Human Steroid Metabolism by Cytochrome P450

细胞色素 P450 的人类类固醇代谢

• 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
• 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

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(申请人提供)：细胞色素P450代表最多产的金属蛋白家族之一，在生命的光谱中有超过18,000个已识别的基因 在进化的“生命之树”的所有主要分支中都有表现。这些血红素蛋白的功能可以分为两个主要部分。在分解代谢的作用下，这些酶可以使底物上未激活的化学位置发挥功能，启动降解以提供基本的食物或作为异物解毒的一种手段。或者，同样的化学转化也用于合成代谢途径，这些途径在细胞信号分子的产生中发挥关键作用，如类固醇激素。在人类中，类固醇激素是通过P450作用于卵巢、肾上腺和睾丸中的胆固醇而产生的。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着NIH支持的研究人员。尽管进行了密集的研究工作，但重要的机制细节仍未解决。我们建议的工作的主要焦点是细胞色素P450(Cyps)在人类类固醇生物合成中的作用。研究中的每种酶都位于产生一类重要荷尔蒙的途径的关键分支点。因此，这些酶是药物干预人类疾病的重要靶点。例如，雄激素和雌激素的形成都需要P450细胞色素P17A1；突变与性激素缺乏和人类由于过量的盐皮质激素水平导致的高血压有关，患者的变异与前列腺癌风险的增加有关。这种酶的抑制剂最近 作为治疗男性前列腺癌和女性雄激素过剩的药物进入市场。CYP19A1抑制剂现在是治疗绝经后女性雌激素敏感型乳腺癌的一线药物。CYP19A1活性降低被认为在多囊卵巢综合征中起作用，该综合征影响10%至20%的育龄妇女，并导致心血管疾病和II型糖尿病风险增加。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在人类疾病治疗中选择性调节这些类固醇生物合成过程的治疗药物的先决条件。通过应用广泛的生化和生物物理方法，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的详细催化机理的重要新见解。