Human Steroid Metabolism by Cytochrome P450

细胞色素 P450 的人类类固醇代谢

基本信息

批准号：
9021669
负责人：
STEPHEN G. SLIGAR
金额：
$ 39.92万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9021669
关键词：
Active Sites Address Adrenal Glands Affect Androgens Applications Grants Aromatase Attention Behavior Binding Biochemical Biophysical Process CYP17A1 gene CYP19A1 gene Carbon Catalysis Cell Nucleus Chemicals Chemistry Cholesterol Cytochrome P450 Cytochromes Cytochromes b5 Dioxygen Drug Metabolic Detoxication Drug Targeting Electron Nuclear Double Resonance Electron Spin Resonance Spectroscopy Electronics Electrons Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Estrogens Family Female of child bearing age Genes Goals Gonadal Steroid Hormones Grant Health Heme Hemeproteins Hormones Human Hydroxylation Hypertension Individual Intervention Investigation Isoenzymes Isotopes Ketones Laboratories Life Link Lyase Magnetism Malignant neoplasm of prostate Marketing Membrane Metalloproteins Methodology Mineralocorticoids Mixed Function Oxygenases Molecular Mutagenesis Mutation Nature Nomenclature Non-Insulin-Dependent Diabetes Mellitus Ovary Oxidation-Reduction Oxygen Pathway interactions Patients Pharmacologic Substance Physiology Play Polycystic Ovary Syndrome Positioning Attribute Postmenopause Process Production Proteins Protons Raman Spectrum Analysis Reaction Research Research Personnel Role Scheme Signaling Molecule Solvents Spectrum Analysis Steroid biosynthesis System Techniques Technology Testis Therapeutic Trees United States National Institutes of Health Variant Woman Work Xenobiotics base biophysical techniques cancer risk cardiovascular disorder risk cold temperature design electronic structure enzyme substrate hormone biosynthesis hormone deficiency human disease inhibitor/antagonist innovation insight malignant breast neoplasm men mutant nanodisk public health relevance pyridine nucleotide response steroid hormone steroid hormone biosynthesis steroid metabolism

项目摘要

DESCRIPTION (provided by applicant): The cytochrome P450s represent one of the most prolific families of metalloproteins, with over 18,000 identified genes across the spectrum of life forms, being represented in all of the major branches in the evolutionary "tree-of-life". The function of these heme proteins can be classified into two major divisions. Operating in a catabolic role, the enzymes can functionalize un-activated chemical positions on a substrate, initiating degradation to provide fundamental foodstuffs or as a means of xenobiotic detoxification. Alternately, the same chemical transformations are used in anabolic pathways that play critical roles in the production of cellular signaling molecules such as the steroid hormones. In humans, steroid hormones are generated by P450 action on cholesterol in the ovaries, adrenals and testes. Due to the critical role of cytochrome P450 in human health, these enzyme systems have occupied NIH supported investigators for many decades. Despite this intense research effort, important mechanistic details remain unresolved. The major focus of our proposed work involves the cytochrome P450s (CYPs) operating in human steroid biosynthesis. Each enzyme under investigation sits at the critical branch point in the pathway that generates an important class of hormones. As such, these enzymes are important targets for pharmaceutical intervention in human disease. For example, P450 CYP17A1 is needed for the formation of both androgens and estrogens; mutations are associated with sex hormone deficiencies and human hypertension due to excess mineralocorticoid levels and patient variants are linked to an increase in prostate cancer risk. Inhibitors of this enzyme have recently reached the market as treatment for prostate cancer in men and androgen excess in women. CYP19A1 inhibitors are now the first line therapy in the treatment of estrogen-responsive breast cancer in post-menopausal women. Decreased activity of CYP19A1 has been suggested to play a role in polycystic ovary syndrome, which affects 10% to 20% of all women of childbearing age and leads to an increased risk of cardiovascular disease and Type II diabetes. Documenting the existence, electronic structure, stability and reactivity of P450 heme-oxygen intermediates is a prerequisite for developing therapeutics that can selectively modulate these steroidal biosynthetic processes in the treatment of human disease. Through the application of a broad array of biochemical and biophysical methods, applied in an integrated problem oriented research plan, we seek important new insights into the detailed catalytic mechanisms of the cytochromes CYP17A1 and CYP19A1.

描述（由申请人提供）：细胞色素 P450 代表最多产的金属蛋白家族之一，在整个生命周期中拥有超过 18,000 个已识别基因形式，体现在进化“生命之树”的所有主要分支中。这些血红素蛋白的功能可分为两大类。这些酶在分解代谢作用中发挥作用，可以使底物上未激活的化学位置功能化，引发降解以提供基本食品或作为异生物质解毒的手段。或者，相同的化学转化用于合成代谢途径，在类固醇激素等细胞信号分子的产生中发挥关键作用。在人类中，类固醇激素是由 P450 对卵巢、肾上腺和睾丸中胆固醇的作用产生的。由于细胞色素 P450 在人类健康中的关键作用，这些酶系统几十年来一直占据 NIH 支持的研究人员的位置。尽管进行了大量的研究工作，但重要的机制细节仍未解决。我们提出的工作的主要焦点涉及在人类类固醇生物合成中发挥作用的细胞色素 P450 (CYP)。所研究的每种酶都位于产生一类重要激素的途径中的关键分支点。因此，这些酶是人类疾病药物干预的重要靶点。例如，雄激素和雌激素的形成都需要P450 CYP17A1；由于盐皮质激素水平过高，突变与性激素缺乏和人类高血压有关，而患者变异与前列腺癌风险增加有关。最近发现了这种酶的抑制剂作为治疗男性前列腺癌和女性雄激素过多症的药物进入市场。 CYP19A1 抑制剂现在是治疗绝经后女性雌激素反应性乳腺癌的一线疗法。 CYP19A1 活性降低被认为与多囊卵巢综合征有关，该综合征影响所有育龄妇女的 10% 至 20%，并导致心血管疾病和 II 型糖尿病的风险增加。记录 P450 血红素-氧中间体的存在、电子结构、稳定性和反应性是开发能够选择性调节这些类固醇生物合成过程来治疗人类疾病的疗法的先决条件。通过应用广泛的生物化学和生物物理方法，并应用于以问题为导向的综合研究计划，我们寻求对细胞色素 CYP17A1 和 CYP19A1 详细催化机制的重要新见解。