Exploring the role of N-acetyltransferases in diseases:a focus on N-acetyltransferase 9 in neurodegeneration

Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivotal to basic cellular processes.Close to 80%-90%of proteins are acetylated during translation,which is an irreversible process that affects protein structure,function,life,and localization.In this review,we have discussed the various N-acetyltransferases present in humans,their function,and how they might play a role in diseases.Furthermore,we have focused on N-acetyltransferase 9 and its role in microtubule stability.We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases.We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.

Polymorphism of N-acetyltransferase 2 (NAT2) Gene Polymorphism in Shanghai population: Occupational and Non-occupational Bladder Cancer Patient Groups

Objective Arylamine N-acetyltransferases (NATs) are involved in the detoxification of aromatic amines and hydrazine. In order to explore the possible association of NAT2 polymorphism with bladder cancer risk in benzidine exposed or non-exposed Chinese individuals, healthy subjects, subjects with bladder cancer of a former benzidine exposed cohort in Shanghai dyestuff industry and a group of bladder cancer patients without known occupational exposure to aromatic amines were genotyped for NAT2 gene polymorphism. Methods NAT2 genotyping was performed with a set of RFLP procedures at seven major polymorphic loci of gene coding area: G191A, C282T, T341C, C481T, G590A, A803G and G857A. Results The wild allele NAT2 *4 was the most prevalent allele (59%) in healthy individuals. The alleles NAT2*6A and NAT2*7B were also frequently observed (21% and 17%, respectively). In contrast to Caucasians, the percentage of slow acetylators was lower (12% in Chinese vs. 58% in Caucasians, P<0.001). No relevant differences were observed for homogenous rapid, heterogeneous rapid/slow and homogeneous slow acetylation genotypes between the healthy subjects and both groups of bladder cancer patients. Conclusion The present work did not support the association of slow acetylating genotypes of NAT2 gene with elevated risk of bladder cancer in Chinese whereas it was documented as an important genetically determined risk factor in Caucasians. Different mechanisms might play a role in individual susceptibility to bladder cancer related with aromatic amine exposure in various races or ethnic groups.

N-Acetyltransferase 2 genetic polymorphisms and risk of colorectal cancer

AIM:To investigate the possible association between meat intake,cigarette smoking and N-acetyltransferase 2 (NAT2) genetic polymorphisms on colorectal cancer (CRC) risk.METHODS:Patients with CRC were matched for gender and age to healthy controls.Meat intake and cigarette smoking were assessed using a specific frequency questionnaire.DNA was extracted from peripheral blood and the genotypes of the polymorphism were assessed by polymerase chain reaction-restriction fragment length polymorphism.Five NAT2 alleles were studied (WT,M1,M2,M3 and M4) using specific digestion enzymes.RESULTS:A total of 147 patients with colorectal cancer (76 women and 90 men with colon cancer) and 212 controls were studied.The mean age of the two groups was 62 years.More than half the subjects (59.8% in the case group and 51.9% in the control group) were NAT2 slow acetylators.The odds ratio for colorectal cancer was 1.38 (95% CI:0.90-2.12) in slow acetylators.Although the number of women was small (n=76 in the case group),the cancer risk was found to be lower in intermediate (W/Mx) acetylators [odds ratio (OR):0.55,95% confidence interval (95% CI):0.29-1.02].This difference was not observed in men (OR:0.56,95% CI:0.16-2.00).Among NAT2 fast acetylators (W/W or W/Mx),meat consumption more than 3 times a week increased the risk of colorectal cancer (OR:2.05,95% CI:1.01-4.16).In contrast,cigarette smoking increased the risk of CRC among slow acetylators (OR:1.97,95% CI:1.02-3.79).CONCLUSION:The risk of CRC was higher among fast acetylators who reported a higher meat intake.Slow NAT2 acetylation was associated with an increased risk of CRC.

