Aralkylamine N-acetyltransferase
Aralkylamine N-acetyltransferase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Aralkylamine N-acetyltransferase | |||||||
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Identifiers | |||||||
Symbol | AANAT | ||||||
Chr. 17 q25 | |||||||
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Aralkylamine N-acetyltransferase (AANAT) (
Nomenclature
The systematic name of this enzyme class is acetyl-CoA:2-arylethylamine N-acetyltransferase. Other names in common use include:
- AANAT
- Arylalkylamine N-acetyltransferase
- Melatonin rhythm enzyme
- Serotonin acetylase
- Serotonin acetyltransferase
- Serotonin N-acetyltransferase
The officially accepted name is aralkylamine N-acetyltransferase.[4]
Function and mechanism
Tissue distribution
The AANAT mRNA transcript is mainly expressed in the central nervous system (CNS). It is detectable at low levels in several brain regions including the pituitary gland as well as in the retina. It is most highly abundant in the pineal gland which is the site of melatonin synthesis. Brain and pituitary AANAT may be involved in the modulation of serotonin-dependent aspects of human behavior and pituitary function.[3]
Physiological function
In the pinealocyte cells of the pineal gland, aralkylamine N-acetyltransferase is involved in the conversion of serotonin to melatonin. It is the penultimate enzyme in the melatonin synthesis controlling the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for seasonal reproduction, modulates the function of the circadian clock in the suprachiasmatic nucleus, and influences activity and sleep. Due to its important role in circadian rhythm, AANAT is subjected to extensive regulation that is responsive to light exposure (see Regulation). It may contribute to multifactorial genetic diseases such as altered behavior in sleep/wake cycle and mood disorders.[2]
The chemical reactions catalyzed by AANAT
The primary
In the
AANAT obeys an ordered ternary-complex mechanism. The substrates bind sequentially (ordered) with acetyl-CoA binding to the free enzyme followed by the binding of serotonin to form the ternary complex. After the transfer of the acetyl group has occurred, the products are orderly released with N-acetyl-serotonin first and CoA last.[7]
Structure
Arylkylamine N-acetyltransferase is a
Several
Aralkylamine N-acetyltransferase has also been crystallized in complex with 14-3-3ζ from the 14-3-3 protein family, with the PDB accession code 1IB1.[11]
The GNAT superfamily
Aralkylamine N-acetyltransferase belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily which consists 10,000 acetyltransferases, named so because of their sequence homology to a class of eukaryotic
All members of this superfamily has a structurally conserved fold consisting of an N-terminal strand followed by two helices, three antiparallel β-strands, followed by a ‘‘signature’’ central helix, a fifth β-strand, a fourth α-helix and a final β-strand. These elements are nearly universally conserved in spite of poor pairwise identity in sequence alignments.[12]
Regulation
Regulation of AANAT varies between species. In some, AANAT levels oscillate dramatically between light and dark periods, and thus control melatonin synthesis. In others, rhythm is regulated primarily on the protein level.[13] One example is in rodents, where AANAT mRNA levels increase more than 100-fold in dark periods. In other species, cyclic AMP plays an important part in inhibition of proteolytic degradation of AANAT, elevating protein levels at night. Experiments using human AANAT expressed in a 1E7 cell line show an ~8-fold increase in enzyme activity upon exposure to forskolin.[14]
Dynamic degradation of AANAT mRNA has proven essential to the circadian action of the enzyme. The 3’UTR sequences have importance with regards to the rhythmic degradation of AANAT mRNA in some species. In rodents, various
Exposure to light induces signals to travel from retinal cells, ultimately causing a drop in
Another protein which interacts and regulates AANAT activity is
Inhibition of the acetyl-CoA-binding to the catalytic site through the formation and cleavage of intramolecular disulfide bonds has been suggested to be a mechanism of regulation. Formation of a disulfide bond between two cystein residues within the protein closes the hydrophobic funnel of the catalytic site, and thus acts as an on/off switch for catalytic activity. It is not yet certain if this mechanism is present in in vivo cells through the regulation of intracellular redox conditions, but it is suggested that glutathione (GSH) could be an in vivo regulator of the formation and cleavage of these disulfide bonds.[18]
AANAT inhibitors and clinical relevance
Melatonin derivatives
Since it was reported that melatonin is a competitive inhibitor of AANAT, this neurotransmitter seems to exert an autoregulatory control on its own biosynthesis. Thus, loose structural analogues of the indolamine hormone were evaluated on AANAT, and moderate inhibitors were discovered.[23]
Peptidic inhibitors
Peptide combinatorial libraries of tri-, tetra-, and pentapeptides with various amino acid compositions were screened as potential sources of inhibitors, to see if it serves as either pure or mixed competitive inhibitor for the hAANAT enzyme.
