The University Record, April 12, 1999

U-M scientists discover how folic acid lowers risk of cardiovascular disease and birth defects

By Sally Pobojewski
News and Information Services

U-M 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 researchers led by Rowena G. Matthews and Martha L. Ludwig 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 study was published in the April 1 issue of Nature Structural Biology.

"This work illustrates why basic scientific research is so important," says Matthews, the G. Robert Greenberg Distinguished University Professor of Biological Chemistry and chair of the 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,L Matthews adds, Ubecause 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," says Ludwig, professor of biological chemistry and research biophysicist.

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 says. "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 says.

"Increased levels of folates help bind FAD more tightly to MTHFRP protecting the enzyme against heat inactivation and allowing the homocysteine-to-methionine conversion pathway to proceed normally," Ludwig says. "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 study included Brian D. Guenther, postdoctoral fellow, graduate students Christal A. Sheppard from the U-M and Pamela Tran from McGill University, and Rima Rozen, a professor at Montreal ChildrenAs 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 the study from the Medical Research Council of Canada.

Findings have important public health implications

The findings of Rowena G. Matthews and Martha L. Ludwig of the biochemical basis for folic acid's ability to reduce amounts of an amino acid in a blood plasma called homocysteine have important public health implications, according to Gilbert S. Omenn, a geneticist and executive vice president for medical affairs. Homocysteine is associated with an increased risk of heart attacks and strokes.

"This important research shows how folic acid helps prevent cardiovascular disease," Omenn says. "Understanding the mechanism strengthens the case for encouraging all adults to increase their intake of folic acid.

"Other studies have demonstrated that folic acid also can help prevent devastating neural tube birth defects like spina bifida, meningomyelocele and anencephaly," Omenn adds. "From a public health perspective, this study reinforces the need for increased efforts to educate physicians, women in the childbearing years and the general public on the importance of taking a daily dose of 400 micrograms of folic acid. Folic acid supplements are safe, inexpensive and readily available. Except for individuals with specific blood disorders, folic acid should be part of a standard health regimen for all adults."

In October 1995, Omenn and three collaborators at the University of Washington published an analysis in the Journal of the American Medical Association of 27 published studies relating homocysteine to cardiovascular disease and 11 studies examining the effects of folic acid on homocysteine levels. The widely-cited JAMA paper estimated that widespread use of supplemental folic acid and fortification of bread and cereal products with folic acid could save about 30,000 U.S. men and 20,000 U.S. women from dying of coronary artery disease each year. The study also concluded that at least 50 percent of the 2,500 neural tube birth defects occurring in the U.S. each year could be prevented if women took 400 micrograms of folic acid daily before and during the first month of pregnancy.