may well result in the development of novel treatments for depression — a major public health problem," said Charles Nemeroff, M.D., Ph.D., Reunette W. Harris professor of psychiatry and behavioral sciences at Emory University School of Medicine and chair of the department. "MAO inhibitors are excellent antidepressants but have an unfavorable side-effect profile. This discovery should allow for the synthesis of novel MAO inhibitors with great selectivity and few side effects."
"The MAO-B structure is a major advance in understanding a medically important target enzyme. It will help unravel previously ill-understood inhibitor structure/activity relationships leading to improved drugs for mental illness and neurodegenerative diseases," said Dr. Peter Preusch, a biochemist at the National Institute of General Medical Sciences NIGMS of the National Institutes of Health (NIH).
The research was supported by grants from the NIGMS, the Consiglio Nazionale delle Richerche and Agenzia Spaziale Italiana. Dr. Edmondson is available for comment at 404-727-5972.
Nature Structural & Molecular Biology