Mechanistic insights into copper metabolism

铜代谢的机制见解

• 批准号: 8372769
• 负责人: JAEKWON LEE
• 金额: $ 28.15万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372769
• 关键词: Adolescent; Anabolism; Anemia; Antioxidants; Biochemical; Biochemical Process; Biological; Biological Process; Cardiovascular Diseases; Cardiovascular system; Cations; Ceruloplasmin; Coiled-Coil Domain; Combat Disorders; Copper; Data; Defect; Degenerative Disorder; Diet; Disease; Dopamine-beta-monooxygenase; Electron Transport; Employee Strikes; Enzymes; Eukaryota; Generations; Genes; Genetic; Growth; Growth and Development function; Health; Hereditary Disease; Human; In Vitro; Intestines; Ions; Iron; Iron deficiency anemia; Knockout Mice; Lead; Life; Liver; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Messenger RNA; Metabolic Diseases; Metabolism; Metalloproteins; Metals; Minerals; Modeling; Molecular; Monophenol Monooxygenase; Mouse Strains; Mus; Neurons; Nutritional; Organism; Outcome; Pathway interactions; Physiological; Placenta; Potassium; Process; Protein-Lysine 6-Oxidase; Protons; Regulation; Research; Respiratory Chain; Role; Saccharomycetales; Structure; Superoxide Dismutase; Up-Regulation; Yeasts; absorption; angiogenesis; antiporter; cofactor; combat; fetal; human disease; innovation; insight; iron metabolism; knockout gene; metal metabolism; method development; mouse model; neurotransmission; novel; nutrition; nutrition related genetics; research study; therapeutic target; uptake

DESCRIPTION (provided by applicant): Copper is a vital metal ion for sustaining life. Dietary and genetic disorders in copper metabolism and copper-implicated degenerative diseases provide striking evidence that optimal copper metabolism is a critical biological process. The mechanism underlying copper uptake and distribution has been an active research question; however, there are significant gaps in our understanding of the biosynthesis of cuproproteins. In particular, it is not known how copper-containing enzymes, such as ferroxidases, superoxide dismutase 3, lysyl oxidase, tyrosinase, and dopamine beta-hydroxylase, assemble copper cofactor(s) at the secretory pathway. This is an important problem because functional defects of these enzymes lead to serious disorders, including iron-deficiency anemia, cardiovascular disorders, cancer, and neuronal diseases. A successful attempt for identification of new genes involved in copper utilization revealed that an intracellular potassium-proton antiporter conserved in eukaryotes is a critical molecular factor for copper metabolism. Several lines of study indicate that potassium transport into the lumen of the cellular secretory pathway facilitates copper incorporation into ferroxidases. This exciting research progress has opened new avenues by which the mechanisms underlying the biosynthesis of functional ferroxidases and possibly other metalloproteins are better understood. Multi-disciplinary approaches using purified ferroxidases, mammalian cells, and mouse models will be employed to pursue the following specific aims: (1) Characterize the roles for potassium in copper and iron metabolism using a mouse strain where a secretory pathway potassium transporter is deleted; (2) Gain mechanistic insights into potassium-facilitated copper metallation of ferroxidases; (3) Define the modes of action and metal-responsive regulation of the potassium transporter; and (4) Determine the effects of potassium in the diet on copper and iron absorption and distribution. This proposed research is significant and innovative in that it (1) characterizes a new molecular factor involved in the metabolism of vital metal ions, copper, iron, and potassium; (2) discovers a novel functional role for potassium, a major intracellular cation; (3) gains better insights into the interactions among nutritional metal ions; and (4) would lead to the development of methods that facilitate absorption and distribution of copper, iron, and potassium. The outcomes of this project should have broad impacts on gaining mechanistic insights into metal metabolism, biosynthesis of metalloproteins, and combating various metal ion-related disorders, such as defects in normal growth and development, anemia, and metabolic and degenerative diseases. PUBLIC HEALTH RELEVANCE: Copper is a mineral vital for sustaining life, yet it is toxic when misplaced or accumulated in excess. Copper levels in the diet and molecular factors involved in copper metabolism have been proposed as a therapeutic target. This project aims to gain mechanistic insights into copper absorption and utilization in the body to enhance our ability to combat various metal-related human diseases, such as anemia, metabolic and degenerative diseases, and cancer.

描述（由申请人提供）：铜是维持生命的重要金属离子。铜代谢中的饮食和遗传疾病以及与铜有关的退行性疾病提供了惊人的证据，表明最佳铜代谢是一个关键的生物过程。铜吸收和分布的机制一直是一个活跃的研究问题；然而，我们对铜蛋白生物合成的理解还存在重大差距。特别是，目前尚不清楚含铜酶（例如亚铁氧化酶、超氧化物歧化酶 3、赖氨酰氧化酶、酪氨酸酶和多巴胺 β-羟化酶）如何在分泌途径中组装铜辅因子。这是一个重要的问题，因为这些酶的功能缺陷会导致严重的疾病，包括缺铁性贫血、心血管疾病、癌症和神经元疾病。鉴定参与铜利用的新基因的成功尝试表明，真核生物中保守的细胞内钾-质子逆向转运蛋白是铜代谢的关键分子因子。多项研究表明，钾转运到细胞分泌途径的内腔有助于铜掺入亚铁氧化酶。这一令人兴奋的研究进展开辟了新的途径，通过这些途径可以更好地理解功能性亚铁氧化酶和可能的其他金属蛋白的生物合成机制。将采用使用纯化的亚铁氧化酶、哺乳动物细胞和小鼠模型的多学科方法来实现以下具体目标：（1）使用删除了分泌途径钾转运蛋白的小鼠品系来表征钾在铜和铁代谢中的作用； (2) 了解钾促进亚铁氧化酶铜金属化的机制； (3) 明确钾转运蛋白的作用模式和金属响应调节； (4)确定饮食中钾对铜和铁吸收和分配的影响。这项拟议的研究具有重要意义和创新性，因为它（1）表征了参与重要金属离子（铜、铁和钾）代谢的新分子因子； (2) 发现钾（一种主要的细胞内阳离子）的新功能作用； (3) 更深入地了解 营养金属离子之间的相互作用； (4) 将导致促进铜、铁和钾吸收和分配的方法的发展。该项目的成果应该对获得金属代谢、金属蛋白生物合成的机制见解以及对抗各种金属离子相关疾病（例如正常生长和发育缺陷、贫血以及代谢和退行性疾病）产生广泛影响。 公共健康相关性：铜是一种对维持生命至关重要的矿物质，但如果放错地方或过量积累，就会产生毒性。饮食中的铜水平和参与铜代谢的分子因素已被提议作为治疗目标。该项目旨在深入了解铜在体内的吸收和利用的机制，以增强我们对抗各种与金属相关的人类疾病的能力，例如贫血、代谢和退行性疾病以及癌症。