The enzyme that manufactures melatonin - hormone which regulates the body's internal clock - originated 500 million years ago, according to a new study which may hold clues to treating jet lag and 'winter blues'.

The research by an international team of scientists led by National Institutes of Health (NIH) indicates that this crucial enzyme likely began its role in timekeeping when vertebrates diverged from their non-vertebrate ancestors.

An understanding of the enzyme's function before and after the divergence may contribute to an understanding of such melatonin-related conditions as seasonal affective disorder, jet lag, and disorders involving vision.

The findings provide strong support for the theory that the time-keeping enzyme originated to remove toxic compounds from the eye and then gradually morphed into the master switch for controlling the body's 24-hour cyclic changes in function.

The researchers isolated a second, non-vertebrate form of the enzyme from sharks and other contemporary animals thought to resemble the prototypical early vertebrates that lived 500 million years ago.

The study was conducted by senior author David C Klein and colleagues at NIH, and at institutions in France, Norway, and Japan.

Melatonin is a key hormone that regulates the body's day and night cycle.

Klein explained that it is manufactured in the brain's pineal gland and is found in small amounts in the retina of the

Melatonin is produced from the hormone serotonin, the end result of a multi-step sequence of chemical reactions. The next-to-last step in the assembly process consists of attaching a small molecule the acetyl group to the nearly finished melatonin molecule.

This step is performed by an enzyme called arylalkylamine N-acetyltransferase, or AANAT.

Because melatonin accumulated at night, the ancestors of today's vertebrates became dependent on melatonin as a signal of darkness, researchers said.

As the need for greater quantities of melatonin grew, the pineal gland developed as a structure separate from the eyes, to keep serotonin and other toxic substances needed to make melatonin away from sensitive eye tissue.

The first evidence of how the vertebrate form of the enzyme originated came when study co-author Steven L Coon, discovered genes for the non-vertebrate and vertebrate forms of AANAT in genomic sequences from the elephant shark, considered to be a living representative of early vertebrates.

This finding indicated that the vertebrate form of AANAT may have resulted after a phenomenon known as gene duplication which is thought to be a major factor influencing evolutionary change, Klein said.

The study was published in the journal PNAS.