Research Article

Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals

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Science  12 May 2017:
Vol. 356, Issue 6338, pp. 608-616
DOI: 10.1126/science.aah3862

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Shipping iron around in small packages

Iron plays a crucial role in a wide variety of biological functions, which in turn rely on the proteins that transport the metal in and out of cells. Grillo et al. used a simple lipophilic small molecule that binds iron ions to restore transport in animal models with deficiencies in iron transporters. This cyclic ketol, hinokitiol, was first tested in yeast and then shown to promote gut iron absorption in rats and mice, as well as hemoglobin production in zebrafish.

Science, this issue p. 608

Abstract

Multiple human diseases ensue from a hereditary or acquired deficiency of iron-transporting protein function that diminishes transmembrane iron flux in distinct sites and directions. Because other iron-transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. Here we report that a small-molecule natural product, hinokitiol, can harness such gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. These findings illuminate a general mechanistic framework for small molecule–mediated site- and direction-selective restoration of iron transport. They also suggest that small molecules that partially mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases.

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