Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tryptophan hydroxylase (TPH) is the first enzyme in both serotonin and melatonin biosynthesis in neuroendocrine cells of the pineal gland. The lack of immortalized neuroendocrine pineal cell lines has been a major obstacle to the study of the tissue-specific and circadian regulation of TPH gene expression in the pineal gland. Previously, we demonstrated that a 6.1 kb 5' upstream region of the mouse TPH gene directs the restricted expression of a lacZ reporter gene to the pineal gland and the raphe nuclei of transgenic mice. Therefore, to develop TPH-expressing pineal cell lines we first established transgenic mice carrying a construct consisting of 6.1 kb of 5' flanking region fused to the SV40 T-antigen. These animals developed highly invasive pineal tumors and died at 12-15 weeks of age. The pineal tumors obtained from the transgenic mice were utilized to establish the immortalized pinealocyte-derived cell lines. These cells express two marker enzymes, TPH and serotonin N-acetyltransferase (NAT). In pineal gland TPH and NAT expressions have been known to be regulated during circadian cycle. The two established cell lines therefore promise to be a valuable in vitro model system for the study of the rhythmic nature of the pineal function at molecular level in mammal.
Brain Res Mol Brain Res 1996 Apr
PMID:Immortalization of neuroendocrine pinealocytes from transgenic mice by targeted tumorigenesis using the tryptophan hydroxylase promoter. 873 33

Genetic polymorphisms with functional effects occur in many of the genes encoding drug metabolizing enzymes and are an important cause of adverse drug reaction. Recent advances in the understanding of the molecular genetics of drug-metabolizing enzymes, particularly the cytochromes P450, has enabled the molecular basis of several polymorphisms to be elucidated and genotyping assays using the polymerase chain reaction to be developed. Polymorphisms in this category include those in the cytochrome P450 genes CYP2D6, CYP2C19, CYP2A6, CYP2C9 and CYP2E1, the glutathione S-transferase genes GSTM1 and GSTT1 and the N-acetyltransferase gene NAT2. The molecular basis and importance to drug metabolism of the various polymorphisms as well as evidence for the existence of polymorphisms in other genes encoding drug-metabolizing enzymes such as the UDP-glucuronosyltransferases, the sulphotransferases and the methyltransferases are discussed.
J Mol Med (Berl) 1995 Nov
PMID:Molecular basis of polymorphic drug metabolism. 875 Nov 38

In a search for genes involved in regulation of the 2'-N-acetyltransferase in Providencia stuartii, a mini-Tn5Cm insertion has been isolated in a locus designated aarD. The aarD1::mini-Tn5Cm mutation resulted in a 4.7-fold increase in the levels of beta-galactosidase accumulation from an aac(2')-lacZ transcriptional fusion and a 32-fold increase in the levels of gentamicin resistance in P. stuartii. The wild-type aarD locus was cloned on a 5.0 kb Cla I fragment and complemented the aarD1 mutation. Nucleotide sequence analysis of this fragment identified two large open reading frames whose deduced products displayed significant amino acid identity, 64% and 64%, respectively, to the CydD and CydC proteins of Escherichia coli, which are involved in formation of the cytochrome d oxidase complex. Physical mapping indicated the aarD1::mini-Tn5Cm insertion was within the open reading homologous to CydD. The strain containing the aarD1 mutation was unable to grow in the presence of toluidine blue or on glycerol minimal media in the presence of zinc, suggesting that aarD is functionally equivalent to cydD. Additional phenotypes resulting from the aarD1 mutation included: altered cell morphology, a reduced growth rate and the inability of cells to grow beyond early log phase. Further examination of this phenomenon revealed that the aarD1 mutant was unable to grow in the presence of a self-produced extracellular factor(s). This novel phenotype was limited to P. stuartii as E. coli cydD and delta cydAB::kan mutants were also sensitive to a self-produced extracellular factor.
Mol Microbiol 1996 Feb
PMID:aarD, a Providencia stuartii homologue of cydD: role in 2'-N-acetyltransferase expression, cell morphology and growth in the presence of an extracellular factor. 883 Feb 42

