Cofactor-Dependent Amine Oxidations

辅因子依赖性胺氧化

• 批准号: 7417522
• 负责人: IRENE LEE
• 金额: $ 18.88万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417522
• 关键词: 6-hydroxydopa quinone; Accounting; Active Sites; Adhesions; Aldehydes; Alkylation; Amines; Arthritis; Atherosclerosis; Behavior Therapy; Binding; Binding Sites; Biogenesis; Biogenic Amines; Biological Assay; Biological Process; Blood Vessels; Bos taurus; Cardiovascular Diseases; Cations; Cattle; Cell division; Chemicals; Chemistry; Class; Collaborations; Complex; Complications of Diabetes Mellitus; Copper; Data; Databases; Deposition; Detection; Development; Development, Other; Diabetes Mellitus; Diamines; Digestion; Disease; Enzymes; Family; Fibrosis; Fingerprint; Flavins; Future; Genetic; Grant; Growth; Human; Immune System Diseases; Individual; Inflammation; Inflammatory; Investigation; Kidney; Kinetics; Life; Ligands; Localized; Mammals; Mass Spectrum Analysis; Mediating; Membrane; Metabolism; Methods; Modality; Modeling; Modification; Molecular; Monoamine Oxidase; Multiple Sclerosis; Nature; Numbers; Organism; Oxidases; Peptides; Pharmacologic Substance; Physiological; Plants; Plasma; Play; Polyamines; Process; Prodrugs; Protein-Lysine 6-Oxidase; Proteins; Public Health; Quinones; Range; Reaction; Research; Research Personnel; Roentgen Rays; Role; Semicarbazides; Sorting - Cell Movement; Spectrometry; Staging; Structure; Study models; System; Time; Tissues; Tyrosine; Work; amine oxidase; analog; base; benzoquinone; biological adaptation to stress; carbamylhydrazine; cofactor; concept; cytotoxic; design; diamino oxhydrase; drug development; human AOC3 protein; immunoregulation; inhibitor/antagonist; interest; molecular modeling; novel; novel strategies; oxidation; polyamine oxidase; preference; programs; propargylamine; protein structure; stable isotope; therapeutic target; tool; transamination

DESCRIPTION (provided by applicant): The copper-containing amine oxidases (CAOs) comprise a ubiquitous class of enzymes in all living organisms. In plants and mammals, CAOs play important roles in metabolizing biogenic amines involved in growth, cell division, differentiation, and the stress response, where metabolism in some cases has cytotoxic consequences. All CAOs utilize a quinone cofactor derived postranslationally from an active-site tyrosine residue to mediate a transaminative conversion of primary amines to aldehydes. Studies using cofactor models in the past grant periods have inspired the discovery of new types of enzyme-activated mechanisms of inhibition. These studies, along with development of other traditional inactivation strategies, have resulted in highly promising degrees of inhibitor selectivity. The selectivity being achieved is discriminating not only between the flavin- and quinone-dependent enzymes, but also among a range of CAOs that have different substrate-structure preferences. Since the time of the last renewal, the genetic basis of the two general classes of human CAOs has been revealed: (i) the trihydroxyphenylalanine quinone (TPQ)-dependent class AOC 1 (the human kidney diamine oxidase), AOC 2, and AOC 3, the latter coincidental with the human vascular adhesion protein-1 (HVAP-1), and (ii) four lysyl oxidase-like (LOXL) proteins in addition to classical LOX. In the next grant period, there will be increased focus on refining inhibitor selectivity for the human enzymes, particularly the kidney/placental diamine oxidase, the soluble and tissue-bound semicarbazide- sensitive monoamine oxidases, and lysyl oxidase. The new aims include the development of sensitive fluorometric assays for detecting and localizing mammalian CAOs, an exploration of new inhibitor selectivity and prodrug constructs, the use of x-ray crystallographic information (through collaboration) for refinement of substrate and inhibitor binding models constructed by molecular modeling, and the use of spectroscopy and mass spectrometry to identify the structural basis of irreversible inhibitor action. Studies on the nature of biogenesis of the (TPQ) cofactor will additionally be completed. RELEVANCE OF THIS RESEARCH TO PUBLIC HEALTH The copper amine oxidases have become important pharmaceutical targets on account of the emerging recognition of their key physiological roles in aspects of inflammation, immune modulation, fibrosis in arthritis and atherosclerosis, and in late-stage complications of diabetes and cardiovascular disease. It is thus important to understand the functioning of these enzymes, both from a mechanistic view and in terms of the structural basis of substrate recognition and the action of inhibitors that can serve a leads in eventual drug development.

描述（由申请人提供）：含铜的胺氧化酶（CAO）包括所有生物体中普遍存在的酶类。在植物和哺乳动物中，CAO在代谢生长，细胞分裂，分化和应激反应中起着重要作用，在某些情况下，代谢具有细胞毒性后果。所有CAO都利用从活性位点酪氨酸残基衍生后衍生的喹酮辅因子来介导伯胺向醛的透射转化。过去使用辅因子模型的研究启发了发现新型酶激活机制的抑制作用。这些研究以及其他传统灭活策略的发展导致了高度有希望的抑制剂选择性。所实现的选择性不仅歧视黄素和喹酮依赖性酶，而且在具有不同底物结构偏好的一系列CAO中区分。自上次更新以来，已经揭示了两个人类CAO的两个一般类别的遗传基础：（i）三羟基苯基丙氨酸醌（TPQ） - 依赖性AOC 1（人类肾脏氧化氧化物氧化酶），AOC 2，AOC 2和AOC 3，AOC 3，AC的四个与人类的敏感蛋白质（II）（HUS）（II）（II）（HUS）（HER）（II）（II）（II）（HER）（HUS）。除经典LOX外，氧化酶样（LOXL）蛋白质。在下一个赠款期间，将增加关注人类酶的抑制剂选择性，尤其是肾脏/胎盘二氨酸氧化酶，可溶性和组织结合的半北极氮敏感性单胺氧化酶和脂基氧化酶。新目的包括开发用于检测和定位哺乳动物CAOS的敏感荧光测定法，对新抑制剂选择性和前药结构的探索，使用X射线晶体学信息（通过协作）来细化底物和抑制剂通过分子模型构建的模型，并使用spectroment of Spectrospopy和spectrement instrormenty instrormenty sectrement instromprys instrorment instrorment instrymenty senter in IRMENTINT构建的模型。 （TPQ）辅因子的生物发生性质的研究还将完成。 这项研究与公共卫生的相关性 铜胺氧化酶已成为重要的药物靶标，因为他们在炎症，免疫调节，关节炎和动脉粥样硬化中的纤维化以及糖尿病后期并发症和心血管疾病的后期并发症中对其在炎症，免疫调节，纤维化的方面的关键作用而成为重要的药物靶标。因此，重要的是要从机械的角度和底物识别的结构基础以及可以在最终药物开发中提供铅的抑制剂的作用来理解这些酶的功能。