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21.
We previously discovered that the budding yeast Saccharomyces cerevisiae Sigma1278b has the MPR1 gene that confers resistance to the proline analogue azetidine-2-carboxylate (AZC). The MPR1-encoded protein (Mpr1) is an N-acetyltransferase that detoxifies AZC and is a novel member of the GCN5-related N-acetyltransferase (GNAT) superfamily. Mpr1 can reduce intracellular oxidation levels and protect yeast cells from oxidative stress, heat shock, freezing, or ethanol treatment. Here, we analyzed the amino acid residues in Mpr1 involved in substrate binding and catalysis by site-directed mutagenesis. The mutated genes were expressed in Escherichia coli, and the recombinant Strep-tagged fusion proteins were analyzed in terms of AZC resistance and acetyltransferase activity. The replacement of Arg145, which is conserved in the GNAT superfamily, by Ala, Asp, Glu, Gly, or Trp led to a growth defect of transformants grown in the presence of AZC. Kinetic studies demonstrated that these mutations caused a large reduction in the affinity for AZC and acetyl-CoA, suggesting that Arg145 interacts with both substrates. Among seven conserved Tyr residues, one of which may be a catalytic residue in the GNAT superfamily, Tyr166Ala- showed no detectable activity and Tyr166Phe-Mpr1, a remarkable decrease of the k(cat)/K(m) value. This result suggests that Tyr166 is critical for the catalysis. 相似文献
22.
大鼠松果体Clock基因和芳烷脘N-乙酰基转移酶基因的昼夜节律性表达及光照影响 总被引:1,自引:1,他引:0
探讨12h光照、12h黑暗交替(12h-light:12h-dark cycle,LD)及持续黑暗(constant darkness,DD)光制下松果体Clock基因和芳烷脘N-乙酰基转移酶基因(arylalkylamine N-acetyltransferase gene,NAT)是否存在昼夜节律性表达及其光反应变化。Sprague-Dawley大鼠在LD和DD光制下分别被饲养4周(n=36)和8周(n=36)后,在一昼夜内每隔4h采集一组松果体组织(n=6),提取总RNA,用竞争性定量RT-PCR测定不同昼夜时点样品中Clock及NAT基因的mRNA相对表达量,通过余弦法和ClockLab软件获取节律参数,并经振幅检验是否存在昼夜节律。结果如下:(1)在DD或LD光制下,松果体Clock和NAT基因mRNA的表达均呈现夜高昼低的节律性振荡(P<0.05)。(2)与DD光制下比较,LD光制下松果体Clock和NAT基因的表达振幅及峰值相的mRNA水平均降低(P<0.05)。(3)在DD或LD光制下,Clock和NAT基因之间显示相似的节律性表达(P>0.05)。结果表明,Clock和NAT基因在松果体中存在同步的内源性昼夜节律表达,光照作用可使其表达下调。 相似文献
23.
Christelle Thibault Jacky Falcón Shelley S. Greenhouse Christopher A. Lowery † William A. Gern Jean-Pierre Collin 《Journal of neurochemistry》1993,61(1):332-339
Abstract: The light/dark cycle influences the rhythmic production of melatonin by the trout pineal organ through a modulation of the serotonin N -acetyltransferase (NAT) activity. In static organ culture, cyclic AMP (cAMP) levels (in darkness) and NAT activity (in darkness or light) were stimulated in the presence of forskolin, isobutylmethylxanthine, or theophylline. Analogues of cAMP, but not of cyclic GMP, induced an increase in NAT activity. Light, applied after dark adaptation, inhibited NAT activity. This inhibitory effect was partially prevented in the presence of drugs stimulating cAMP accumulation. In addition, cAMP accumulation and NAT activity increase, induced by forskolin, were temperature dependent. Finally, melatonin release, determined in superfused organs under normal conditions of illumination, was stimulated during the light period of a light/dark cycle by adding an analogue of cAMP or a phosphodiesterase inhibitor. However, no further increase in melatonin release was observed during the dark phase of this cycle in the presence of the drugs. This report shows for the first time that cAMP is a candidate as intracellular second messenger participating in the control of NAT activity and melatonin production by light and temperature. 相似文献
24.
Cultivation of mammalian pineal cells: Retention of organization and function in tissue culture 总被引:1,自引:0,他引:1
Mark A. Nathanson Sue Binkley S. Robert Hilfer 《In vitro cellular & developmental biology. Plant》1977,13(12):843-848
Summary By means of a newly developed method of cultivating pineal tissue in vitro, the types of cells which comprise rat pineal glands
have been identified. Previous in vitro studies have involved short-term culture more suitably called “organ culture” and
provide no means of assessing the contribution of a putative “pineal” cell versus any other cell type found in the cultures.
Short-term outgrowths of minced rat pineal glands provided a reproducible and easily dissociated source of pineal-derived
cells. In monolayer culture these cells continued to have pineal enzyme activities which were sensitive to pineal-activating
substances, and the cells aggregated to mimic the lobular organization of intact glands. Two types of aggregates were found,
each composed of a single morphological cell type. In addition to the transient appearance of skeletal muscle straps, connective
tissue and neural/glial tissue was consistently found. The cell types are discussed in relation to their in vivo counter-parts.
Supported by NSF Grant GB-43215 to S.B. and NSF Grant GB-20919 to S.R.H. 相似文献
25.
