Researchers Determine Three Dimensional Structure Of Melatonin Producing Enzyme

Researchers from two NIH institutes have determined the three-dimensional structure of an enzyme that produces melatonin--a key hormone that regulates the body's internal clock. The accomplishment may lead to the eventual design of drugs to fight jet lag, to help shift workers adjust to variable schedules, and to combat depression.

The finding, appearing in the January issue of Molecular Cell, represents the first time that the structure of a protein involved in regulating the body's day/night rhythms has been determined.

The authors of the paper were Alison Burgess Hickman and David C. Klein, of the Laboratory of Developmental Neurobiology at the National Institute of Child Health and Human Development (NICHD) and Fred Dyda, of the Laboratory of Molecular Biology at the National Institute of Diabetes and Digestive and Kidney Diseases.

Briefly, Dr. Klein explained, melatonin is made in the pineal gland of the brain from the brain chemical, serotonin, with the help of two enzymes: arylalkylamine N-acetyl transferase (AA-NAT) and hydroxyindole-O-methyl transferase (HIOMT). AA-NAT appears to be the "melatonin rhythm enzyme," because a large increase in the activity of AA-NAT is responsible for the high levels of melatonin found in the brain and in the bloodstream at night.

Similarly, low levels of melatonin formed during the day reflect low levels of this enzyme. This difference in day and night levels of melatonin is important for setting the body's circadian clock.

In the current paper, the three NIH researchers determined the three dimensional structure of AA-NAT. This advance will allow researchers to more precisely determine how melatonin is produced in response to darkness, and how production is switched off in response to light. In the Molecular Cell paper, the investigators wrote that such knowledge may, in turn, lead to the eventual design of drugs to that would prevent AA-NAT from being produced or destroyed. A drug interfering with AA-NAT production might promote wakefulness, and a drug preventing the enzyme from being degraded might enhance sleep. Similarly, a drug that inhibits AA-NAT might provide a way to elevate brain levels of serotonin, thereby providing a treatment for serotonin-related diseases, such as depression.