U-M Biochemists Discover How Folic Acid Lowers Risk of Cardiovascular
Disease
Rowena G. Matthews and
Martha L. Ludwig |
University of Michigan scientists have solved the mystery behind
folic acid’s ability to reduce amounts of a compound called
homocysteine, which is associated with an increased risk of
heart attacks, strokes and birth defects in humans. A team of
U-M researchers led by Rowena G. Matthews, Ph.D., and Martha
L. Ludwig, Ph.D., discovered the chemical and structural basis
for folic acid’s effectiveness while conducting research
on an enzyme called methylenetetrahydrofolate reductase (MTHFR).
This enzyme catalyzes a critical step in the biochemical chain
reaction within cells that converts homocysteine to an essential
amino acid called methionine. The U-M study was published in
the April 1, 1999 issue of Nature Structural Biology.
“This work illustrates why basic scientific research is
so important,” said Matthews, the G. Robert Greenberg Distinguished
University Professor of Biological Chemistry and chair of the
Biophysics Research Division in the College of Literature, Science
and the Arts. “Our original goal was simply to learn more
about the biochemistry of MTHFR. We had no prior indication
of any specific healthrelated application for our work, nor
did we imagine that this enzyme would prove to be so important
for human health.”
Since the 1970s researchers have known that administration
of folic acid dramatically protects against the development
of birth defects like spina bifida in humans. More recent evidence
has suggested a correlation between high levels of homocysteine
in blood and an increased risk of cardiovascular disease or
spina bifida. In the mid-1990s, scientists discovered that increased
folic acid intake reduced homocysteine. But no one understood
how folic acid exerted its effect until the U-M study.
Using X-ray crystallography, Ludwig, Matthews and colleagues
were able to picture the molecular structure of MTHFR from the
bacterium E. coli. “We used E. coli as a surrogate for
human MTHFR, because there is a high degree of similarity between
the two enzymes and human MTHFR is not yet available for biochemical
analysis,” said Ludwig, a professor of biological chemistry
and research biophysicist in the Biophysics Research Division.
Nestled within the barrel-shaped MTHFR molecule is a vitamin-derived
molecule called flavin adenine dinucleotide or FAD. “The
critical discovery in our work was that a common mutation in
MTHFR promotes the loss of FAD from the enzyme,” Matthews
said. “If FAD is lost, the enzyme can’t do its job.
If the enzyme is inactivated, the conversion to methionine cannot
take place and homocysteine builds up in blood plasma.”
According to Matthews, about 10 percent of people have abnormally
high levels of homocysteine, because they inherited a genetic
mutation from both parents that alters the DNA specifying their
MTHFR enzymes. “Mutated MTHFR is 11 times more susceptible
to loss of this essential flavin molecule than the normal enzyme,”
Matthews said.
“Increased levels of folates help bind FAD more tightly
to MTHFR—protecting the enzyme against heat inactivation
and allowing the homocysteine-to-methionine conversion pathway
to proceed normally,” Ludwig said. “Our results suggest
that folic acid supplementation will reduce homocysteine levels
for normal humans as well as those with the mutant MTHFR.”
Collaborators on the U-M study included Brian D. Guenther,
postdoctoral fellow, graduate students Christal A. Sheppard
from U-M and Pamela Tran from McGill University, and Rima Rozen,
a professor at Montreal Children’s Hospital and McGill
University. The research was supported by the National Institute
of General Medical Sciences of the National Institutes of Health.
Rozen received additional funding from the Medical Research
Council of Canada.
Matthews can be reached at
rmatthew@umich.edu; Ludwig can be reached at Ludwig@umich.edu
 
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