Scientists Determine the Structure
of Human Monoamine Oxidase B (MAO B)
Scientists from Emory University School of Medicine and
the University of Pavia, 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 will be published in the January 2002 print edition
of Nature Structural Biology and in the online edition on Nov.
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
"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.