January 22, 2002
Enzyme discovery could open doors for new drugs
By Holly Korschun
Scientists from the School of Medicine and the University of Pavia in
Italy have determined for the first time the three-dimensional structure
of monoamine oxidase B (MAO-B)an enzyme important in several major
disease processes; particularly age-related neurological disorders.
Understanding the detailed structure of the enzyme should provide a framework
for designing new neuroprotective drugs. The research is published in
the January 2002 edition of Nature Structural Biology.
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 Parkinsons and Alzheimers diseases. MAO-A
and MAO-B are attached to the outer membrane of the mitochondriathe
energy powerhouses of cellsand oxidize amine neurotransmitters such
as dopamine and serotonin.
Through their model of the enzymes structure, the Emory and Pavia
scientists revealed the architecture of the enzymes 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 Parkinsons
disease and to provide neuroprotective effects in patients with pre-Parkinsons
Recent studies have 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, professor of biochemistry and co-principal investigator
of the project.
MAO-B has been shown to be elevated more than threefold 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 under way in several centers to target increased
levels of MAO-B that have been identified in astrocytes (a type of brain
cell) in Alzheimers 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, 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 depressiona major public health problem, said Charles
Nemeroff, Reunette W. Harris professor of psychiatry and behavioral sciences.
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.
Other researchers in the study included co-principal investigator Andrea Mattevi, from the University of Pavias genetics and microbiology department, and postdoctorals Claudia Binda, Paige Newton-Vinson and Frantisek Hubalek.
Emory University, Copyright 2002