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)

Over 30 MAK (maintenance of killer) genes are necessary for propagation of the killer toxin-encoding M1 satellite double-stranded RNA of the L-A virus. Sequence analysis revealed that MAK7 is RPL4A, one of the two genes encoding ribosomal protein L4 of the 60S subunit. We further found that mutants with mutations in 18 MAK genes (including mak1 [top1], mak7 [rpl4A], mak8 [rpl3], mak11, and mak16) had decreased free 60S subunits. Mutants with another three mak mutations had half-mer polysomes, indicative of poor association of 60S and 40S subunits. The rest of the mak mutants, including the mak3 (N-acetyltransferase) mutant, showed a normal profile. The free 60S subunits, L-A copy number, and the amount of L-A coat protein in the mak1, mak7, mak11, and mak16 mutants were raised to the normal level by the respective normal single-copy gene. Our data suggest that most mak mutations affect M1 propagation by their effects on the supply of proteins from the L-A virus and that the translation of the non-poly(A) L-A mRNA depends critically on the amount of free 60S ribosomal subunits, probably because 60S association with the 40S subunit waiting at the initiator AUG is facilitated by the 3' poly(A).
Mol Cell Biol 1995 May
PMID:Yeast virus propagation depends critically on free 60S ribosomal subunit concentration. 773 58

Bladder cancer is a common multifactorial disease and is known to be associated with occupational exposure to arylamines. Smoking is also a recognised contributory environmental cause. Occupational bladder cancer has previously been associated with slow acetylation by N-acetyltransferase (NAT) in humans in phenotyping studies, but more recently there has been some controversy regarding this issue. NAT is an enzymic activity involved in the metabolism of arylamines, and its 'classical' polymorphism is due to multiple alleles at the NAT2 locus. A genotyping approach has been used to investigate NAT2 type in a population of 189 Caucasian bladder cancer patients attending a clinic at a hospital in Birmingham. Genomic DNA was prepared from a blood sample donated by each of the patients and was used in the polymerase chain reaction with primers specific for all NAT2 alleles. Restriction fragment length polymorphism analysis was used to determine which alleles were present. Results have been compared to those from an age-matched non-malignant Caucasian control population (59 individuals) from the same region. Occupational and smoking history was determined by questionnaire and a significant excess of genotypic slow acetylators is found in those groups of bladder cancer patients exposed to arylamines as a result of their occupation or who are cigarette smokers. A higher proportion of slow acetylators is also found in those bladder cancer patients without identified exposure to arylamines when compared to the non-malignant controls. Slow NAT genotype is therefore a contributory risk factor in bladder carcinogenesis which acts through influencing individual response to environmental carcinogens.
Hum Mol Genet 1995 Feb
PMID:Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. 775 72

Hereditary peculiarities in individual responses to environmental chemicals are a common occurrence in human populations. Genetic variation in glutathione S-transferase, CYP1A2, N-acetyltransferase, and paraoxonase exemplify the relationship of metabolic variation to individual susceptibility to cancer and other toxicants of environmental origin. Heritable receptor protein variants, a subset of proteins of enormous pharmacogenetic potential that have not thus far been extensively explored from the pharmacogenetic standpoint, are also considered. Examples of interest that are considered include receptor variants associated with retinoic acid resistance in acute promyelocytic leukemia, with paradoxical responses to antiandrogens in prostate cancer, and with retinitis pigmentosa. Additional heritable protein variants of pharmacogenetic interest that result in antibiotic-induced deafness, glucocorticoid-remediable aldosteronism and hypertension, the long-QT syndrome, and beryllium-induced lung disease are also discussed. These traits demonstrate how knowledge of the molecular basis and mechanism of the variant response may contribute to its prevention in sensitive persons as well as to improved therapy for genetically conditioned disorders that arise from environmental chemicals.
Environ Mol Mutagen 1995
PMID:Influence of heredity on human sensitivity to environmental chemicals. 778 56

Since, in the Harderian gland (HG) of the hamster, the N-acetyltransferase (NAT), the specific enzyme involved in the biosynthesis of melatonin, exhibits a sexual dimorphism, in the present study, we investigated whether such a dimorphism is present also in the HG of the green frog Rana esculenta. In intact frogs, no significant differences emerged between males and females in the HG NAT activity under both cold (10 degrees C) and warm (22 degrees C) temperature conditions. In female frogs, the HG NAT activity was significantly decreased by both gonadectomy (P < 0.001) and warm temperature (P < 0.001), the two effects being not additive. In male animals, neither gonadectomy nor temperature alone significantly affected the activity of the NAT enzyme in the HG. However, gonadectomized male frogs exposed to warm temperature exhibited a significant drop in the HG NAT activity (P < 0.005). These data show that, in Rana esculenta, although no sexual dimorphism exists in the HG NAT activity, a sex difference is evident in the modulation of the enzyme activity by gonads and temperature, the female frogs being more sensitive to the impairing effects of both gonadectomy and higher temperature.
Comp Biochem Physiol B Biochem Mol Biol 1995 Jan
PMID:Effects of gonadectomy and temperature on the N-acetyltransferase activity in the harderian gland of the green frog Rana esculenta. 785 48

