Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Discover New Route to Hemoglobin Synthesis

18.08.2005


Researchers studying zebrafish that die from anemia have discovered a new pathway for the synthesis of heme, the deep red, iron-containing molecule that is a component of hemoglobin and myoglobin. The research suggests that defects in this pathway may be an overlooked cause of anemia in humans.



A research team led by Leonard I. Zon, a Howard Hughes Medical Institute investigator at Children’s Hospital Boston and Harvard Medical School, published its findings in the August 18, 2005, issue of the journal Nature. Zon and his colleagues in Boston collaborated on the studies with researchers from the University of Rochester Medical Center and the University of Utah School of Medicine.

The researchers began their studies hoping to learn why a zebrafish mutant known as shiraz (sir) failed to produce hemoglobin. The sir mutant zebrafish, which were first isolated by Zon and colleagues in the Tübingen Screen Consortium in Germany, intrigued the researchers because they die from anemia caused by lack of hemoglobin.


Over the years, Zon and his colleagues have discovered many zebrafish mutants that fail to make hemoglobin because of defects in iron metabolism. As they have teased out the causes of these defects, they have learned that the biochemical pathway involved in hemoglobin synthesis in zebrafish has been largely conserved over the 300 million years of evolution between fish and humans. According to Zon, the easily manipulable fish constitutes an excellent model organism for studying the regulation of heme formation.

In the current study, the researchers traced the hemoglobin defect to the gene for an enzyme known as glutaredoxin 5 (grx5). But the researchers found early on that the enzyme was not directly connected to hemoglobin production. “Nobody had worked on this gene in vertebrates before, but we found in the scientific literature that this gene in yeast was required for the production of iron-sulfur clusters in the mitochondria,” said Zon. Iron-sulfur clusters are incorporated into certain proteins to enable their enzymatic functions. In further experiments, the researchers confirmed that versions of grx5 in zebrafish, yeast, mice and humans are functionally equivalent.

“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 traps them in mitochondria, where they cannot interact with IRP1 to control it.

In a search for possible treatments for the anemia, Zon and his colleagues are exploring the genetic machinery of hemoglobin production in zebrafish for targets of drugs that could restore normal levels of iron-sulfur clusters. “The pathway that we have found is very sensitive, so our findings might be extended to enable treatments for other forms of anemia,” said Zon.

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Magic number colloidal clusters
13.12.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

nachricht Record levels of mercury released by thawing permafrost in Canadian Arctic
13.12.2018 | University of Alberta

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

Im Focus: Topological material switched off and on for the first time

Key advance for future topological transistors

Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...

Im Focus: Researchers develop method to transfer entire 2D circuits to any smooth surface

What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.

Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Magic number colloidal clusters

13.12.2018 | Life Sciences

UNLV study unlocks clues to how planets form

13.12.2018 | Physics and Astronomy

Live from the ocean research vessel Atlantis

13.12.2018 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>