Mechanisms and Functions of Human Sulfotransferases

人类磺基转移酶的机制和功能

• 批准号: 7939462
• 负责人: Guangping Chen
• 金额: $ 13.37万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939462
• 关键词: Acetaminophen; Active Sites; Adverse drug effect; Amino Acids; Biological Assay; Biological Process; Bypass; Caco-2 Cells; Carcinogens; Catalysis; Computer Simulation; Cytosol; Data; Dopamine; Drug Interactions; Drug Metabolic Detoxication; Enzymes; Escherichia coli; Estrogens; Etiology; Goals; Health; Hormones; Human; Human Activities; Hydroxyl Radical; Inorganic Sulfates; Intestines; Investigation; Isotopes; Kinetics; Knowledge; Lead; Literature; Liver; Measures; Metabolic Biotransformation; Methods; Modification; Oxidation-Reduction; Oxidative Regulation; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenols; Physiological; Play; Protein Isoforms; Rattus; Reaction; Regulation; Research; Research Personnel; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Role; Scheme; Site-Directed Mutagenesis; Structure; Sulfhydryl Compounds; Toxic effect; Unspecified or Sulfate Ion Sulfates; Western Blotting; Xenobiotics; base; cancer prevention; chemical kinetics; clinical effect; dehydroepiandrosterone; drug development; drug metabolism; enzyme mechanism; hormone metabolism; hormone regulation; in vivo; inhibitor/antagonist; interest; monoamine-sulfating phenol sulfotransferase; programs; sulfation; sulfotransferase

Phase II drug metabolizing enzymes sulfotransferases (SULTs) catalyzed sulfation is important in the regulation of different hormones and the detoxification of drugs and other xenobiotics. Sulfation also leads to bioactivation of procarcinogens leading to toxic effect. The long-term goal of this research project is to understand human SULT biological functions and to investigate their relevance to human health under physiological and pathological conditions. Specific aims in this proposal are as follows: 1. To Investigate Mechanisms of Catalysis, Substrate Inhibition, and Product Inhibition/Activation of Human SULTs. The proposed bypass ordered mechanism and related alternative mechanisms will be investigated using kinetic analysis, isotope exchange, sulfated active site amino acid residue identification, and site-directed mutagenesis. The information will have important implications for the prediction of biotransformation pathways. 2. To Investigate the Effect of Sulfated Drugs on Human SULT Catalytic Activities. The inhibition and activation effect of clinically important drug sulfates on catalytic activities of human SULTs will be investigated. E. coli expressed and purified human SULTs; human intestinal cytosols; and human Hep G2 and Caco-2 cells will be used for these investigations. The effect of clinical drugs on human SULT activities may interfere SULT normal biological functions in hormone regulation and xenobiotic detoxification. 3. To Define Oxidative Regulation Mechanisms of Human SULT1E1. Oxidative regulation of human SULT1E1 in Hep G2 and Caco-2 cells and redox thiol regulation mechanisms of purified human SULT1E1 will be investigated using enzyme assay, Western blot, RT-PCR, amino acid modification, site-directed mutagenesis, kinetic analysis, crystal structure analysis, and computer modeling methods. Knowledge on oxidative regulation of certain human SULT is important in understanding the ability of SULT functioning under physiological and pathological conditions. This proposal studies human SULTs. These studies will be significant in understanding SULT biological functions including hormone regulation, drug metabolism, xenobiotic detoxification and procarcinogen bioactivation. The knowledge will be important in understanding drug side effect, drug-drug interaction, drug development, and the potential roles SULTs play in cancer prevention and causation.

II相药物代谢酶磺基转移酶（SULT）催化的硫酸化在药物代谢中是重要的。 调节不同的激素和解毒药物和其他外源性物质。硫酸化也导致 导致毒性作用的前致癌物的生物活化。该研究项目的长期目标是 了解人类SULT的生物学功能，并研究它们与人类健康的相关性， 生理和病理条件。本提案的具体目标如下：1.探讨 人SULT的催化、底物抑制和产物抑制/激活机制。的 提出的旁路有序机制和相关的替代机制将使用动力学研究 分析、同位素交换、硫酸化活性位点氨基酸残基鉴定和定点 诱变这些信息将对生物转化的预测具有重要意义 途径。2.研究硫酸化药物对人SULT催化活性的影响。的抑制 临床上重要的药物硫酸盐对人SULT催化活性的活化作用将是 研究了E.大肠杆菌表达和纯化的人SULT;人肠胞质溶胶;和人Hep G2 Caco-2细胞将用于这些研究。临床药物对人SULT活性的影响 可能干扰SULT在激素调节和异生物质解毒方面的正常生物学功能。3.到 定义人SULT 1 E1的氧化调节机制。人SULT 1 E1在人乳腺癌中的氧化调节作用 Hep G2和Caco-2细胞以及纯化的人SULT 1 E1的氧化还原巯基调节机制将在本研究中进行。 采用酶法、Western blot、RT-PCR、氨基酸修饰、定点 诱变、动力学分析、晶体结构分析和计算机建模方法。知识 某些人SULT的氧化调节对于理解SULT功能的能力是重要的 在生理和病理条件下。 该提案研究人类SULT。这些研究对于理解SULT具有重要意义 生物功能包括激素调节、药物代谢、异生物质解毒和 前致癌物生物活化这些知识对于了解药物副作用、药物-药物非常重要 相互作用，药物开发，以及SULT在癌症预防和病因中的潜在作用。

项目成果

Effect of folic acid on methotrexate induction of sulfotransferases in rats.

• DOI: 10.2174/187231208784040997
• 发表时间: 2008-04-01
• 期刊: Drug metabolism letters
• 作者: Dutta, Sangita Maiti;Maiti, Smarajit;Chen, Guangping
• 通讯作者: Chen, Guangping

Estrogen-related receptor ERRα-mediated downregulation of human hydroxysteroid sulfotransferase (SULT2A1) in Hep G2 cells.

• DOI: 10.1016/j.cbi.2011.04.002
• 发表时间: 2011-07-15
• 期刊: CHEMICO-BIOLOGICAL INTERACTIONS
• 影响因子: 5.1
• 作者: Huang, Chaoqun;Zhou, Tianyan;Chen, Yue;Sun, Teng;Zhang, Shufen;Chen, Guangping
• 通讯作者: Chen, Guangping

Methamphetamine regulation of sulfotransferase 1A1 and 2A1 expression in rat brain sections.

• DOI: 10.1016/j.neuro.2012.09.010
• 发表时间: 2013-01
• 期刊: NEUROTOXICOLOGY
• 影响因子: 3.4
• 作者: Zhou, Tianyan;Huang, Chaoqun;Chen, Yue;Xu, Jiaojiao;Shanbhag, Preeti Devaraya;Chen, Guangping
• 通讯作者: Chen, Guangping