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Originally published In Press as doi:10.1074/jbc.R600036200 on December 12, 2006

J. Biol. Chem., Vol. 282, Issue 7, 4233-4237, February 16, 2007
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Arylalkylamine N-Acetyltransferase: "the Timezyme"*Formula

David C. Klein1

From the Section on Neuroendocrinology, Office of Scientific Director, NICHD, National Institutes of Health, Bethesda, Maryland 20892


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Aanat Genes and Evolution
 Role of Retinal AANAT
 Structure and Function
 Regulation
 Final Comment
 REFERENCES
 
Arylalkylamine N-acetyltransferase controls daily changes in melatonin production by the pineal gland and thereby plays a unique role in biological timing in vertebrates. Arylalkylamine N-acetyltransferase is also expressed in the retina, where it may play other roles in addition to signaling, including neurotransmission and detoxification. Large changes in activity reflect cyclic 3',5'-adenosine monophosphate-dependent phosphorylation of arylalkylamine N-acetyltransferase, leading to formation of a regulatory complex with 14-3-3 proteins. This activates the enzyme and prevents proteosomal proteolysis. The conserved features of regulatory systems that control arylalkylamine N-acetyltransferase are a circadian clock and environmental lighting.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Aanat Genes and Evolution
 Role of Retinal AANAT
 Structure and Function
 Regulation
 Final Comment
 REFERENCES
 
Arylalkylamine N-acetyltransferase (AANAT; EC 2.1.3.87 [EC] )2 plays a unique role in vertebrate biology by controlling the rhythmic production of melatonin in the pineal gland (Fig. 1) (1). Activity increases 10- to 100-fold at night, causing an increase in the production and release of melatonin. The dynamics of AANAT activity are remarkable: the doubling time is ~15 min at night, and the halving time of the decrease that follows a night -> light transition is ~3.5 min (2, 3). Circulating melatonin levels parallel changes in synthesis and release, due to rapid clearance by the liver (1).

The rhythmic pattern of activity in the melatonin pathway is a conserved feature of vertebrate biology, consistent with the role of melatonin as the vertebrate hormone of time, i.e. high levels signal night and low levels signal day. Although this signaling pattern is conserved, it is used in a variety of species-dependent ways to optimally control seasonal and daily changes in physiology (1). The unique role that AANAT plays in vertebrate time keeping justifies the title of "the Timezyme." Our knowledge of the biological chemistry of AANAT is summarized in this overarching review.


   Aanat Genes and Evolution
TOP
 ABSTRACT
 INTRODUCTION
 Aanat Genes and Evolution
Role of Retinal AANAT
 Structure and Function
 Regulation
 Final Comment
 REFERENCES
 
The AANAT Family—Aanat and Aanat homologs form the AANAT family, which is part of the large Gcn5-related acetyltransferase (GNAT) superfamily (4, 5). All GNAT family members share common structural features associated with acetyl coenzyme A (AcCoA) binding; in addition, each member family has unique features reflecting substrate specificity for each of a wide range of substrates (e.g. aminoglycosides, diamines, puromycin, histones, and arylalkylamines). The GNAT superfamily also includes another arylalkylamine N-acetyltransferase family, represented by dopamine N-aceyltransferase (Dat), which is expressed in Drosophila melanogaster (6). Dat is not involved time keeping; rather, it functions in cuticle sclerotization and neurotransmission (6). DAT and AANAT family members have not been found in the same genome.

AANAT family members have only been found in Gram-positive bacteria, fungi, algae, cephalochordates, and vertebrates; family members are not found in higher plants, insects, nematodes, or urochordates (7). This distribution may be explained by the initial appearance of the ancestral Aanat in Gram-positive bacteria, reflecting evolution from a GNAT family member. Following this, independent horizontal gene transfer events may have taken place (7, 8). For example, an Aanat homolog may have been horizontally transferred from Gram-positive bacteria into the germ cell line of an ancestral vertebrate (7, 9). Gene loss may also have influenced the distribution of Aanat family members.

