"It seemed like the whole process was evolutionarily conserved," said Zon. "But the difference is that yeast do not make hemoglobin. So we needed to figure out a mechanism that would explain why these fish that have problems making iron-sulfur clusters could not make hemoglobin."
Other researchers' studies had indicated that the presence of iron-sulfur clusters in the cell is important for controlling an enzyme called iron regulatory protein 1 (IRP1). In turn, IRP1 regulates another enzyme called ALAS2 that plays a key role in heme synthesis. Indeed, experiments by Zon and his colleagues demonstrated that the loss of grx5 in the mutant zebrafish inappropriately activates IRP1, which blocks the synthesis of ALAS2, and thus heme production. For example, when they restored ALAS2 by injecting into the sir mutants a truncated form of ALAS2 that lacked the portion of the molecule sensitive to IRP1, they complete restored the mutant zebrafish hemoglobin production.
"People have always thought that hemoglobin synthesis required only enough iron in the cell for heme production to proceed and then just the addition of the globin protein to form hemoglobin," said Zon. "Now, we've added a fourth component, iron-sulfur clusters, which are required for heme production. This is a very interesting and unpredicted finding from what we had known before, and our experiments have really defined a new pathway for hemoglobin production," he said.
Zon said that the findings could apply to developing new treatments for a rare form of anemia, known as sideroblastic anemia, in which elevated IRP1 activity causes a deficiency of ALAS2. In most cases, an increase in IRP1 is likely caused by a mutation in a transporter for iron-sulfur clusters that
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
17-Aug-2005