Benzidine and 4-aminobiphenyl (4-ABP) are promutagenic bicyclic aromatic amines that are activated into frameshift and base pair substitution mutagens by plant systems. Using the plant cell/microbe coincubation assay, plant-activated benzidine from 0 to 50 microM induced a concentration-response in Salmonella typhimurium. At concentrations above 5 microM, plant-activated benzidine induced frameshift and base pair substitution mutations in the N- or O-acetyltransferase over-expressing strains, DJ460, YG1024, and YG1029. With plant-activated 4-ABP, concentrations above 250 microM induced a significant mutagenic response in strains YG1024 and YG1029. A tobacco cell-free mixture, TX1MX, activated benzidine and 4-ABP into mutagenic metabolites in S. typhimurium strains YG1024, YG1029, and DJ460. The mutagenic sensitivities of plant-activated benzidine and 4-ABP were the same with two different types of plant activation systems, TX1 suspension cells and TX1MX cell-free medium. The plant activation of these aromatic amines is mediated by tobacco cell peroxidase. Plant-activated benzidine and 4-ABP are converted into intermediates that serve as substrates for bacterial or humanacetylCoA: N-hydroxyarylamine N-acetyltransferase to generate the ultimate mutagenic products.
Environ Mol Mutagen 1997
PMID:Plant-activation of the bicyclic aromatic amines benzidine and 4-aminobiphenyl. 902 Mar 11

Mammalian pineal function is regulated by norepinephrine acting through alpha1beta- and beta1-adrenergic receptors (ARs). Noradrenergic stimulation of alpha1beta-ARs potentiates the beta1-AR-driven increase in cAMP, serotonin N-acetyltransferase, and melatonin production. In the present study, we describe a 3-fold daily rhythm in mRNA-encoding alpha1beta-ARs in the pineal gland, with a peak at midnight. Pharmacological studies indicate that this increase in alpha1beta-AR mRNA is due to activation of beta-ARs. Second messenger studies indicate that alpha1beta-AR mRNA is increased by agents that increase cAMP, including dibutyryl cAMP, cholera toxin, forskolin, or vasoactive intestinal peptide. These observations indicate that alpha1beta-AR mRNA can be physiologically regulated by a beta-AR-dependent enhancement of cAMP. It also was observed that in vivo and in vitro changes in alpha1beta-AR mRNA are not accompanied by similar changes in alpha1beta-AR binding, indicating that turnover of alpha1beta-AR protein is significantly slower than that of alpha1beta-AR mRNA and that post-transcriptional mechanisms play an important role in regulating alpha1beta-AR binding.
Mol Pharmacol 1997 Apr
PMID:Regulation of pineal alpha1B-adrenergic receptor mRNA: day/night rhythm and beta-adrenergic receptor/cyclic AMP control. 910 18

The genus Mycobacterium comprises clinically important pathogens such as M. tuberculosis, which has reemerged as a major cause of morbidity and mortality world-wide especially with the emergence of multidrug-resistant strains. The use of fast-growing species such as Mycobacterium smegmatis has allowed important advances to be made in the field of mycobacterial genetics and in the study of the mechanisms of resistance in mycobacteria. The isolation of an aminoglycoside-resistance gene from Mycobacterium fortuitum has recently been described. The aac(2')-Ib gene is chromosomally encoded and is present in all isolates of M. fortuitum. The presence of this gene in other mycobacterial species is studied here and genes homologous to that of M. fortuitum have been found in all mycobacterial species studied. In this report, the cloning of the aac(2')-Ic gene from M. tuberculosis H37Rv and the aac(2')-Id gene from M. smegmatis mc(2)155 is described. Southern blot hybridizations have shown that both genes are present in all strains of this species studied to date. In addition, the putative aac(2')-Ie gene has been located in a recent release of the Mycobacterium leprae genome. The expression of the aac(2')-Ic and aac(2')-Id genes has been studied in M. smegmatis and only aac(2')-Id is correlated with aminoglycoside resistance. In order to elucidate the role of the aminoglycoside 2'-N-acetyltransferase genes in mycobacteria and to determine whether they are silent resistance genes or whether they have a secondary role in mycobacterial metabolism, the aac(2')-Id gene from M. smegmatis has been disrupted in the chromosome of M. smegmatis mc(2)155. The disruptant shows an increase in aminoglycoside susceptibility along with a slight increase in the susceptibility to lysozyme.
Mol Microbiol 1997 Apr
PMID:Aminoglycoside 2'-N-acetyltransferase genes are universally present in mycobacteria: characterization of the aac(2')-Ic gene from Mycobacterium tuberculosis and the aac(2')-Id gene from Mycobacterium smegmatis. 915 28

