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Biological Chemistry

Molecular prosthetic moves iron into, out of, and within cells

Small molecule stands in for missing iron transporters associated with anemia

by Michael Torrice
May 11, 2017 | A version of this story appeared in Volume 95, Issue 20

Three images of zebrafish: one is a normal fish stained to highlight hemoglobin; a second is a fish engineered so that it is missing mitoferrin; and the third is an engineered fish treated with hinokitiol.
Credit: Science
Hemoglobin in these zebrafish is stained brown (arrow, left). Fish engineered so that they lack the iron transporter mitoferrin had lower levels of hemoglobin (center). But adding hinokitiol to the engineered fish’s tank returned those levels to normal (right).

A prosthetic hand or leg can’t do everything that a lost appendage once did. But these devices often restore enough function to help people regain some quality of life that loss of a limb takes away.

Small molecules might similarly help patients with diseases caused by absent or defective proteins, according to a new study. Researchers report a “molecular prosthetic” that can move iron to where it’s needed in cells and animals that lack proteins to transport the metal (Science 2017, DOI: 10.1126/science.aah3862).Martin D. Burke of the University of Illinois, Urbana-Champaign, one of the study’s lead scientists, thinks the compound represents a possible new type of therapeutic.

Credit: Science
Three molecules of hinokitiol bind to a single iron ion.
A line structure of hinokitiol and a crystal structure of it bound to iron.
Credit: Science
Three molecules of hinokitiol bind to a single iron ion.

Many small molecule drugs treat disease by shutting down unwanted protein activity. “But if a patient is sick not because of too much protein function but instead because of a deficiency, then the classic paradigm of pharmacology falls apart,” Burke says. “There is no target to inhibit.”

For example, some rare cases of anemia are caused by the lack of iron transporters responsible for moving iron ions across lipid membranes and into, out of, or within cells. Without these proteins’ activity, the ions pool on one side of a membrane, unable to eventually reach cellular compartments where hemoglobin is built.

Burke, along with Jonghan Kim of Northeastern University, Marianne Wessling-Resnick and Barry H. Paw of Harvard University, and others, found a natural product, hinokitiol, that can rescue stranded iron. The researchers think that three hinokitiol molecules bind a single iron ion, forming a greasy sphere around the charged species that can then move through hydrophobic membranes.

In experiments in cells and animals, the team demonstrated that hinokitiol could mimic the activity of three different iron transporters. For example, zebrafish genetically engineered to lack the transporter mitoferrin had low levels of hemoglobin in their blood cells. The scientists could return those levels to normal by adding hinokitiol to the fish tank.

Developing a molecule that can move iron to where it’s needed in cells is novel and potentially important, says Nancy C. Andrews, dean of the Duke University School of Medicine. Such a molecule, she says, could help treat anemias involving iron imbalances seen in diseases such as cancer and rheumatoid arthritis. But, Andrews says, the scientists first need to test the efficacy and toxicity of hinokitiol in animal models of these conditions.

Burke says the team plans to further examine hinokitiol’s therapeutic potential, but he thinks the lesson of the study’s findings is “imperfection is enough”: Although transporters are much larger and more complex than hinokitiol, the molecule could mimic enough of the proteins’ activity to restore cells’ normal physiology. Burke’s lab hopes to use this concept to find molecular prosthetics for other conditions involving missing proteins.



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