Are polymorphisms of N-acetyltransferase genes susceptible to primary liver cancer in Luoyang, China?

AIM: To identify whether the polymorphisms of the Nacetyltransferase (NAT) genes are susceptible to primary liver cancer (PLC) in Luoyang, a PLC low-incidence area of China.METHODS: The NAT1 and NAT2 genotypes of 96 PLC cases and 173 controls were determined by PCR-RFLP.Both interaction between NAT1 or NAT2 and environmental risk factors were analyzed based on case control study.RESULTS: Compared to the control group, the frequencies of alleles NAT1*3, NAT1*4, NAT1*10, NAT1*14B and alleles NAT2*4, NAT2*6, NAT2*7 in PLC group showed no statistically significant difference (x2 = 2.61 and 4.16,respectively, both P＞0.05). The frequencies of NAT1 genotypes NAT1*3/*3, NAT1*3/*4, NAT1*3/*10,NAT1*3/*14B, NAT1*4/*4, NAT1*4/*10, NAT1*4/*14B,NAT1*10/*10, NAT1*10/*14B, and NAT2 genotypes NAT2*4/*4, NAT2*4/*6, NAT2*4/*7, NAT2*6/*6,NAT2*6/*7 and NAT2*7/*7 also had no statistically significant difference between the two groups (x2 = 11.86 and 2.94respectively both, P＞0.05). Neither the frequencies of rapid and slow NAT1 acetylators nor the frequencies of rapid and slow NAT2 acetylators were significantly different between the two groups (x2 = 0.598 and 0.44,respectively, both P＞0.05). The interaction betweenNAT1*10 and occupational exposures was found significant with an odds ratio of 3.40 (x2 = 8.42, P = 0.004,OR 95%CI:1.03-11.22). But no interaction was found between NAT2 and any environmental risk factors.CONCLUSION: The polymorphisms of NAT1 and NAT2are not susceptible to PLC in Luoyang. Allele NAT1*10interacts with occupational exposures.

Crohn's disease in Japanese is associated with a SNP-haplotype of N-acetyltransferase 2 gene

AIM： To investigate the frequency and distribution of /V-acetyltransferase 2 （NAT2） and uridine 5＇-diphosphate （UDP）-glucuronosyltransferase 1A7 （UGT1A7） genes in patients with ulcerative colitis （UC） and Crohn＇s disease （CD）. METHODS： Frequencies and distributions of IVAT2 and UGT1A7SNPs as well as their haplotypes were investigated in 95 patients with UC, 60 patients with CD, and 200 gender-matched, unrelated, healthy, control volunteers by PCR-restriction fragment length polymorphism （RFLP）, PCR-denaturing high-performance liquid chromatography （DHPLC）, and direct DNA sequencing. RESULTS： Multiple logistic regression analysis revealed that the frequency of haplotype, NAT2＊7B, significantly increased in CD patients, compared to that in controls （P= 0.0130, OR = 2.802, 95%CI = 1.243-6.316）. However, there was no association between NAT2 haplotypes and UC, or between any UGT1A7haplotypes and inflammatory bowel disease （IBD）. CONCLUSION： It is likely that the NAT2 gene is one ofthe determinants for CD in Japanese. Alternatively, a new CD determinant may exist in the 8p22 region, where NAT2 is located.

Inflammatory cytokines suppress arylamine N-acetyltransferase 1 in cholangiocarcinoma cells