Bisubstrate analogs
It is suggested that AANAT catalyzes the transfer of an acetyl group from acetyl-CoA to serotonin, with the involvement of an intermediate ternary complex, to produce N-acetylserotonin. Based on this mechanism, it might be expected that a bisubstrate analog inhibitor, derived from the tethering of indole and CoASH parts, could potentially mimic the ternary complex and exert strong inhibition of AANAT.[25] The first bisubstrate analog (1), which links tryptamine and CoA via an acetyl bridge, was synthesized by Khalil and Cole, and shown to be a very potent and specific AANAT inhibitor.[26]
N-Haloacetylated derivatives
AANAT has shown that it also has a secondary alkyltransferase activity as well as acetyltransferase activity.[27] N-Haloacetyltryptamines were developed and serve as substrates of AANAT alkyltransferase and are also potent (low micromolar) in vitro inhibitors against AANAT acetyltransferase activity. AANAT catalyzes reaction between N-bromoacetyltryptamine (BAT) and reduced CoA, resulting a tight-binding bisubstrate analog inhibitor.[27][28] The first synthesized cell-permeable inhibitor of AANAT N-bromoacetyltryptamine was studied further on melatonin secretion from rat and pig pineal glands.[29] New N-halogenoacetyl derivatives leading to a strong in situ inhibition of AANAT. The concept behind the mechanism of action of these precursors was studied by following the biosynthesis of the inhibitor from tritiated-BAT in a living cell.[20]
Rhodanine-based compounds
The first druglike and selective inhibitors of AANAT has been identified. Lawrence M. Szewczuk et al. have virtually screened more than a million compounds by 3D
The recent study about inhibitor of AANAT has described the discovery of a new class of nonpeptidic AANAT inhibitors based on a 2,2′-bithienyl scaffold.[22]
See also
References
- ^ PMID 11902838.
- ^ a b c "Entrez Gene: arylalkylamine N-acetyltransferase".
- ^ PMID 8661026.
- ^ "IUBMB Enzyme Nomenclature EC 2.3.1.87". Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB). Retrieved 15 November 2014.
- ^ "EC 2.3.1.87 - aralkylamine N-acetyltransferase". BRENDA. Technische Universität Braunschweig. July 2014. Retrieved 10 November 2014.
- ^ PMID 12052171.
- PMID 9446620.
- S2CID 18272015.
- PMID 10024876.
- PMID 11884405.
- S2CID 9564413.
- PMID 15581578.
- PMID 9238858.
- PMID 11313340.
- PMID 15798208.
- PMID 18771288.
- S2CID 42638894.
- PMID 12215431.
- ^ PMID 17924613.
- ^ PMID 14717709.
- PMID 12941292.
- ^ PMID 20196559.
- PMID 8832214.
- PMID 10722724.
- ^ Page, A.I. (1990). "Enzyme inhibition". Comprehensive Medicinal Chemistry. 2: 61–87.
- .
- ^ PMID 10535937.
- PMID 11325593.
- PMID 16264397.
Further reading
- Voisin P, Namboodiri MA, Klein DC (1984). "Arylamine N-acetyltransferase and arylalkylamine N-acetyltransferase in the mammalian pineal gland". J. Biol. Chem. 259 (17): 10913–8. PMID 6469990.
- Fauchere JL, Boutin JA (2000). "Substrate specificity and inhibition studies of human serotonin N-acetyltransferase". J. Biol. Chem. 275 (12): 8794–805. PMID 10722724.
- Khalil EM, Cole PA (1998). "A potent inhibitor of the melatonin rhythm enzyme". J. Am. Chem. Soc. 120 (24): 6195–6196. .
External links
- Serotonin+N-Acetyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- AANAT human gene location in the UCSC Genome Browser.
- AANAT human gene details in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.