Aanat Homologs—AANAT homolog proteins lack several features that characterize AANATs (Fig. 2A) (9), including differences within the catalytic core, which explain why AANAT is >1000-fold more active than the yeast homolog (10), and the presence of flanking regulatory regions. These changes appear to have occurred at a point in evolution after the emergence of cephalochordates and before the emergence of vertebrates.

The AANAT homolog in fungi acetylates polyamines and arylalkylamines at relatively similar rates and has been referred to as a polyamine acetyltransferase (10, 11). This pattern of substrate preference is consistent with a broad role in substituted alkylamine detoxification. Acetylation detoxifies amines by promoting elimination and blocking further reactions. Accordingly, it appears that the highly active and precisely regulated "Timezyme" may have evolved from a relatively sluggish detoxifying enzyme.

Aanats—Aanats are expressed at high levels in the pinealocyte and retinal photoreceptor (12), reflecting their evolutionary origin from a common ancestral photodetector (supplemental Fig. 1); many other genes dedicated to photodetection or melatonin synthesis share this pattern (13, 14). A single Aanat occurs among vertebrate classes other than fish, which have three Aanats (Aanat1a, Aanat1b, and Aanat2). This multiplicity reflects genome and gene duplication events in the fish line (9). Aanat1s are preferentially expressed in the fish retina and have similar affinity for phenylethylamines and indolylethylamines. Aanat2 is preferentially expressed in the fish pineal gland; the encoded protein prefers indolylethylamines over phenylethylamines (15, 16).


Figure 1
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  		FIGURE 1.
Daily rhythms in pineal indole metabolism. Shaded area represents darkness. The increase in AANAT activity and the resulting changes in indole metabolism normally occur at night in the dark. "Lights-off" during the day does not cause these changes. The rhythmic pattern continues in constant darkness because AANAT is stimulated by an endogenous circadian clock. Under conditions of constant darkness, the rhythm is not entrained to the environmental lighting cycle and is "free-running" with a period of 23.5 to 24.5 h. In contrast, in a constant lighting regimen rhythmic changes in AANAT do not occur because circadian clock stimulation of AANAT is blocked in response to environmental lighting. The dotted lines represent the very rapid changes in each parameter, which occur following "lights-on" at night. Further details are available in the text.

 

   Role of Retinal AANAT
TOP
 ABSTRACT
 INTRODUCTION
 Aanat Genes and Evolution
 Role of Retinal AANAT
Structure and Function
 Regulation
 Final Comment
 REFERENCES
 
Whereas it is clear that AANAT in the pineal gland functions in the melatonin pathway, the role of AANAT in the retina is less apparent. Although there is evidence that retinal AANAT is involved in local signaling via melatonin or N-acetylserotonin (17), several findings suggest there are other functions. Arguing against a role of melatonin in signaling is that the last enzyme in melatonin synthesis, hydroxyindole-O-methyltransferase (Fig. 1), is absent from primate and ungulate retinas, whereas both express high levels of Aanat (13, 14, 18, 19). In addition, the findings that fish retina AANAT has a distinctly broader substrate preference than that in the pineal gland and that activity increases during the day, not night (20), also point toward non-signaling roles.

Candidate functions/roles include neurotransmission, which is consistent with the finding that AANAT acetylates dopamine, a retinal transmitter (21); acetylation of dopamine might also lead to a novel messenger. Another possible role is detoxification (supplemental Fig. 2); this is especially relevant in the retina because arylalkylamines can undergo Schiff base conjugation with retinaldehyde, the visual chemical required for photon capture (13, 14). Depletion of retinaldehyde by this route would erode photosensitivity. Moreover, the resulting bis-retinyl products are potentially toxic by virtue of photo-oxidation (22). Accordingly, in this context, retinal AANAT can be seen as an adjunct member of the retinoid cycle by preventing retinoid depletion (23). This effect of detoxification may have been the selective factor that led to the acquisition of Aanat by the ancestral photodetector (13, 14).


