AANAT

AANAT, short for arylalkylamine N-acetyltransferase, is a cytosolic enzyme that catalyzes the acetylation of arylalkylamines, most notably serotonin, to form N-acetylserotonin. In vertebrates, AANAT is considered the rate-limiting step in melatonin biosynthesis, which occurs predominantly in the pineal gland and, to a lesser extent, in the retina and other tissues. The acetyl group is donated by acetyl-CoA, and the subsequent step to melatonin is carried out by arylalkylamine N-acetyltransferase-like (ASMT, also known as HIOMT), which methylates N-acetylserotonin.

AANAT activity is tightly regulated by circadian cues. After darkness, sympathetic nerve activity releases norepinephrine onto pinealocytes, increasing cyclic AMP (cAMP) and activating protein kinase A. This signaling pathway phosphorylates and stabilizes AANAT, rapidly increasing its activity and promoting melatonin synthesis during the night. AANAT has a relatively short half-life, enabling rapid changes in melatonin production at dawn or in response to shifts in the light-dark cycle.

In humans, the AANAT gene encodes the enzyme and its expression exhibits a robust circadian rhythm governed by the central clock in the suprachiasmatic nucleus and peripheral clock genes such as CLOCK, BMAL1, PER, and CRY. Disruption of AANAT activity or melatonin production is associated with circadian rhythm disturbances, jet lag, and seasonal affective disorders. Melatonin supplementation is used clinically to manage related sleep and circadian disorders.