Melatonin (N-acetyl-5-methoxytryptamine) and the activities of two melatonin-synthesizing enzymes, serotonin N-acetyltransferase (acetyl coenzyme A: arylalkylamine N-acetyltransferase EC 2.3.1.87; NAT) and hydroxyindole-O-methyltransferase (S-adenosyl-L-methionine: N-acetylserotonin-O-methyltransferase EC 2.1.1.4; HIOMT), were assayed in extracts of ovaries obtained from virgin Wistar-derived rats (7-9 week-old) during the light period of a 12 h light/12 h dark cycle. Melatonin was detected in the rat ovary using reverse-phase high-performance liquid chromatography (HPLC) coupled with fluorometric detection and radioimmunoassay (RIA). In addition, NAT and HIOMT activities were found in rat ovary. The apparent Michaelis constants (Km) for the substrates of NAT and HIOMT in the rat ovary were similar to those reported for the pineal gland and retina. These data suggest that the rat ovary, like the pineal gland and the retina, may synthesize melatonin from serotonin by the sequential action of NAT and HIOMT.
Mol Cell Endocrinol 1997 Dec 31
PMID:Detection of melatonin and serotonin N-acetyltransferase and hydroxyindole-O-methyltransferase activities in rat ovary. 951 62

Pineal melatonin synthesis (serotonin --> N-acetylserotonin --> melatonin) is severely compromised in most inbred strains of mice, in many cases because serotonin is not acetylated by serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT). We have found that in the C57BL/6J strain, AANAT mRNA encodes a severely truncated AANAT protein, because a pseudo-exon containing a stop codon is spliced in. This is the first identification of a natural mutation which knocks down melatonin synthesis. The decrease in melatonin signaling may have been a selective factor in the development of laboratory strains of mice because melatonin can inhibit reproduction and modify circadian rhythmicity.
Brain Res Mol Brain Res 1998 Dec 10
PMID:Natural melatonin 'knockdown' in C57BL/6J mice: rare mechanism truncates serotonin N-acetyltransferase. 983 7

Conversion of serotonin to N-acetylserotonin, the precursor of the circadian neurohormone melatonin, is catalyzed by serotonin N-acetyltransferase (AANAT) in a reaction requiring acetyl coenzyme A (AcCoA). 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. Three polypeptide loops converge above the AcCoA binding site, creating a hydrophobic funnel leading toward the cofactor and serotonin binding sites in the protein interior. Two conserved histidines not found in other NATs are located at the bottom of the funnel in the active site, suggesting a catalytic mechanism for acetylation involving imidazole groups acting as general acid/base catalysts.
Mol Cell 1999 Jan
PMID:Melatonin biosynthesis: the structure of serotonin N-acetyltransferase at 2.5 A resolution suggests a catalytic mechanism. 1002 76

The presence of melatonin (N-acetyl-5-methoxytryptamine) and its precursors, serotonin (5-hydroxytryptamine) and N-acetylserotonin, was demonstrated in extracts of human ovary using reverse-phase high-performance liquid chromatography coupled with fluorometric detection. In addition, activities of two melatonin-synthesizing enzymes, arylalkylamine N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), were found in human ovary homogenates. The apparent Michaelis constants for the substrates of NAT and HIOMT in the human ovary were similar to those reported for the pineal glands of humans and other mammals. These findings strongly suggest that the human ovary, like the pineal gland, may synthesize melatonin from serotonin by the sequential action of NAT and HIOMT.
Mol Hum Reprod 1999 May
PMID:Melatonin, its precursors, and synthesizing enzyme activities in the human ovary. 1033 62


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