Processivity and Catalytic Mechanism of Aldosterone Synthase

醛固酮合酶的持续合成能力和催化机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的通过调节水和钠保留率，醛固酮的细胞产生可控制血压。然而，醛固酮的过量产生导致原代醛固酮主义，这是次生的主要形式高血压。这种矿物皮质激素是由细胞色素P450 11B2（CYP11B2）产生的，也已知作为醛固酮合酶。虽然已经建立了通过抑制CYP11B2降低醛固酮水平作为一种潜在的治疗方法，这种策略有一些挑战。例如，CYP11B2 与生产皮质醇的P450 11B1（CYP11B1）共享93％的序列身份。尽管有相似之处在CYP11B1和CYP11B2之间，存在关键的功能和结构差异。总体而言，这项研究旨在了解这些微妙的差异如何促进这些酶的催化功能，以便援助药物开发。