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Nature Paper Connects Body Clock
with Essential Molecule
Heme, a workhorse molecule best known for its crucial role carrying oxygen in red blood cells, is a vital cog in the body’s biological clock, according to a study published in July in the journal Nature.
Cheng Chi Lee, Ph.D.
Senior author Cheng Chi Lee, Ph.D., associate professor of biochemistry and molecular biology at The University of Texas Medical School at Houston, said the findings mark a breakthrough in the fundamental scientific understanding of two crucial biological processes and also point to therapeutic potential of heme’s molecular cousins, including vitamin B12.
“What we’ve found is that the biological process that makes heme and the process that controls our sleep-wake cycle are tied together. These processes are talking to each other all of the time,” Lee said.
It was previously known that circadian clock proteins controlled the synthesis of heme and heme containing proteins, which perform a variety of crucial functions. The paper by Lee and lead author Krista Kaasik, now at the Institute of Molecular and Cell Biology at Tartu University in Estonia, puts heme in the middle of the circadian clock’s function.
Lee, who also holds a faculty appointment at the UT Graduate School of Biomedical Sciences at Houston, and Kaasik demonstrated through a series of genetic and behavioral experiments that heme plays a crucial role in the expression of a central clock protein known as mammalian Per2 (mPer2). This protein regulates two other clock proteins that in turn control Alas1, a protein that is crucial for heme synthesis.
While heme is the key element in hemoglobin, which binds and carries oxygen in red blood cells, it also plays a vital role in association with a variety of other proteins in many important biological processes, Lee said. Heme allows these proteins to respond to gases (mainly oxygen, nitric oxide and carbon monoxide) that play important signaling roles.
Kaasik and Lee found that heme dampened expression of mPer2 and enhanced expression of another clock gene, mPer1, in mice and reduced their wheelrunning activity at night, when mice are expected to be most active.
Because vitamin B12 is similar to heme in structure and research by others had shown that vitamin B12 can shift the mammalian body clock, Lee and Kaasik examined its impact on the mouse circadian clock.
They observed that B12, when given to mice, has the opposite effect of that caused by heme.
Both heme and the B12 analog used in the experiment contain a chemical ring in their structure known as porphyrin. “This provides a chance for us to examine a whole new class of molecules, these porphyrin-containing molecules, for their potential use as drugs,” Lee said, to treat sleep disorders, for example.
“I think we have provided the molecular mechanism that explains why vitamin B12 is capable of affecting the mammalian body clock,” Lee said.
Citing other studies that have observed a link between B12 and tumor suppression, the Nature paper suggests that B12 and other porphyrin-containing molecules that target circadian-regulators might help people undergoing chemotherapy and radiation therapy.
Lee joined the Medical School faculty in January from Baylor College of Medicine, where the bulk of the research for this paper was conducted.
— Scott Merville, Public Affairs