ANN ARBOR---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 with the tongue-twisting name 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 is being published in the April 1 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 U-M's Biophysics Research Division. "Our original goal was simply to learn more about the biochemistry of MTHFR. We had no prior indication of any specific health-related application for our work, nor did we imagine that this enzyme would prove to be so important for human health.
"Much of the credit should go to the National Institute of General Medical Sciences of the National Institutes of Health," Matthews added, "because they continue to provide funding for this type of untargeted basic research."
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 in the U-M Medical School and research biophysicist in the U-M's 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 for this study from the Medical Research Council of Canada.
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