New insight into how protein E75 may control circadian rhythms and metabolic processes

Jul 28 2005

University of Toronto researchers have gained new insight into how a specific protein may control circadian rhythms and metabolic processes, which has implications for treating cholesterol-related diseases.

U of T professor Henry Krause and his colleagues have identified heme, an iron compound, best known for its oxygen carrying capabilities in hemoglobin, as the molecule that allows the protein E75 to regulate a number of key developmental processes. In a paper published in the July 29 issue of Cell, the researchers use fruit flies to show that heme attaches itself to E75, allowing the protein to respond to a variety of cellular signals necessary for controlling systemic processes such as metabolism and circadian rhythms, the human body's clock.

Since the human body contains a nuclear hormone receptor comparable to E75, the research is an important first step to understanding how people metabolize fat, how their circadian rhythms are regulated and how their bodies age. The researchers studied fruit flies, because they have many genes similar to those found in humans and they reproduce rapidly.

"The important role heme plays in the body's smooth operation has been previously identified, but it was quite unexpected to find it binding to a member of the nuclear hormone receptor family of proteins," says Krause, a professor in the Banting and Best Department of Medical Research and the Department of Medical Genetics and Microbiology."

There are practical reasons for exploring the relationship between heme and E75, says Krause, whose lab purified the protein, then used mass spectrometry to analyze it. About 15 per cent of successful drugs on the market target nuclear hormone receptors like E75.

"In addition to finding out how E75 and its human counterpart control metabolic processes, and learning how to control these functions, it should also help us to discover the other hormones that control the rest of this nuclear hormone receptor family," says Krause. As they are identified, new drugs can be designed to control the many metabolic diseases, such as high cholesterol, associated with the malfunction of these proteins.

Other researchers involved in this study include U of T professor Aled Edwards, head of the Structural Genomics Consortium; U of T post-doctoral student Jeff Reinking, master's degree holder Mandy Lam, doctoral students Keith Pardee and Heidi Sampson and post-doctoral fellow Ping Yang; researchers Shawn Williams and Wendy White from GlaxoSmithKline; and technician Suya Liu and Professor Gilles Lajoie from the University of Western Ontario.