Figure 2
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  		FIGURE 2.
AANAT and the AANAT/14-3-3 {zeta} complex. A, organization of AANAT and AANAT homologs (9). B, the AANAT/14-3-3 {zeta} complex viewed from above the 14-3-3 {zeta} dimer half-pipe (27). C, the AANAT/14-3-3 {zeta} complex viewed along the long axis of the 14-3-3 {zeta} dimer half-pipe (27).

 

   Structure and Function
TOP
 ABSTRACT
 INTRODUCTION
 Aanat Genes and Evolution
 Role of Retinal AANAT
 Structure and Function
Regulation
 Final Comment
 REFERENCES
 
AANAT is a globular ~23-kDa cytosolic protein that forms a reversible regulatory complex with 14-3-3 proteins (8, 12, 24–30) (Fig. 2, B and C and supplemental Fig. 3).

Catalytic Core—The catalytic core of AANAT forms a cavity encompassing the arylalkylamine and AcCoA binding pockets. As with other GNAT superfamily members (5), AcCoA binds by contacts between the pantethiene moiety and the edge of a rigid beta sheet directing the thioacetyl group into the center of the enzyme; the adenosine moiety is at the surface (31, 32) (Fig. 2).

Arylalkylamines bind in a funnel-shaped pocket formed by three protein loops, which contact the aromatic ring of substrates via aromatic residues. This positions the protonated amine group of substrates close to the AcCoA thioacetyl group (31–33). AANAT preferentially acetylates arylethylamines, including the naturally occurring amines serotonin, tyramine, dopamine, tryptamine, dopamine, and phenylethylamine, and synthetic naphthyl-, benzofuryl-, and benzothienylethylamines (supplemental Fig. 4). Diamines and monoamines are relatively poor substrates of AANAT as are arylamines and arylalkylamines with 1-carbon side chains (8, 34–38).

Loops 2 and 3 are relatively rigid compared with loop 1, which is floppy (32, 33). In the absence of AcCoA, a portion of loop 1 can extend into and occupy the AcCoA binding domain. Loop 1 can be displaced by AcCoA (39), favoring completion of the arylalkylamine binding pocket (Fig. 2, B and C, and supplemental movie 1). Loop 1 is longer in AANAT than in homologs due to the addition of a conserved tripeptide (64CPL66; residue numbering is based on ovine AANAT) (Fig. 2A), which is likely to impact binding or catalysis or both.

Mechanism of Enzyme Action—Acetyl transfer is initiated by deprotonation of the protonated amine. This is indirectly facilitated by neighboring histidines (His120, 122) (Fig. 2A) (40) that are part of a "proton wire" conducting protons to the surface through a water-filled channel (32).

Deprotonation leads to attack on the thioester bond of AcCoA and formation of a transient ternary complex. This decomposes into the N-acetylated arylalkylamine and CoAS– (coenzyme AS–). The former is ejected by the hydrophilic to hydrophobic conversion due to amine acetylation. Ejection of CoASH from the binding pocket requires tyrosine (Tyr168)-dependent protonation of CoAS (32, 40). A synthetic mimic of the ternary complex, CoA-S-N-acetyltryptamine, is a highly potent and specific AANAT inhibitor (27, 31, 32, 38, 41).

AANAT Regulatory Regions—Evolutionary acquisition of the flanking regulatory regions represents a pivotal change in AANAT biology because it enabled cAMP to control rapid activation/inactivation and protection/degradation switching (26, 42, 43) by phosphorylating the Ser/Thr residues in the PKA/14-3-3 motifs (PKA-dependent phosphorylation site nested within a nascent 14-3-3 binding motif) (Fig. 2A).

The N-terminal regulatory region is ~30 residues in length. The primary structure of the PKA/14-3-3 motif 28RRHpTLP33 resembles that of a canonical "mode I" 14-3-3 binding motif (RSX(pS/pT)XP) whereas the three-dimensional configuration of this sequence in the AANAT/14-3-3 complex resembles that of a bound peptide with a "mode II" motif (RX(Y/F)X(pS/pT)XP) (27). The sequence external to this site is disordered; the only conserved feature is a lysine (Lys10), which is thought to be critical for proteosomal proteolysis (44).

