Processivity and Catalytic Mechanism of Aldosterone Synthase

醛固酮合酶的持续合成能力和催化机制

• 批准号: 10600520
• 负责人: Juan Jose Valentin-Goyco
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-05 至 2025-01-04
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600520
• 关键词: Adrenodoxin; Adverse effects; Affect; Aldosterone; Amino Acids; Analytical Chemistry; Aryl Hydrocarbon Hydroxylases; Binding; Biological Assay; CYP11B2 gene; Cardiovascular system; Cells; Cellular Assay; Cessation of life; Cholesterol; Clinical Research; Complex; Corticosterone; Cortodoxone; Coupled; Cytochrome P450; Deoxycorticosterone; Devices; Disease; Dissociation; Drug Design; Embryo; Enhancers; Enzyme Kinetics; Enzymes; Event; Ferredoxin-NADP Reductase; Functional disorder; Heart failure; Homeostasis; Hormones; Hydrocortisone; Hydroxylation; Hyperaldosteronism; Hypertension; Impairment; In Vitro; Incidence; Inner mitochondrial membrane; Isoenzymes; Kidney Failure; Kinetics; Knowledge; Length; Mass Spectrum Analysis; Mineralocorticoid Receptor; Mineralocorticoids; Mitochondria; Monitor; Mutation; Myocardial Infarction; Operative Surgical Procedures; Oxidases; Oxidation-Reduction; Patients; Phospholipids; Physiologic pulse; Plague; Point Mutation; Production; Property; Publishing; Rare Diseases; Rattus; Reaction; Renin-Angiotensin System; Research; Role; Secondary Hypertension; Sodium; Spironolactone; Steroid biosynthesis; Stroke; Structure; Tachycardia; Testing; Therapeutic; Water; antagonist; blood pressure control; blood pressure regulation; crosslink; drug development; experimental study; heart cell; high risk; inhibitor; nanodisk; oxidation; protein expression; reconstitution; side effect; standard of care; steroidogenic acute regulatory protein; therapy design

Abstract The finely tuned production of aldosterone controls blood pressure by regulating water and sodium retention. The overproduction of aldosterone, however, leads to primary aldosteronism, the major form of secondary hypertension. This mineralocorticoid hormone is produced by cytochrome P450 11B2 (CYP11B2), also known as aldosterone synthase. While lowering aldosterone levels through inhibition of CYP11B2 has been established as a potential therapeutic approach, a few challenges are associated with this tactic. For example, CYP11B2 shares a 93% sequence identity with the cortisol-producing P450 11B1 (CYP11B1). Despite the similarities between CYP11B1 and CYP11B2, there exist key functional and structural differences. Overall, this research aims to understand how these subtle differences contribute to the catalytic function of these enzymes in order to aid drug development.

摘要