AIM： To evaluate the effect of inflammatory cytokines on arylamine N-acetyltransferase 1 （NAT1）, which is a phase-U enzyme involved in the biotransformation of aromatic and heterocyclic amines found in food, drugs and the environment. METHODS： Human cholangiocarcinoma KKU-100 cells were treated with a mixture of proinflammatory cytokines （interferon-7, interleukin-l and tumor necrosis factor-m） for 48 h, and the effect on NAT1 activity was assessed by high performance liquid chromatography, while NAT1 expression was determined by reverse-transcription polymerase chain reaction. The oxidative stress on the cells was examined by the formation of nitric oxide, superoxide anion and glutathione （GSH） levels. The cells were also treated with S-nitroso-glutathione （GSNO）, a nitric oxide donor, to see if the responses were similar to those obtained with the inflammatory cytokines. RESULTS： Cytokines suppressed NAT1 activity, reducing the Vmax without affecting the Am. Cytokines also had a significant impact on the induction of nitric oxide production and in reducing the redox ratios of glutathione （GSH） and GSH disulfide. Treatment with GSNO for 2-48 h reduced NAT1 activity without affecting the GSH ratio. Moreover, inflammatory cytokines and GSNO suppressed NAT1 mRNA expression. CONCLUSION： These findings indicate an association between inflammation and suppression of NAT1, which perhaps contributes to chemical-mediated toxicity and carcinogenesis,

Density Functional Theory Study on the Histidine-assisted Mechanism of Arylamine N-Acetyltransferase Acetylation

Arylamine N-acetyltransferases （NATs, EC 2.3.1.5） catalyze the N-acetylation of primary arylamines, and play a key role in the biotransformation and metabolism of drugs, carcinogens, etc. In this paper, three possible reaction mechanisms are investigated and the results indicate that if the acetyl group directly transfers from the donor to the acceptor, the high activation energies will make it hard to obtain the target products. When using histidine to mediate the acetylation process, these energies will drop in the 15-45 kJ/mol range. If the histidine residue is protonated, the corresponding energies will be decreased by about 35-87 kJ/mol. The calculations predict an enzymatic acetylation mechanism that undergoes a thiolate-imidazolium pair, which agrees with the experimental results very well.

N-acetyltransferase 2: Slow, intermediate or fast? A booming question of the molecular epidemiology in cancer research

Throughout history, humanity has referred to reactions occurring with food, plants and, recently, medicines or drugs. The increase in pulmonary tuberculosis cases and the availability of treatment showed that genetic human differences can interfere in the capacity to metabolize drugs. There are remarkable genetic polymorphisms of N-acetyltransferase 2 (NAT2) activity that have been associated with different levels of susceptibility to developing many kinds of cancers. This review considers the field as an open window for the application of molecular epidemiology tools that led to the development of pharmacogenomics. We cover historical data and the most recent knowledge about NAT2 genetic polymorphisms and its distribution in different populations, which is an important concept being incorporated in epidemiological studies of cancer risk. We present up to date information about these studies, including meta-analysis based on the NAT2 distribution in different types of cancer. A critical broad at advances in NAT2 research, high-lighting recent studies related to NAT2 alleles in cancer susceptibility. Although there are multifactorial aspects involved in cancer risk, the variability in NAT2 allelic frequency can be related to carcinogenesis through alterations in the metabolic rate after exposure to carcinogens.

Night-time Rise in Rat Pineal N-Acetyltransferase due to Carbaryl Administration Is Reduced by Propranolol Treatment

The purpose of the present study was to examine the effects of administration of sublethal doses of carbaryl on nighttime rat pineal melatonin synthesis in the presence and absence of propranolol, a β-adrenergic receptor antagonist. Two groups of adult male albino rats were administered orally N-methyl-l-naphthylcarbamate (carbaryl) (8. 33mg/kg BW daily in corn oil) for six successive days; another two groups received corn oil only.On the last day of carbaryl treatment, half of the animals received an intraperitoneal injection of propranolol (20 mg/kg body weight, one hour before lights off). The other two groups were given a saline injection. Four hours after darkness onset, pineal N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) activities as well as pineal concentrations of 5-hydroxytryptophan (5HTP), serotonin (5HT),5-hydroxyindole acetic acid (5HIAA) and pineal and serum melatonin levels were measured. Nocturnal NAT activity was increased due to carbaryl administration but the pesticide was ineffective in stimulating NAT activity in rats treated with propranolol.Pineal 5HT was decreased due to carbaryl administration but 5HTP and 5HIAA levels were unaffected. Pineal and serum melatonin levels were decreased due to propranolol treatment. The results indicate that carbaryl may influence pineal NAT activity by a mechanism that involves β-adrenergic neural transmission.