The C-terminal regulatory region contains the PKA/14-3-3 motif 200RRNpSG(C/R)205. This represents a "mode III" 14-3-3 binding motif ((pS/pT)X1–2-COOH). AANAT can bind to 14-3-3 proteins via either PKA/14-3-3 motif; however, binding via both is required for activation (24, 25, 27, 45).

Formation of the AANAT/14-3-3 Complex—Dark-dependent phosphorylation of AANAT and binding to 14-3-3 occurs in vivo as a function of environmental lighting (24, 25, 28–30, 46). PKA/14-3-3 motifs bind to amphipathic grooves on the inner surface of the half-pipe 14-3-3 dimer (24, 25). In addition, a significant contribution to binding comes from multiple contacts outside these regions (Fig. 2, B and C). Biochemical studies with the 14-3-3 {zeta} isoform argue that one AANAT binds to a single 14-3-3 dimer. However, structural studies with a mono-phosphorylated truncated AANAT (pT31 AANAT2–201) indicate that two AANATs can bind to a single 14-3-3 {zeta} dimer, each contacting 14-3-3 via the N-terminal PKA/14-3-3 motif (Fig. 2, B and C). The physiological stoichiometry of AANAT/14-3-3 complexes is unknown.

Binding of AANAT to 14-3-3 activates the enzyme by favoring an optimal configuration of Loop 1, in which affinity for arylalkylamines is increased. It also shields AANAT from proteins involved in dephosphorylation and degradation and may also prevent thiol-dependent inactivation (24, 25, 27, 30, 47–49).


   Regulation
TOP
 ABSTRACT
 INTRODUCTION
 Aanat Genes and Evolution
 Role of Retinal AANAT
 Structure and Function
 Regulation
Final Comment
 REFERENCES
 
Tissue-specific Expression—Pineal/retinal expression of Aanat is regulated by photoreceptor conserved elements (PCEs) in the promoter region, which control expression of many phototransduction/melatonin synthesis genes (16, 50–53). PCEs bind members of the orthodenticle CRX/OTX transcription factor family, which are expressed in the pinealocyte and retina throughout life (16, 50, 51, 54–60). In addition, E-box elements contribute by blocking ectopic expression (16).3

Circadian Rhythmicity and Photic "Turnoff"—Nearly all vertebrate AANAT control systems have two elements that regulate dynamics: a circadian clock and a photic turnoff mechanism. The clock is an autonomous ~24-h oscillator constructed of transcriptional/translational feedback loops that act through interactions with E-boxes in clock gene promoters (61–63). The clock is entrained to the environmental lighting cycle by light. Turnoff mechanisms cause rapid suppressive effects of light by decreasing cAMP levels, leading to dissociation of the AANAT/14-3-3 complex, followed by inactivation and proteosomal proteolytic destruction (supplemental Fig. 3) (44). An exception to this general bipartite clock/turnoff model is found in salmonoid fish, in which AANAT activity is not regulated by a clock but only by a photic turnoff mechanism (64).

This general model of regulation takes two forms, as regards the location of the clock and photodetectors (65): submammalian pinealocytes and vertebrate retinal photoreceptors or mammalian pinealocytes.

Submammalian Pinealocytes and Vertebrate Retinal Photoreceptors—In submammalian pinealocytes and in retinal photoreceptors, the clock and AANAT are located in the same cell (17, 50, 64, 66, 67). Light acts directly on these cells through two photoreceptor systems. One resets the clock and the other turns off AANAT activity by reducing cAMP levels. Aanat transcription is controlled primarily through the transcription factors that are part of the clockworks, which bind to circadian E-box elements in the Aanat promoter (68–70). In addition, in the avian retina, cAMP can influence transcription through cyclic AMP response elements (CREs) in the Aanat promoter. cAMP levels are not only regulated by light but also by the clock (17, 67, 71).