Jae-Cheon Shin Hoe-Yune Jung Amaravadhi Harikishore Oh-Deog Kwon Ho Sup Yoon Kyong-Tai Kim Bo-Hwa Choi 《Biochemical and biophysical research communications》2013
Melatonin is secreted during the hours of darkness and is thought to influence the circadian and seasonal timing of a variety of physiological processes. AANAT, which is expressed in the pineal gland, retina, and various other tissues, catalyzes the conversion of serotonin to N-acetylserotonin and is the rate-limiting enzyme in the biosynthetic pathway of melatonin. The compounds that modulate the activity of AANAT can be used to treat patients with circadian rhythm disorders that are associated with specific circadian rhythm alterations, such as shift work disorder. In the present study, we screened modulators of AANAT activity from the water extracts of medicinal plants. Among the 267 tested medicinal plant extracts, Myricae Cortex (Myrica rubra), Perillae Herba (Perilla sikokiana), and Eriobotryae Folium (Eriobotrya japonica) showed potent inhibition of AANAT activity. Myricetin (5,7,3′,4′,5′-pentahydroxyflavonol), a main component of the Myricae Cortex, strongly inhibited the activity of AANAT and probably block the access to the substrate by docking to the catalytic residues that are important for AANAT activity. Myricetin significantly decreased the nocturnal serum melatonin levels in rats. In addition, the locomotor activity of rats treated with myricetin decreased during the nighttime and slightly increased throughout the day. These results suggest that myricetin could be used as a therapy to increase nighttime alertness by changing the circadian rhythm of serum melatonin and locomotor activity. 相似文献
26.
27.
Koji Watanabe Teruhiko Beppu Kei Arima 《Bioscience, biotechnology, and biochemistry》2013,77(12):2113-2116
The “citrate transport-enhancing factor” obtained from Aerobacter cloacae did stimulate uptake of radioactive citrate by Escherichia coli, having an intrinsic barrier against citrate permeation. In order to prove function of the factor in the cells of Aerobacter, citrate transport-negative mutants of A. cloacae were isolated. These mutants were found to be lacking in the factor. Addition of the factor to these mutants resulted in stimulation of uptake of citrate. These results evidenced that the factor played an essential role in the citrate transport system of A. cloacae. 相似文献
28.
《Bioscience, biotechnology, and biochemistry》2013,77(2):582-586
The budding yeast Saccharomyces cerevisiae Σ1278b contains the MPR1 gene encoding N-acetyltransferase, which detoxifies the L-proline analog L-azetidine-2-carboxylate (AZC). Of 131 yeasts tested, AZC acetyltransferase activity was detected in 17 strains of 41 strains that showed AZC resistance. Degenerate-PCR analysis revealed that two strains, i.e., Candida saitoana AKU4533 and Wickerhamia fluorescens AKU4722, contained a DNA fragment highly homologous to MPR1. This indicates that AZC acetyltransferases are widely distributed in yeasts. 相似文献
29.
Human serotonin N-acetyltransferase (hAANAT), included in the melatonin biosynthesis, plays a pivotal role in the regulation of the biological clock and the daily rhythm. In this research, a reliable model of hAANAT was first constructed by the homology modelling method. Then the inhibition mode of two representative rhodanine-based inhibitors was explored by molecular dynamics simulations and energy analyses. The results show that the inhibitor class could share a similar inhibition mechanism in which the carboxyl moiety is positioned in the Ac-CoA binding region while the other end spans the serotonin binding pocket. The interaction between the inhibitor's carboxyl and the enzyme seems to be more important according to the decomposition of binding free energy. Based on the proposed inhibition mode, the inhibitor's improvement was carried out to obtain a more potent compound. The newly designed inhibitor, with the larger binding free energy, exhibits the stronger interaction with the related residues of the enzyme by the added chemical groups. This work will shed light on the inhibition mechanism of the rhodanine-based inhibitors and promote the development of a new drug targeting hAANAT. 相似文献
30.
Isaac M. Westwood Sanjib Bhakta Angela J. Russell Elizabeth Fullam Akane Kawamura Matthew C. Anderton Edith Sim Andrew W. Mulvaney Richard J. Vickers Stephen G. Davies Veemal Bhowruth Gurdyal S. Besra Ajit Lalvani 《蛋白质与细胞》2010,1(1):82
New anti-tubercular drugs and drug targets are urgently needed to reduce the time for treatment and also to identify agents that will be effective against Mycobacterium tuberculosis persisting intracellularly. Mycobacteria have a unique cell wall. Deletion of the gene for arylamine N-acetyltransferase (NAT) decreases mycobacterial cell wall lipids, particularly the distinctive mycolates, and also increases antibiotic susceptibility and killing within macrophage of Mycobacterium bovis BCG. The nat gene and its associated gene cluster are almost identical in sequence in M. bovis BCG and M. tuberculosis. The gene cluster is essential for intracellular survival of mycobacteria. We have therefore used pure NAT protein for high-throughput screening to identify several classes of small molecules that inhibit NAT activity. Here, we characterize one class of such molecules— triazoles—in relation to its effects on the target enzyme and on both M. bovis BCG and M. tuberculosis. The most potent triazole mimics the effects of deletion of the nat gene on growth, lipid disruption and intracellular survival. We also present the structure-activity relationship between NAT inhibition and effects on mycobacterial growth, and use ligand-protein analysis to give further insight into the structure-activity relationships. We conclude that screening a chemical library with NAT protein yields compounds that have high potential as anti-tubercular agents and that the inhibitors will allow further exploration of the biochemical pathway in which NAT is involved. 相似文献