面向业务构件的黑白盒混合的领域框架的设计与实现

在 OO领域框架与构件化领域框架的基础上 ,兼顾两者优点 ,利用业务构件技术 ,并借助于 CCM构件模型标准 ,提出了面向业务构件的黑白盒混合的领域框架设计思想 .设计了管理调度中心 ,依据领域规则 ,将业务构件库的构件、热点知识库的热点子系统粘贴起来 ,实现构件在框架上的即插即用 .重点设计了领域规则库及管理调度中心 ,并结合订单处理系统的实例 ,说明了面向业务构件的黑白盒混合的领域框架的具体实现 .

时频域零炮检距地震道拟合技术在高分辨率资料处理中的应用

在地震资料处理中 ,水平叠加的作用是压制随机噪声和消除多次波 ,但伴随的缺点是降低了地震资料分辨率 ,且模糊了振幅特征。为了提高地震资料分辨率和振幅保真 ,许多学者提出了多种拟合方法代替水平叠加。然而 ,这些拟合方法也有其自身的弱点 ,如在提高信噪比方面的能力较弱等。本文从应用角度出发 ,讨论了时频域零炮检距拟合方法的特点及在海上高分辨率地震资料处理中应用叠前消除各种线性干扰和多次波的必要性。实际资料处理结果表明 ,只要在叠前做好去噪工作 ,应用时频域零炮检距地震道拟合方法代替水平叠加有利于改善地震资料的分辨率和振幅保真。

混合自激力模型在桥梁风致抖振时域分析中的应用

提出一种可应用于大跨度桥梁抖振时域分析的混合自激力模型 .其中直接自激力采用Y .K .Lin自激力模型 ,仅采用一个线性滤波器来模拟非定常自激气动力 ,耦合自激力由准定常气动力模型经完全泰勒展开获得 .当风洞试验不能给出完整气动导数试验数据特别是耦合气动导数时 ,采用本文中所提出的混合自激力模型是一个很好的选择 .最后以崖门大桥为例 ,采用本文方法进行计算 。

一个新的人类乙酰转移酶基因hNATL的克隆与表达谱研究

从小鼠cDNA序列入手,依据同源分析的电子克隆方法得到一个包含N末端乙酰转移酶结构域的人类新基因hNATL(Human NAT Like)。hNATL的cDNA长1803bp,编码区621bp,Genbank 登陆号AY632082。hNATL编码的蛋白长206个氨基酸残基,包含有N乙酰转移酶结构域。hNATL 基因定位于人染色体17q25．2区,包括6个外显子和5个内含子。基因表达汇编分析结果显示, hNATL在人脑和生殖腺中高表达。Northern杂交显示,在成年小鼠中hNATL在心脏,脾脏和卵巢中出现表达。整体原位杂交的结果显示,hNATL特异表达于E7．5和E8．5的小鼠胚胎脑部和HH10期鸡胚胎的头部。上述结果提示,hNATL对胚胎期脑的发育和成体中重要器官行使正常功能发挥十分重要的作用。

试析煤炭环保产业的发展机制和优先领域

分析了环保产业成为当代朝阳产业的时代原因 ,指出市场经济不但有利于环保事业 ,也有利于环保产业的发展。煤炭工业发展环保产业时机适合 ,必须结合经济体制改革 ,以市场为导向 ,以产业结构和产品结构调整为契机。