Mammalian Pinealocytes—The clock controlling the mammalian pinealocyte is located in the suprachiasmatic nucleus of the hypothalamus (SCN), which receives photic input from the retina via the retinohypothalamic tract. Light acts through this tract to entrain the clock and also acts downstream of the clock to block SCN stimulation of the pineal gland. The SCN is hardwired to the pineal gland by a neural pathway that traverses the brain, spinal cord, and superior cervical ganglia. Postganglionic projections from the latter innervate the pineal gland. At night, SCN stimulation releases norepinephrine into the pineal perivascular space (26, 45, 72).

Norepinephrine activates adenylyl cyclase via beta1-adrenergic receptors and increases intracellular Ca2+ and protein kinase C activity via {alpha}1B-adrenergic receptors (73, 74), thereby potentiating beta1-adrenergic receptor activation of adenylyl cyclase (75). This "cross-talk" causes a large and rapid increase in cAMP (73, 76–78).

As described above, cAMP promotes formation of the AANAT/14-3-3 complex. In ungulates and primates, this is the only cellular mechanism known to control AANAT activity. However, in rodents, cAMP also controls Aanat transcription. The mechanism involves PKA-dependent phosphorylation of CREB (cyclic AMP regulatory element-binding protein) bound to CREs in the Aanat promoter (41, 53, 79–83), which increases Aanat mRNA ≥ 100-fold. The amplitude of this increase is modulated by inducible cAMP early repressor, which competes with CREB for CRE sites (84–86).

Other factors appear to modulate Aanat transcription, including [Ca2+]i (87), an unidentified rapidly turning over protein repressor (88) and endogenous clock control of cAMP production (17, 67, 89, 90). In summary, Aanat expression requires ongoing activation via PCEs. In addition, in some cases, a rhythmic pattern of transcription is conferred by one or two mechanisms: cAMP-dependent activation via CREs (e.g. rat pinealocytes) or activation by clock gene products via E-boxes (e.g. zebrafish and chicken pinealocytes, rat and chicken retinal photoreceptors); both mechanisms operate in chicken photoreceptors. Vertebrate AANAT protein and activity are regulated via binding to 14-3-3 proteins.


   Final Comment
TOP
 ABSTRACT
 INTRODUCTION
 Aanat Genes and Evolution
 Role of Retinal AANAT
 Structure and Function
 Regulation
 Final Comment
REFERENCES
 
Continued research on AANAT is expected to lead to the development of drugs and genetic treatments that control activity of the enzyme. As a result, it may be possible to modulate endocrine function, sleep, mood, and behavior through effects on pineal melatonin synthesis and to improve vision by promoting detoxification of amines in the retina.


   FOOTNOTES
 
* This minireview will be reprinted in the 2007 Minireview Compendium, which will be available in January, 2008. This work was supported by the Intramural Research Program of the NICHD, National Institutes of Health. Back

Formula The online version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4 and supplemental movie 1. Back

1 To whom correspondence should be addressed. Tel.: 301-496-6915; Fax: 301-480-5570; E-mail: kleind{at}mail.nih.gov.

2 The abbreviations used are: AANAT, arylalkylamine N-acetyltransferase; AcCoA, acetyl coenzyme A; CRE, cAMP response element; CREB, cyclic AMP response element-binding protein; DAT, dopamine N-acetyltransferase; GNAT, Gcn5-related N-acetyltransferase; PCE, photoreceptor conserved element; PKA, cAMP-dependent protein kinase; PKA/14-3-3 sequence, PKA phosphorylation site nested within a nascent 14-3-3 binding motif; SCN, suprachiasmatic nucleus of the hypothalamus. Back

3 A. Humphries, T. Wells, R. Baler, D. C. Klein, and D. A. Carter, unpublished observations made with transgenic mice. Back


   ACKNOWLEDGMENTS
 
I wish to express appreciation to Drs. P. Michael Iuvone, Yoav Gothilf, and Steven L. Coon for their careful review of this paper and constructive contributions.



   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 Aanat Genes and Evolution
 Role of Retinal AANAT
 Structure and Function
 Regulation
 Final Comment
 REFERENCES
 

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