Reductive Dehalogenation in Mammals by Iodotyrosine Deiodinase

碘酪氨酸脱碘酶在哺乳动物中的还原脱卤作用

• 批准号: 7871329
• 负责人: STEVEN E ROKITA
• 金额: $ 31.22万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871329
• 关键词: Active Sites; Alanine; Amino Acids; Anabolism; Bacteria; Binding; Biological; Biology; Catalysis; Chemistry; Congenital Abnormality; Crystallization; Data; Dependence; Diet; Distant; Electrons; Environment; Enzymes; Evolution; Family; Flavins; Flavoproteins; Funding; Health; Homeostasis; Homologous Gene; Hormones; Human; Human Activities; Hydrogen Bonding; Hydrolysis; Hypothyroidism; Investigation; Iodide Peroxidase; Iodides; Iodine; Life; Mammals; Measures; Mediating; Metabolic; Metabolism; Microbe; Mono-S; NADH oxidase; NADP; Organism; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Personal Satisfaction; Positioning Attribute; Process; Property; Proteins; Pyrimidine; Pyrimidines; Reaction; Recruitment Activity; Recycling; Role; Selenocysteine; Structure; Substrate Interaction; Substrate Specificity; Testing; Thyroid Gland; Thyroxine; Time; Tissues; Trees; analog; base; carboxyl radical; cofactor; dehalogenation; deiodination; design; dietary requirement; fascinate; functional group; gaze; hormone biosynthesis; mutant; novel; oxidation; progenitor; public health relevance; research study

DESCRIPTION (provided by applicant): Organohalides are ubiquitous in the environment through natural and human activities. Most organisms detoxify and degrade these compounds by enzyme-mediated hydrolysis, elimination or oxidation. Certain microbes are also capable of promoting reductive dehalogenation, although this is primarily limited to anaerobic metabolism. Mammals provide a fascinating exception to this general observation. The essential hormone, thyroxine (3-[4-[4-hydroxy-3,5-diiodophenoxy]-3,5-diiodophenyl]alanine), is reductively deiodinated in a variety of tissues by selenocysteine-containing enzymes. Quite surprisingly, an entirely different strategy has been recruited in the thyroid to deiodinate 3-iodo- and 3,5-diiodotyrosine. In this case, a unique flavoprotein, iodotyrosine deiodinase, is responsible for reducing the iodinated amino acids in order to salvage iodide for reuse in thyroxine biosynthesis. Investigations are now proposed to identify the unprecedented chemistry and mechanism of this mammalian deiodinase. The novel properties of this enzyme will extend the known repertoire of flavin-dependent catalysis and pathways available in biology to process halogenated compounds. Our description of catalysis will focus on the reduction of the C-I bond and concomitant oxidation of the reduced flavin in IYD. Spectroscopic and product analyses will be used to differentiate between one and two electron processes and, for the first time, reveal the full range of substrates that are processed by IYD. Activation of both the substrate and flavin cofactor will be described by independently measuring recognition and catalytic properties of enzyme mutants and substrate analogues. Concurrently, substrate-dependent control of the flavin chemistry will be detected by changes in its redox properties. These investigations will be enriched as well by continuing crystallographic studies of IYD. Finally, the origins of this unusual deiodination will be examined by expressing and characterizing homologous genes from organisms that are successively more distant from mammals in the "Tree of Life." PUBLIC HEALTH RELEVANCE: Iodide is a necessary component of our diet and used to produce an iodide-containing hormone in the thyroid that is required for regulating the metabolic rate of our entire body. The process by which we recycle iodide from byproducts formed during hormone biosynthesis will be investigated and is crucial to understand the basis for certain congenital defects leading to hypothyroidism.

描述（由申请人提供）：通过自然和人类活动在环境中无处不在。大多数生物通过酶介导的水解，消除或氧化来解毒并降解这些化合物。某些微生物也能够促进还原性去盐化，尽管这主要限于厌氧代谢。哺乳动物为这一一般观察提供了一个有趣的例外。必需的激素，甲状腺素（3- [4- [4-羟基-3,5-二二苯氧化氧基] -3,5-二苯基]丙氨酸），通过硒环固结型酶还原在多种组织中的脱位。令人惊讶的是，在甲状腺中招募了完全不同的策略，以除去3-碘和3,5-二碘酪氨酸。在这种情况下，独特的黄蛋蛋白碘酪氨酸脱碘酶负责减少碘化氨基酸，以挽救碘化物以在甲状腺素生物合成中再利用。现在，提出了调查来确定该哺乳动物脱碘酶的前所未有的化学和机制。该酶的新特性将扩展已知的黄素依赖性催化和生物学中可用途径的曲目，以处理卤化化合物。我们对催化的描述将集中于减少C-I键和IYD中减少黄素的氧化。光谱和产品分析将用于区分一个和两个电子过程，并首次揭示由IYD处理的全部底物。底物和黄素辅因子的激活将通过独立测量酶突变体和底物类似物的识别和催化特性来描述。同时，将通过其氧化还原特性的变化检测到黄素化学的底物依赖性控制。通过继续对IYD进行晶体学研究，这些研究也将丰富。最后，将通过表达和表征来自“生命之树”中与哺乳动物更遥远的有机体的同源基因来研究这种异常去牙的起源。公共卫生相关性：碘化物是我们饮食的必要组成部分，用于在甲状腺中产生含碘的激素，这是调节整个身体代谢率所必需的。我们将研究从激素生物合成期间形成的副产物中回收碘化物的过程，将研究，对于了解导致甲状腺功能减退症的某些先天性缺陷的基础至关重要。