N-乙酰基转移酶2(NAT2)基因多态性与肺癌易感性关系的Meta分析

目的探讨分析NAT2多态性与肺癌易感性的关系。方法在中英文数据库中按照统一的检索策略,全面检索至2013年8月1日有关NAT2多态性与肺癌风险关系的观察性研究相关文献。按照纳入与排除标准选择文献、提取资料和评价质量进行Meta分析。结果共纳入23篇文献,分别来自15个国家,累计肺癌病例4 425人,对照病例6 663人。结论本Meta分析结果表明:NAT2基因多态性与肺癌易感性之间未见显著关联。

一种基于多agent的合作智能教学系统模型方法

提出了采用agent方法和基于WEB超媒体组件集成的合作智能教学系统模型方法.系统模型结构主要有学生、教师、专家、多agent智能教学系统以及确保它们进行交互的接口模块.系统模型能有效实现基于超媒体的交互式的动态的远程教学.

角域内亚纯函数的值分布

应用角域内的Nevanlinna理论,研究了角域内亚纯函数的增长级和取值之间的关系,证明了如下结果:假设Ω(α,β)和Ω(α′,β′)是两个角域,满足α<α′<β′<β,f(z)在Ω(α,β)上亚纯,如果limr→∞logSα′β′(r,f)logr≡ρ,那么limr→∞logn(r,Ω(α,β),f=a)logr≥ρ对任意a∈C∞成立,至多除去两个例外.

Relationship between metabolic enzyme polymorphism and colorectal cancer

AIM: To clarify the influence of genetic polymorphisms on colorectal cancer. METHODS: The results of 42 related studies from 1990 to 2001 were analyzed by meta-analysis. Mantel-Haenzel fixed-effect model or Dersimonian-Laird random-effect model and ReviewManager 4.1 statistical program were applied in processing the data. RESULTS: Meta analysis of these studies showed that GSTT1 deletion (pooled OR= 1.42), N-acetyltransferase 2 (NAT2)-rapid acetylator phenotype and genotye (pooled OR = 1.08) and NAT2-rapid acetylator phenotype (pooled OR = 1.15) had a significantly increased risk for colorectal cancer (P<0.05), other genotypes like GSTM1 deletion, GSTP1 1le105Val, NAT1*10, NAT2-rapid acetylator genotype CYP1A1 Lle462Val, CYP1A1 MspI*C, MTHFR C677T and MTR A2759G had no significant relationship with colorectal cancer (P>0.05). CONCLUSION: Risks for colorectal cancer are significantly associated with the genetic polymorphisms of GSTT1 deletion, NAT2-rapid acetylator phenotype and genotye and NAT2-rapid acetylator phenotype.

A pilot study of the modulation of sirtuins on arylamine N-acetyltransferase 1 and 2 enzymatic activity

Arylamine N-acetyltransferase(NAT; E.C. 2.3.1.5) enzymes are responsible for the biotransformation of several arylamine and hydrazine drugs by acetylation. In this process, the acetyl group transferred to the acceptor substrate produces NAT deacetylation and, in consequence, it is susceptible of degradation. Sirtuins are protein deacetylases, dependent on nicotine adenine dinucleotide,which perform post-translational modifications on cytosolic proteins. To explore possible sirtuin participation in the enzymatic activity of arylamine NATs, the expression levels of NAT1, NAT2,SIRT1 and SIRT6 in peripheral blood mononuclear cells(PBMC) from healthy subjects were examined by flow cytometry and Western blot. The in situ activity of the sirtuins on NAT enzymatic activity was analyzed by HPLC, in the presence or absence of an agonist(resveratrol) and inhibitor(nicotinamide) of sirtuins. We detected a higher percentage of positive cells for NAT2 in comparison with NAT1, and higher numbers of SIRT1t cells compared to SIRT6 in lymphocytes. In situ NAT2 activity in the presence of NAM inhibitors was higher than in the presence of its substrate, but not in the presence ofresveratrol. In contrast, the activity of NAT1 was not affected by sirtuins. These results showed that NAT2 activity might be modified by sirtuins.

Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars

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.