Scientists Identify Protein Essential For Iron Absorption

BUFFALO, N.Y. -- A protein that is the single most critical known element in iron metabolism has been identified and characterized by scientists at the University at Buffalo and Children's Hospital in Boston, which is affiliated with Harvard University.

The first protein to be identified as essential for normal intestinal iron absorption and the first mammalian iron transporter to be characterized at the molecular level, it appears to be involved in not just one, but several, critical roles in iron metabolism.

The results will be published in the Feb. 3 issue (Vol. 95, Issue 3) of the Proceedings of the National Academy of Sciences.

"This finding allows us to take a major step forward in our understanding of iron metabolism," said Michael Garrick, Ph.D., professor of pediatrics and biochemistry at UB and co-author on the paper.

The discovery of the protein, called Nramp2, will allow researchers to boost their understanding of iron-deficiency anemia, the most prevalent disease in the world, especially common in underdeveloped countries.

It also will provide them with necessary information about ways to treat hemochromatosis, or iron overload, the most common recessively inherited disease, for which the usual treatment is the periodic bleeding of patients.

Other UB co-authors are Laura M. Garrick, Ph.D., clinical assistant professor of biochemistry, and Michelle A. Romano, research technician. Children's Hospital co-authors are Nancy C. Andrews, M.D., Ph.D.; Mark Fleming, M.D., D.Sc., and Maureen A. Su, M.D.-Ph.D. candidate.

The research highlights what the scientists describe as a stunning example of biological conservatism, where the same amino-acid change in the same gene in the same protein is responsible for iron-deficiency anemia in two different animal models.

All cells in the body require iron to function, but the details of iron metabolism, particularly which proteins are specifically responsible for iron absorption in the intestine and iron traffic within cells, have long eluded researchers.

The researchers said their results demonstrate that the protein is implicated in at least two, and probably three, important functions in iron metabolism.

Garrick explained. "So if you are iron-deficient, you're very efficient at absorbing iron from food. If you are iron-replete, then you will be much less efficient at iron uptake."

The researchers have concluded that it is Nramp2 that actually takes up iron in the GI tract.

Later, when iron is absorbed into cells in the body, it must be delivered to the mitochondria, the energy apparatus inside each cell where the heme in hemoglobin is made.

"This protein also is the major one involved in this critical, intercellular traffic step," said Garrick.

According to Laura Garrick, the results, as well as recent research conducted at the University of Western Australia at Nedlands, suggest that the protein also probably is implicated in a third type of iron transport, called nontransferrin-bound iron transport.

This type of transport comes into play, she explained, when there is excess iron in the body, a condition that, if prolonged, can lead to abnormal iron deposits and health problems, such as cirrhosis of the liver and heart damage.

The findings of the UB and Children's Hospital researchers build on decades of work at UB led by the late Robin Bannerman, M.D., and Helen Ranney, M.D., both formerly UB professors of medicine, and John A. Edwards, M.D., UB professor of medicine, and colleagues that resulted in the characterization of animal models of two types of iron-deficiency anemia: the Belgrade rat and the microcytic mouse.

Both animals are unable to properly absorb iron in the GI tract or sufficiently take it up at the cellular level.

"It has taken 30 years from the discovery of these animal models to finding out the true cause of these anemias," commented Garrick.

The research received a boost from efforts in the mid-90s to map the rat genome. This provided enough markers on the rat genome to begin to map the Belgrade rat and conduct the DNA analysis to find the gene that encoded the critical protein.

"The publication in 1995 of the rat genome inspired us to get together with the Harvard group to map the Belgrade rat," said Garrick.

At the same time, the Children's Hospital researchers were attempting to map the microcytic mouse.

What the two groups found was akin to lightning striking twice, Garrick said.

"We were looking at two different models," he said. "We didn't know we'd find the same thing. Not only is it the same gene encoding the same protein in both animals, but it is the same amino-acid change that distinguishes the normal animal from the mutant," he said. "It's a fantastic coincidence."

He cautioned that Nramp2 is not the only iron-transport protein controlling iron uptake.

A group at Brigham and Women's Hospital in Boston independently found the same protein, but did not have a mutant animal that could help identify its role.

"This protein doesn't answer all the questions in iron transport," he said. "What's remarkable is that it shows up in so many ways."