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Biological trick reveals key step in melatonin's regulation

Johns Hopkins researchers have uncovered a key step in the body's regulation of melatonin, a major sleep-related chemical in the brain. In the advance online section of Nature Structural Biology, the research team reports finding the switch that causes destruction of the enzyme that makes melatonin -- no enzyme, no melatonin.

Melatonin levels are high at night and low during the day. Even at night, melatonin disappears after exposure to bright light, a response that likely contributes to its normal daily cycle, but plagues shift workers and jet setters by leading to sleeplessness. To help understand melatonin's light-induced disappearance, the Hopkins researchers turned to the enzyme that makes it, a protein called AANAT.

One way cells turn proteins like AANAT on and off is by modifying them, attaching or removing small bits, such as phosphate groups, to particular spots along the protein's backbone. For AANAT, the key spot turns out to be building block number 31, the researchers have found.

"We have discovered that addition and removal of the phosphate group at this position is the key step in regulating the enzyme's stability," says Philip Cole, M.D., Ph.D., professor and director of pharmacology and molecular sciences in Hopkins' Institute for Basic Biomedical Sciences. "When this phosphate group is present, the enzyme is stable."

To test the importance of the phosphate group to the enzyme's stability, research associate Weiping Zheng, Ph.D., developed a mimic of the key building block with the equivalent of a permanently affixed phosphate group.

Zheng inserted the mimic into the appropriate place in the enzyme, and research associate Zhongsen Zhang injected the altered enzyme into cells. The altered enzyme stayed intact in the cells much longer than the normal enzyme, whose phosphate group can easily be removed, the scientists report.

The researchers' next step is to determine how exposure to light accelerate
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-615-5105
Johns Hopkins Medical Institutions
26-Oct-2003


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