An international team of scientists led by National Institutes of Health researchers has traced the likely origin of the enzyme needed to manufacture the hormone melatonin to roughly 500 million years ago. Their work indicates that this crucial enzyme, which plays an essential role in regulating the body’s internal clock, likely began its role in timekeeping when vertebrates (animals with spinal columns) diverged from their nonvertebrate 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 to the understanding of 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, nonvertebrate form of the enzyme from sharks and other contemporary animals thought to resemble the prototypical early vertebrates that lived 500 million years ago.
Melatonin is a key hormone that regulates the body’s day and night cycle. Dr. Klein explained that it is manufactured in the brain’s pineal gland and is found in small amounts in the retina of the eye. Melatonin is produced from the hormone serotonin, the end result of a multistep 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.
After analyzing DNA from sea creatures thought to resemble early vertebrates, researchers have pieced together a theory of pertaining to the origin of melatonin, which regulates the body’s circadian rythms. The AANAT enzyme, or timezyme, is essential for producing melatonin. One form of AANAT is found only in non-vertebrates, and appears to detoxify potentially hazardous compounds. The researchers contend that a second copy of the gene for producing AANAT appeared about 500 million years ago, when the original gene was duplicated. As vertebrate animals evolved, the second copy of the AANAT gene evolved, eventually specializing in producing melatonin. The theory also holds that the original copy of the AANAT gene later disappeared, and its function was taken over by other genes. In support of their theory, the researchers discovered that two animals thought to be like early vertebrates, the elephant shark and the ratfish, produce both the non-vertebrate and vertebrate forms of AANAT. Two other animals thought to have originated later in vertebrate evolution, the catshark and the sea lamprey, had only the vertebrate AANAT gene.
Before the current study, the researchers lacked proof of their theory, particularly in regard to the question of how the vertebrate form of the enzyme originated because it did not appear to exist in non-vertebrates and had been found only in bony fishes, reptiles, birds, and mammals — all of which lacked the non-vertebrate form.
The first evidence of how the vertebrate form of the enzyme originated came when study co-author Steven L. Coon, also of NICHD, discovered genes for the nonvertebrate 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, Dr. Klein said. Gene duplication, he added, typically results from any of a number of genetic mishaps during cell division. Instead of one copy of a gene resulting from the process, an additional copy results, so that there are two versions of a gene where only one existed previously. The phenomenon is thought to be a major factor influencing evolutionary change.