Mechanisms of Aromatic Amino Acid Hydroxylases

芳香氨基酸羟化酶的机制

• 批准号: 7178536
• 负责人: Jorge Alexander Pavon
• 金额: $ 2.8万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7178536
• 关键词: 5-Hydroxytryptophan; Adrenal Glands; Alcoholism; Amino Acids; Anabolism; Aromatic Amino Acids; Brain; Carbon; Catalysis; Catecholamines; Chemicals; Complement; Deuterium; Disease; Enzymes; Family; Fellowship; Goals; Hydroxylation; Individual; Inherited; Iron; Isotopes; Kinetics; Liver; Measures; Mechanics; Mental Depression; Mixed Function Oxygenases; Mossbauer Spectroscopy; Mutation; Names; Neurotransmitters; Oryctolagus cuniculus; Oxygen; Parkinson Disease; Phenylalanine; Phenylalanine Hydroxylase; Proteins; Publishing; Rate; Reaction; Reporting; Research; Serotonin; Temperature; Tryptophan; Tryptophan 5-monooxygenase; Tyrosine; Tyrosine 3-Monooxygenase; Violence; Work; insight; mutant; neurotransmitter biosynthesis; quantum; research study; tetrahydropterin

DESCRIPTION (provided by applicant): Phenylalanine hydroxylase (PheH), tyrosine hydroxylase (TyrH) and tryptophan hydroxylase (TrpH) make up the family of tetrahydropterin dependent hydroxylases. These enzymes catalyze the iron-dependent aromatic hydroxylation of their respective substrates. PheH in the liver catalyzes the hydroxylation of phenylalanine to tyrosine. Mutations in PheH result in the inherited disease phenylketonuria. TyrH in the brain and adrenal gland catalyzes the hydroxylation of tyrosine to DOPA, the first step in the biosynthesis of the catecholamine neurotransmitters. Mutations in TyrH have been associated with Parkinson's disease. TrpH in the brain catalyzes the hydroxylation of tryptophan to 5-hydroxytryptophan, the first step in the biosynthesis of the neurotransmitter serotonin. Low levels of serotonin have been associated with depression, violence, and alcoholism. The chemical mechanism of TyrH has been studied extensively, and this proposal will expand on the previous work. The mechanism of oxygen activation by PheH and TrpH will be studied using 18O kinetic isotope effects. The reactivity of the hydroxylating intermediate in all three enzymes will be studied by measuring deuterium isotope effects on benzylic and aromatic hydroxylation. Rapid quench EPR and Mossbauer spectroscopy will be used for spectroscopic characterization of the proposed hydroxylating intermediate.

描述（由申请人提供）：苯丙氨酸羟化酶（PheH）、酪氨酸羟化酶（TyrH）和色氨酸羟化酶（TrpH）组成四氢蝶呤依赖性羟化酶家族。这些酶催化其各自底物的铁依赖性芳族羟基化。肝脏中的PheH催化苯丙氨酸羟基化为酪氨酸。PheH突变导致遗传性疾病苯丙酮尿症。脑和肾上腺中的TyrH催化酪氨酸羟基化为多巴，这是儿茶酚胺神经递质生物合成的第一步。TyrH突变与帕金森病有关。大脑中的TrpH催化色氨酸羟基化为5-羟基色氨酸，这是神经递质血清素生物合成的第一步。血清素水平低与抑郁、暴力和酗酒有关。TyrH的化学机制已被广泛研究，这一建议将扩展以前的工作。将使用18 O动力学同位素效应研究PheH和TrpH的氧活化机制。在所有三种酶的羟基化中间体的反应性将通过测量氘同位素对苄基和芳香族羟基化的影响进行研究。快速淬灭EPR和穆斯堡尔谱将用于拟定的羟基化中间体的光谱表征。