Acetyl CoA synthetase (ACS; EC 6.2.1.1) was studied in the mosquito, Aedes togoi, by a novel assay which coupled the acetyl-CoA generated to p-aminosalicylic acid (ASA). The N-acetylated product was determined by an HPLC-fluorimetric procedure. High ACS activity was observed in the newly-pupated pupae of both sexes and in the adult male mosquito whose activity was five times that of the female. Acetyl CoA-dependent N-acetyltransferase (NAT; EC 2.3.1.5) activity toward serotonin (5HT) was also studied using HPLC-electrochemical detection (HPLC-ECD). A progressive increase in the 5HT-NAT activity was observed from the fourth-instar larvae to the adult mosquito with the latter showing 6-fold higher activity in the head compared to the abdomen-thorax region. Kinetic studies on the pupal enzyme extracts showed that the apparent Km values for 5HT and acetyl CoA were 63 and 66 microM respectively. Tryptamine inhibited 5HT-NAT non-competitively with a Ki value of 8 microM.
Insect Biochem Mol Biol 1994 May
PMID:Acetyl CoA generation and N-acetylation of serotonin (5HT) in the mosquito, Aedes togoi. 791 72

Cytosolic activities in liver, stomach, small intestine, colon, lung, kidney, brain and spleen of hamster have been shown to be capable of N-acetylation, O-acetylation and N,O-acetyltransfer utilizing aromatic amine derivatives as substrates. These activities, which have been implicated in the metabolic activation and carcinogenicity of these compounds, were highest in the liver and small intestine. N-Acetylation could be demonstrated with either acetyl CoA or N-hydroxy-N-acetylaminoarenes serving as acetyl donors. Each of these tissues gave two immunoreactive bands (approximately 29 and 31 kDa) on Western blots using anti-rat AT monoclonal antibodies for detection. Single copies of two distinct acetyltransferase genes, designated AT1 and AT2, were detected in hamster DNA by Southern blot analysis using gene-specific hybridization probes for the 3' end of the AT coding regions. A third gene with > 80% sequence similarity to codons 118-158 of AT2 was also detected. Sequence analysis of the two AT genes showed that both had intronless, 0.87 kb coding regions. One was identical with the AT1 reported by Abu-Zeid et al. (Abu-Zeid,M., Nagata, K., Miyata,M., Ozawa,S., Fukuhara,M. and Yamazoe,Y., 1991, An arylamine acetyltransferase (AT-1) from Syrian golden hamster liver: cloning, complete nucleotide sequence, and expression in mammalian cells. Mol. Carcinogen., 4, 81-88). The second, AT2 (GenBank accession number L24912), coded for a 290 amino acid sequence that was 79% homologous with hamster AT1 and had a calculated molecular weight of 33.8 kDa, a theoretical pI of 5.96 and the three cysteines that have been conserved in all known vertebrate ATs at positions 44, 68 and 223. Northern blot hybridization using gene-specific AT probes detected mRNAs for both AT1 and AT2 in each of the eight tissues analyzed. Two AT1 transcripts, approximately 1.7 and 2.3 kb, were found in approximately equal ratios in all eight tissues. Three transcripts for AT2, approximately 1.9, 2.1 and 2.4 kb, were present in approximately equal ratios in the brain, small intestine, lung and colon. The liver, stomach, kidney and spleen had primarily the smaller two AT2 mRNAs. The overall abundance of AT mRNAs was highest in liver, small intestine and colon. The coding sequences of all AT mRNAs analyzed were identical to their corresponding genes, although the lengths of both the 5' and 3' untranslated transcript regions varied.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical and genetic analysis of two acetyltransferases from hamster tissues that can metabolize aromatic amine derivatives. 805 37

