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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In birds, rhythmic changes in pineal serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, Aanat) transcripts are controlled by an oscillator located in the pinealocytes themselves which is comprised by clock genes. Our previous data indicated a temporal association between the expressions of chicken Bmal1 clock gene and Aanat suggesting a functional molecular link between them. Here, we studied the effect of cBmal1 antisense oligonucleotides containing locked nucleic acid on cAanat transcripts and melatonin production in cultured chicken pinealocytes transfected in superfusion system. These oligonucleotides synthesized for activating RNase H or blocking the binding of the translation machinery were able to reduce significantly cAanat transcription and melatonin secretion, whereas control inverted oligonucleotides were ineffective. These results indicate the key role of cBmal1 in the regulation of indole metabolism. The superfusion cell culture with reduced transfection toxicity may provide a useful tool for antisense drug design to influence the highly conserved clockwork also in man.
Mol Cell Endocrinol 2006 Apr 25
PMID:Suppression of serotonin N-acetyltransferase transcription and melatonin secretion from chicken pinealocytes transfected with Bmal1 antisense oligonucleotides containing locked nucleic acid in superfusion system. 1651 56

Arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes involved in the detoxification of numerous aromatic chemicals. The NAT-dependent N-acetylation pathway has not previously been detected in plants. We demonstrate here the occurrence of the NAT-dependent pathway in leguminous plants, due to symbiosis with Mesorhizobium loti. We cloned two NAT enzymes from M. loti and showed that these two recombinant enzymes catalysed the N-acetylation of several known NAT substrates, including aniline-derived pesticide residues. We also demonstrate the existence of a functional NAT-dependent acetylation pathway in the root nodules of Lotus japonicus inoculated with M. loti. M. loti is the first non-eukaryotic organism shown to express two catalytically active NAT isoforms. This work also provides the first evidence for acquisition of a xenobiotic detoxification pathway by a plant through symbiosis with a soil microbe.
Mol Microbiol 2006 Apr
PMID:Cloning, functional expression and characterization of Mesorhizobium loti arylamine N-acetyltransferases: rhizobial symbiosis supplies leguminous plants with the xenobiotic N-acetylation pathway. 1657 98

Daily rhythms of melatonin production are controlled by changes in the activity of arylalkylamine-N-acetyltransferase (AANAT). Zebrafish possess two aanats, aanat1 and aanat2; the former is expressed only in the retina and the latter is expressed in both the retina and the pineal gland. Here, their differential expression and regulation were studied using transcript quantification and transient and stable in vivo and in vitro transfection assays. In the pineal gland, the aanat2 promoter exhibited circadian clock-controlled activity, as indicated by circadian rhythms of Enhanced green fluorescent protein (EGFP) mRNA in AANAT2:EGFP transgenic fish. In vivo transient expression analyses of the aanat2 promoter indicated that E-box and photoreceptor conserved elements (PCE) are required for expression in the pineal gland. In the retina, the expression of both genes was characterized by a robust circadian rhythm of their transcript levels. In constant darkness, the rhythmic expression of retinal aanat2 persisted while the aanat1 rhythm disappeared; indicating that the former is controlled by a circadian clock and the latter is also light driven. In the light-entrainable clock-containing PAC-2 zebrafish cell line, both stably transfected aanat1 and aanat2 promoters exhibited a clock-controlled circadian rhythm, characteristic for an E-box-driven expression. Transient co-transfection experiments in NIH-3T3 cells revealed that the two, E-box- and PCE-containing, promoters are driven by the synergistic action of BMAL/CLOCK and orthehodenticle homeobox 5. This study has revealed a shared mechanism for the regulation of two related genes, yet describes their differential phases and photic responses which may be driven by other gene-specific regulatory mechanisms and tissue-specific transcription factor profiles.
J Mol Endocrinol 2006 Apr
PMID:Zebrafish arylalkylamine-N-acetyltransferase genes - targets for regulation of the circadian clock. 1659 4

Photoreceptor cells of the pineal gland express distinct sets of proteins dedicated to photoreception, phototransduction and to rhythmic melatonin production. This review discusses the function of key regulatory sequences and nuclear factors that determine tissue-restricted expression of photoreceptor genes, specifically, the photoreceptor conserved element (PCE) and the E-box and their cognate binding proteins. Recent research in zebrafish revealed that PCE and E-box mediate the action of OTX5 and BMAL/CLOCK, respectively. These transcription factors drive enhanced expression of serotonin-N-acetyltransferase-2 (aanat2) in the pineal gland by synergistic interaction. Extensive research of other photoreceptor-specific genes suggested that the presence of several PCEs along with additional sequence elements is required to drive enhanced tissue-specific expression of these genes. Therefore, the mechanism identified for zebrafish aanat2, or at least part of it, may apply to other photoreceptor-specific genes in zebrafish and other species.
Mol Cell Endocrinol 2006 Jun 27
PMID:Mechanism of pineal-specific gene expression: the role of E-box and photoreceptor conserved elements. 1664 8

