Iron Man molecule restores balance to cells

Robert F. Service in Science:

Iron Man may have the cool moniker and that whole flying suit of armor thing, but we all depend on iron for some pretty special abilities. Our bodies rely on the metal to ferry oxygen in our blood and convert blood sugar to cellular energy, among other jobs. Still, too much or too little iron can wreak havoc, and problems moving the element in and out of cells cause dozens of different diseases including anemia and cystic fibrosis. Now, researchers have found a molecule that can correct some of those iron delivery problems in animals. The new compound could help scientists better understand those conditions, and may one day lead to new compounds to treat them. To maintain the proper balance of iron in cells and tissues, a network of proteins either burn energy to pump iron atoms across cell membranes or passively allow them to travel through if too much builds up on one side. Problems arise when one or more of these proteins is mutated or missing. That can lead to diseases such as anemia (too little iron) or hemochromatosis (too much). Such diseases are difficult to treat with drugs, because most medicines work by blocking or changing an existing protein’s activity. What’s needed in these cases is restoring the function of an iron transport protein that’s defective or missing altogether.

Martin Burke, a chemist at the University of Illinois in Champaign, has spent years searching for ways to restore the functions of absent proteins. In this case, to investigate problems with transporting iron, Burke’s group started with yeast cells and deleted the gene for a passive iron transporter, which stopped the cell’s growth. They then assembled a library of naturally occurring so-called small molecules, adding them one by one to the yeast culture to see whether any could restore the cells’ ability to grow. When they added a molecule called hinokitiol, originally isolated from the Taiwanese hinoki tree, growth was immediate. “It popped out of the assay,” Burke says. Tests with two other yeast cultures missing a different iron transporter turned up similar results. Burke’s team later revealed that trios of hinokitiol molecules initially surround iron atoms isolating them from their surroundings. Meanwhile, the outward-facing ends of the hinokitiol molecules contain oil-loving groups that readily dissolve in the fatty membranes that surround cells. This allows iron-baring hinokitinol trios to enter cell membranes and wiggle through, depositing their cargo on the inside. Burke and his colleagues went on to study whether hinokitiol worked when given to animals engineered to be missing iron transport proteins. In today’s issue of Science they report that orally administered hinokitiol restored iron uptake in the guts of mice and rats. Simply adding it to the tank of zebrafish reestablished the animals’ ability to produce hemoglobin.

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