Human polymorphic N-acetyltransferase (NAT2) catalyzes the N-acetylation of arylamine drugs and carcinogens. Human acetylator phenotype is regulated at the NAT2 locus and has been associated with differential risk to certain drug toxicities or cancer. We examined arylamine substrate and acetyl coenzyme A cofactor affinities, and the N-acetyltransferase catalytic activities of the wild-type and 14 different mutant or chimeric human NAT2 alleles expressed in an Escherichia coli JM105 expression system. NAT2 alleles contained nucleic acid substitutions at positions 191(G-->A; Arg64-->Gln), 282(C-->T; silent), 341(T-->C; Ile114-->Thr), 481(C-->T; silent), 590(G-->A; Arg197-->Gln), 803(A-->G; Lys268-->Arg), 857(G-->A; Gly286-->Glu) and various combinations (282/590; 282/803; 282/857; 341/481; 341/803; 341/481/803; 481/803) of the 870 base pair NAT2 coding region. Expression of all 15 NAT2 alleles produced immunoreactive NAT2 protein with N-acetylation activity. NAT2 proteins encoded by alleles with nucleic acid substitutions at positions 191, 341, 590, 282/590, 341/481, 341/803, and 341/481/803 exhibited arylamine N-acetyltransferase maximum velocities significantly (P < 0.001) lower than the wildtype NAT2. Thus, nucleic acid substitutions at positions 191, 341, and 590 either alone or in combination with other silent or conservative amino acid substitutions were sufficient to result in NAT2 proteins with significant reductions in N-acetylation activities. The recombinant NAT2 proteins also showed relative differences in intrinsic stability following incubation at 37 degrees C and 50 degrees C. NAT2 encoded by alleles with nucleotide substitutions at positions 191 and 857 were particularly unstable relative to the wild type.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1994 May
PMID:Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes. 808 59

Melatonin is synthesized from serotonin by the enzymes serotonin N-acetyltransferase (SNAT) and hydroxyindole-O-methyl-transferase (HIOMT). We have previously reported that C57BL/6 mice do not have SNAT activity because of a mutation in an autosomal gene which is responsible for the absence of normal SNAT activity. In the present study, we have tried to map the loci of Nat-2 (the locus controlling SNAT activity) on chromosomes using a set of the BxH recombinant inbred strains which were derived from an initial cross between C3H/He with SNAT and C57BL/6 without the enzyme. Based on strain distribution patterns (SDPs), a close linkage on chromosome 11 was found between Nat-2, Es-3 (esterase-3), Glk (the locus controlling galactokinase activity) and Myla (myosin alkali light chains expressed in cardiac atrial muscle). The linkage between Nat-2 and Es-3 was confirmed by a conventional linkage test and the recombination frequency between these loci was estimated to be 16.1 +/- 3.6% (mean +/- S.E.M.).
Brain Res Mol Brain Res 1994 Feb
PMID:The locus controlling pineal serotonin N-acetyltransferase activity (Nat-2) is located on mouse chromosome 11. 817 Mar 56

1. Innervation of the mammalian pineal gland is mainly sympathetic. Pineal synthesis of melatonin and its levels in the circulation are thought to be under strict adrenergic control of serotonin N-acetyltransferase (NAT). In addition, several putative pineal neurotransmitters modulate melatonin synthesis and secretion. 2. In this review, we summarize what is currently known on the pineal cholinergic system. Cholinergic signaling in the rat pineal gland is suggested based on the localization of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), as well as muscarinic and nicotinic ACh binding sites in the gland. 3. A functional role of ACh may be regulation of pineal synaptic ribbon numbers and modulation of melatonin secretion, events possibly mediated by phosphoinositide (PI) hydrolysis and activation of protein kinase C via muscarinic ACh receptors (mAChRs). 4. We also present previously unpublished data obtained using primary cultures of rat pinealocytes in an attempt to get more direct information on the effects of cholinergic stimulus on pinealocyte melatonin secretion. These studies revealed that the cholinergic effects on melatonin release are restricted mainly to intact pineal glands since they were not readily detected in primary pinealocyte cultures.
Cell Mol Neurobiol 1995 Apr
PMID:Cholinergic signaling in the rat pineal gland. 859 Apr 50

Melatonin (N-acetyl-5-methoxytryptamine) was identified in the head and hemolymph of the silkworm, Bombyx mori, using reversed-phase high-performance liquid chromatography coupled with fluorometric detection and radioimmunoassay. In addition, evidence of arylakylamine (serotonin) N-acetyltransferase (NAT) a key enzyme controlling the synthesis of melatonin in vertebrates, was found in the head of the silkworm. Melatonin levels in the head and hemolymph and the NAT activity in the head were significantly higher during the dark period than during the light period of a 12-h light/12-h dark cycle. The day-night changes persisted in constant darkness but were suppressed by constant light. The results suggest that the synthesis and release of melatonin in the silkworm head occur as a circadian rhythm that is entrained by environmental light/dark cycles, as it is in the pineal gland of vertebrates. Melatonin in the silkworm head may function as a neurochemical mediator of photoperiodic control of developmental events such as molting, eclosion and diapause.
Mol Cell Endocrinol 1995 Nov 30
PMID:Melatonin and arylalkylamine N-acetyltransferase activity in the silkworm, Bombyx mori. 867 65


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