Unlike mammals, rhythmic changes in serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase [AANAT]) transcripts in chicken pineal cells are controlled by an oscillator located in the pinealocytes themselves, which is comprised of clock genes. Asimilar clock-dependent pathway has been postulated to regulate the retinal melatonin rhythm. In chicken retinal photoreceptor cells and pinealocytes, the chicken AANAT gene (cAANAT) is coexpressed with clock genes, including cBmal1 and cClock, which might regulate cAANAT transcription. Here, we have studied the temporal profile of cBmal1, cClock, and cAANAT mRNAexpressions in retinal cells in vivo with chickens housed in a 14/10-h light/dark (LD) cycle for 2 wk and in vitro cultured in a superfusion system for 4 LD cycles. mRNA levels of these genes were analyzed by RT-PCR and compared with their corresponding pineal transcripts. cBmal1 mRNA showed a peak during the light phase between Zeitgeber time (ZT) 8 and 10, preceding the amplitude of the nocturnal increase in cAANAT expression at ZT 16-17. Retinal cBmal1 and cAANAT mRNAs exhibited less robust cycling than their corresponding pineal transcripts in the same animal. cClock mRNAlevels failed to exhibit a well-detectable rhythm. The phase of the rhythms of retinal cBmal1 and cAANAT mRNAs suggests a link between retinal cBmal1 and cAANAT expressions similar to the regulation of pineal cAANAT transcription. Based on the highly conserved nature of the clockwork, it is reasonable to consider that chicken retina and pineal gland might serve as a useful tool for the development of drugs that could influence clock function in man.
J Mol Neurosci 2006
PMID:Circadian expression of Bmal1 and serotonin-N-acetyltransferase mRNAs in chicken retina cells and pinealocytes in vivo and in vitro. 1667 54

Arylamine N-acetyltransferases (NATs) catalyze the acetylation of arylamines, a key step in the detoxification of many carcinogens. The determinants of NAT substrate specificity are not known, yet this knowledge is required to understand why NAT enzymes acetylate some arylamines, but not others. Here, we use NMR spectroscopy and homology modeling to reveal the structural determinants of arylamine acetylation by NATs. In particular, by using chemical shift perturbation analysis, we have identified residues that play a critical role in substrate binding and catalysis. This study reveals why human NAT1 acetylates the sunscreen additive p-aminobenzoic acid and tobacco smoke carcinogen 4-aminobiphenyl, but not o-toluidine and other arylamines linked to bladder cancer. Our results represent an important step toward predicting whether arylamines present in new products can be detoxified by mammalian NATs.
J Mol Biol 2006 Oct 13
PMID:NMR-based model reveals the structural determinants of mammalian arylamine N-acetyltransferase substrate specificity. 1695 63

Heterocyclic amine carcinogens such as 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) are present in diet and cigarette smoke. Bioactivation in humans includes N-hydroxylation catalyzed by cytochrome P4501A2 possibly followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells were stably transfected with human CYP1A2 and either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles. CYP1A2 and NAT2 catalytic activities were undetectable in untransfected CHO cell lines. CYP1A2 catalytic activity levels did not differ significantly (P > 0.05) among the CYP1A2-transfected cell lines. Cells transfected with NAT2*4 had significantly higher levels of N-acetyltransferase (P = 0.0001) and N-hydroxy-PhIP O-acetyltransferase (P = 0.0170) catalytic activity than cells transfected with NAT2*5B. PhIP caused dose-dependent decreases in cell survival and significant (P < 0.001) increases in mutagenesis measured at the hypoxanthine phosphoribosyl transferase (hprt) locus in all the CYP1A2-transfected cell lines. Transfection with NAT2*4 or NAT2*5B did not further increase hprt mutagenesis. PhIP-induced hprt mutant cDNAs were sequenced, and 80% of the mutations were single base substitutions at G:C base pairs. dG-C8-PhIP DNA adduct levels were dose-dependent in the order: untransfected < transfected with CYP1A2 < transfected with CYP1A2 and NAT2*5B < transfected with CYP1A2 and NAT2*4. Following incubation with 1.2 microM PhIP, DNA adduct levels were significantly (P < 0.05) higher in CHO cells transfected with CYP1A2/NAT2*4 versus CYP1A2/NAT2*5B. These results strongly support an activation role for CYP1A2 in PhIP-induced mutagenesis and DNA damage and suggest a modest effect of human NAT2 and its genetic polymorphism on PhIP DNA adduct levels.
Mol Carcinog 2007 Jul
PMID:2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine-induced DNA adducts and genotoxicity in chinese hamster ovary (CHO) cells expressing human CYP1A2 and rapid or slow acetylator N-acetyltransferase 2. 1729 38

