Arylalkylamine N-acetyltransferase (AANAT; EC 2.1.3.87) plays a unique role in vertebrate biology by controlling rhythmic production of melatonin in the pineal gland. Its activity increases 10- to 100-fold at night, leading to increased production and release of melatonin. AANAT is also expressed in retina, where it may play other roles in addition to signaling, including neurotransmission and detoxification (Klein, 2007).

Using a cDNA expression library, Coon et al. (1995) cloned cDNA encoding ovine AANAT. The abundance of AANAT mRNA during the day was high in the ovine pineal gland and somewhat lower in retina. Unexpectedly, AANAT mRNA was found in the pituitary gland and in some brain regions. The night-to-day ratio of ovine pineal AANAT mRNA is less than 2; in contrast, the ratio exceeds 150 in rats. Coon et al. (1996) reported that the open reading frame encodes a 23.2-kD polypeptide of 207 amino acids that is approximately 80% identical to the sheep and rat protein. The AANAT transcript (approximately 1 kb) is highly abundant in pineal gland and is expressed at lower levels in retina and in a retinoblastoma cell line. AANAT mRNA is also detectable at low levels in several brain regions and the pituitary gland, but not in several peripheral tissues examined.

Coon et al. (2002) determined that, in rhesus macaque, Aanat mRNA is abundant in the pineal gland and retina, but not elsewhere; Aanat mRNA was uniformly distributed in the pineal gland, but was limited primarily to the photoreceptor outer segments in the retina. They found that the day and night levels of rhesus macaque pineal and retinal Aanat mRNA were similar, but the protein levels increased more than 4-fold at night in both tissues.

Coon et al. (1996) reported that the human AANAT gene spans approximately 2.5 kb and contains 4 exons.

Coon et al. (1996) mapped the AANAT gene to chromosome 17q25 by PCR analysis of a monochromosomal human/rodent somatic cell hybrid panel and by fluorescence in situ hybridization. Yoshimura et al. (1997) demonstrated that this gene, which they symbolized Nat4, maps to mouse chromosome 11.

Amounts of circulating melatonin increase 10-fold at night in all vertebrates. Coon et al. (1995) noted that this rhythm is generated by variation in the activity of AANAT. The nocturnal increase in pineal AANAT activity also markedly decreases serotonin. The rhythm in melatonin is essential for seasonal reproduction, modulates the function of the circadian clock in the suprachiasmatic nucleus, and influences activity and sleep. AANAT is rapidly inactivated when animals are exposed to light at night. Arylalkylamines are strongly preferred as substrates over other amines.

In studies performed in cultured hamster retina, Tosini and Menaker (1996) found that the mammalian retina contains 1 or more circadian oscillators that regulate melatonin synthesis. These circadian oscillators can be entrained by light. The investigators noted that the mutant tau gene in hamster (Ralph and Menaker, 1988) influenced the period of circadian oscillators in the retina and in the supraoptic nucleus. Tosini and Menaker (1996) found that retinas from wildtype hamsters averaged a retinal rhythm period of 23.5 to 24.5 hours, while retina from homozygous tau mutants had periods ranging from 20.0 to 22.1 hours. (See also Joy et al., 1992).

Zheng et al. (2003) studied the significance of the phosphorylation of AANAT using a semisynthetic enzyme in which a nonhydrolyzable phosphoserine/threonine mimetic, phosphonomethylenealanine (Pma), was incorporated at position 31 (AANAT-Pma31). The results of studies in which AANAT-Pma31 and related analogs were injected into cells provided the first evidence that threonine-31 phosphorylation controls AANAT stability in the context of the intact cells by binding to 14-3-3-zeta (601288) protein. Zheng et al. (2003) concluded that their findings established threonine-31 phosphorylation as an essential element in the intracellular regulation of melatonin production.

By measuring the protein content and enzymatic activity in rat pineal Aanat, Gastel et al. (1998) found that, when neural stimulation was switched off by either light exposure or beta adrenergic blockade by L-propranolol, both Aanat activity and protein content decreased rapidly. The effects of L-propranolol were blocked in vitro by dibutyryl cAMP or proteasome inhibitors. The authors concluded that adrenergic-cAMP regulation of Aanat is mediated by proteolysis. Ganguly et al. (2001) identified a regulatory sequence in rat Aanat that, upon cAMP dependent phosphorylation, promoted the formation of a complex between Aanat and 14-3-3 (see 601288) proteins. Formation of the Aanat/14-3-3 complex enhanced melatonin production by shielding Aanat from dephosphorylation and/or proteolysis and by decreasing the Km for serotonin.

Kim et al. (2007) found that rhythmic control of Aanat mRNA translation in rats was mediated by a highly conserved internal ribosome entry site (IRES) element within the Aanat 5-prime UTR and its partner hnRNPQ (SYNCRIP; 616686), with a peak in the middle of the night. Knockdown of the hnRNPQ level elicited a dramatic decrease in peak amplitude in the Aanat protein profile parallel to reduced melatonin production in pinealocytes.

Reviews

Klein (2007) reviewed the biologic chemistry of AANAT.

For discussion of a possible association between susceptibility to delayed sleep phase syndrome (DSPD; 614163) and mutation in the AANAT gene, see 600950.0001.

Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including AANAT, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.