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Gene Review:

AANAT - aralkylamine N-acetyltransferase

Ovis aries

Coon, S.L. et al., Garidou, M.L. et al., Zheng, W. et al., Coon, S.L. et al., Gauer, F. et al., et al.

Gauer, Poirel, Garidou, Simonneaux, Pévet,

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Disease relevance of AA-NAT

The AA-NAT transcript (approximately 1 kb) is highly abundant in the pineal gland and is expressed at lower levels in the retina and in the Y79 retinoblastoma cell line [1].

High impact information on AA-NAT

Pineal serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, or AA-NAT) generates the large circadian rhythm in melatonin, the hormone that coordinates daily and seasonal physiology in some mammals [2].
The abundance of AA-NAT messenger RNA (mRNA) during the day was high in the ovine pineal gland and somewhat lower in retina [2].
AA-NAT mRNA was found unexpectedly in the pituitary gland and in some brain regions [2].
AANAT is a globular protein consisting of an eight-stranded beta sheet flanked by five alpha helices; a conserved motif in the center of the beta sheet forms the cofactor binding site [3].
Large changes in activity are linked to cyclic AMP-dependent protein kinase-mediated phosphorylation of AANAT T31 [4].

Biological context of AA-NAT

In Arvicanthis, Aa-nat gene expression is markedly increased at the beginning of the night and is followed by a large increase in AA-NAT activity and melatonin content [5].
In this study, we cloned the cDNA coding for Aa-nat and analysed the mechanisms of AA-NAT enzyme activation in the pineal gland of the diurnal grass rat, Arvicanthis ansorgei, and compared them to those of the nocturnal Wistar rat, Rattus norvegicus [5].
The open reading frame encodes a 23.2-kDa protein that is approximately 80% identical to sheep and rat AA-NAT [1].
The scAANAT sequence conformed to the three-dimensional structure of ovine AANAT catalytic core; however, an important structural element (loop 1) was found to be shorter and to lack a proline involved in substrate binding [6].

Associations of AA-NAT with chemical compounds

In the chicken, cyclic AMP acts primarily at the protein level and a rhythm in AA-NAT mRNA is driven by a noncyclic AMP-dependent mechanism linked to the clock within the pineal gland [7].
Brain and pituitary AA-NAT could modulate serotonin-dependent aspects of human behavior and pituitary function [1].
Serotonin N-acetyltransferase (arylalkylamine N-ace-tyltransferase (AANAT)) catalyzes the reaction of serotonin (or tryptamine) with acetyl-CoA to form N-acetylserotonin (or N-acetyltryptamine) and is responsible for the melatonin circadian rhythm in vertebrates [8].
This study evaluates a series of indoleamine analogs as alternate substrates of AANAT [8].
To accomplish this, a C-terminal AANAT peptide containing the phosphonodifluoromethylene alanine at Ser-205 was synthesized and fused to bacterially expressed AANAT(30-199) using expressed protein ligation [9].

Other interactions of AA-NAT

Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205 [4].

Analytical, diagnostic and therapeutic context of AA-NAT

The first part of our study was dedicated to the molecular cloning of a Syrian hamster AA-NAT cDNA [10].
In situ hybridization using an AA-NAT cRNA probe revealed that the AA-NAT mRNA expression undergoes strong daily fluctuations in the Syrian hamster pineal, with undetectable level in the second half of the light period and a dramatic increase at night [10].
The resulting semisynthetic protein has enhanced affinity for the expressed 14-3-3 protein and exhibits greater cellular stability in microinjection experiments, as compared with the unmodified AANAT [9].
Third, arylamine N-acetyltransferase and arylalkylamine N-acetyltransferase inactivated at different rates at 4 degrees C. Fourth, the two enzymes were resolved by size exclusion chromatography [11].

References

The human serotonin N-acetyltransferase (EC 2.3.1.87) gene (AANAT): structure, chromosomal localization, and tissue expression. Coon, S.L., Mazuruk, K., Bernard, M., Roseboom, P.H., Klein, D.C., Rodriguez, I.R. Genomics (1996) [Pubmed]
Pineal serotonin N-acetyltransferase: expression cloning and molecular analysis. Coon, S.L., Roseboom, P.H., Baler, R., Weller, J.L., Namboodiri, M.A., Koonin, E.V., Klein, D.C. Science (1995) [Pubmed]
Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism. Hickman, A.B., Klein, D.C., Dyda, F. Mol. Cell (1999) [Pubmed]
Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205. Ganguly, S., Weller, J.L., Ho, A., Chemineau, P., Malpaux, B., Klein, D.C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
Pineal arylalkylamine N-acetyltransferase gene expression is highly stimulated at night in the diurnal rodent, Arvicanthis ansorgei. Garidou, M.L., Gauer, F., Vivien-Roels, B., Sicard, B., Pévet, P., Simonneaux, V. Eur. J. Neurosci. (2002) [Pubmed]
Characterization of the Saccharomyces cerevisiae homolog of the melatonin rhythm enzyme arylalkylamine N-acetyltransferase (EC 2.3.1.87). Ganguly, S., Mummaneni, P., Steinbach, P.J., Klein, D.C., Coon, S.L. J. Biol. Chem. (2001) [Pubmed]
The melatonin rhythm-generating enzyme: molecular regulation of serotonin N-acetyltransferase in the pineal gland. Klein, D.C., Coon, S.L., Roseboom, P.H., Weller, J.L., Bernard, M., Gastel, J.A., Zatz, M., Iuvone, P.M., Rodriguez, I.R., Bégay, V., Falcón, J., Cahill, G.M., Cassone, V.M., Baler, R. Recent Prog. Horm. Res. (1997) [Pubmed]
Indoleamine analogs as probes of the substrate selectivity and catalytic mechanism of serotonin N-acetyltransferase. Khalil, E.M., De Angelis, J., Cole, P.A. J. Biol. Chem. (1998) [Pubmed]
Cellular stability of serotonin N-acetyltransferase conferred by phosphonodifluoromethylene alanine (Pfa) substitution for Ser-205. Zheng, W., Schwarzer, D., Lebeau, A., Weller, J.L., Klein, D.C., Cole, P.A. J. Biol. Chem. (2005) [Pubmed]
Molecular cloning of the arylalkylamine-N-acetyltransferase and daily variations of its mRNA expression in the Syrian hamster pineal gland. Gauer, F., Poirel, V.J., Garidou, M.L., Simonneaux, V., Pévet, P. Brain Res. Mol. Brain Res. (1999) [Pubmed]
Arylamine N-acetyltransferase and arylalkylamine N-acetyltransferase in the mammalian pineal gland. Voisin, P., Namboodiri, M.A., Klein, D.C. J. Biol. Chem. (1984) [Pubmed]

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