Melatonin is an indoleamine widely distributed in the evolution that shows a great functional versatility, playing an important role as a transmitter of photoperiodic information and exhibiting antioxidant, oncostatic, anti-aging and immunomodulatory properties. In vertebrates, this molecule is produced by the pineal gland and other extrapineal sites. The present study was carried out to investigate the presence of melatonin in thymus and the possibility of an endogenous melatonin synthesis in this organ, in which T cells are matured. In this work, we demonstrate in humans and rats that thymus contains melatonin, expresses the mRNAs encoding N-acetyltransferase and hydroxyindol-O-methyltransferase, the two key enzymes of the melatonin synthesis, and has this biosynthetic machinery activated. In addition, rat thymocytes cultured for 24 h exhibited high levels of melatonin. The results presented here suggest that human and rat thymuses are able to synthesize melatonin, which could have intracrine, autocrine and paracrine functions.
Cell Mol Life Sci 2007 Mar
PMID:Melatonin biosynthesis in the thymus of humans and rats. 1733 63

Major aspects of the pathway of de novo arginine biosynthesis via acetylated intermediates in microorganisms must be revised in light of recent enzymatic and genomic investigations. The enzyme N-acetylglutamate synthase (NAGS), which used to be considered responsible for the first committed step of the pathway, is present in a limited number of bacterial phyla only and is absent from Archaea. In many Bacteria, shorter proteins related to the Gcn5-related N-acetyltransferase family appear to acetylate l-glutamate; some are clearly similar to the C-terminal, acetyl-coenzyme A (CoA) binding domain of classical NAGS, while others are more distantly related. Short NAGSs can be single gene products, as in Mycobacterium spp. and Thermus spp., or fused to the enzyme catalyzing the last step of the pathway (argininosuccinase), as in members of the Alteromonas-Vibrio group. How these proteins bind glutamate remains to be determined. In some Bacteria, a bifunctional ornithine acetyltransferase (i.e., using both acetylornithine and acetyl-CoA as donors of the acetyl group) accounts for glutamate acetylation. In many Archaea, the enzyme responsible for glutamate acetylation remains elusive, but possible connections with a novel lysine biosynthetic pathway arose recently from genomic investigations. In some Proteobacteria (notably Xanthomonadaceae) and Bacteroidetes, the carbamoylation step of the pathway appears to involve N-acetylornithine or N-succinylornithine rather than ornithine. The product N-acetylcitrulline is deacetylated by an enzyme that is also involved in the provision of ornithine from acetylornithine; this is an important metabolic function, as ornithine itself can become essential as a source of other metabolites. This review insists on the biochemical and evolutionary implications of these findings.
Microbiol Mol Biol Rev 2007 Mar
PMID:Surprising arginine biosynthesis: a reappraisal of the enzymology and evolution of the pathway in microorganisms. 1734 18

Evidence has shown that N-acetyltransferase (NAT) acetylated 2-aminofluorene (AF) to form N-acetyl-2-aminofluorene (AAF). Then it was metabolized by cytochrome P450 (CYP) enzyme to form ring or N-hydroxylated metabolites. Sulfotransferase and other enzymes participated to form the ultimate metabolites which bind to DNA to form DNA-AF adducts which may have led to cancer development. The aim of the present study is to demonstrate whether paclitaxel (taxol) can inhibit the NAT activity, NAT gene expression and DNA-AF adduct formation in human stomach tumor cell line (SC-M1). The activity of NAT was determined by high performance liquid chromatography (HPLC) assaying for the amounts of acetylated AF (AAF) or p-aminobenzoic acid (N-Ac-PABA) and nonacetylated AF or PABA. While SC-M1 cell cytosols were used for examining NAT activity, intacts cells were used for examining all three: NAT activity, gene expression and DNA-AF adduct formation. As compared with the control group, the paclitaxel- treated group showed decreased NAT activity and DNA-AF adduct formation in SC-M1 cells and the decrease was dose-dependent. The results also indicated that paclitaxel decreased the apparent values of K(m) and V(max) from SC-M1 cells in both cytosol and intact cells. Palitaxel did significantly affect NAT gene expression (NAT1 mRNA) in SC-M1 cells.
Res Commun Mol Pathol Pharmacol 2004
PMID:Paclitaxel inhibits N-acetyltransferase activity and gene expression in human stomach tumor cells (SC-M1). 1756 3


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