Reductive Dehalogenation in Mammals by Iodotyrosine Deiodinase

描述（由申请人提供）：通过自然和人类活动，有机卤化物在环境中无处不在。大多数生物体通过酶介导的水解、消除或氧化来解毒和降解这些化合物。某些微生物也能够促进还原脱卤，尽管这主要限于无氧代谢。哺乳动物为这一普遍观察提供了一个令人着迷的例外。必需激素甲状腺素（3-[4-[4-羟基-3,5-二碘苯氧基]-3,5-二碘苯基]丙氨酸）在多种组织中被含硒半胱氨酸的酶还原脱碘。令人惊讶的是，甲状腺中采用了一种完全不同的策略来脱碘 3-碘-和 3,5-二碘酪氨酸。在这种情况下，一种独特的黄素蛋白，碘酪氨酸脱碘酶，负责减少碘化氨基酸，以回收碘化物以在甲状腺素生物合成中重新使用。现在建议进行研究以确定这种哺乳动物脱碘酶前所未有的化学性质和机制。这种酶的新特性将扩展已知的黄素依赖性催化作用和生物学中可用于加工卤代化合物的途径。我们对催化的描述将集中于 IYD 中 C-I 键的还原以及伴随的还原黄素的氧化。光谱和产物分析将用于区分一个和两个电子过程，并首次揭示 IYD 处理的全系列基材。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底物和黄素辅因子的激活。同时，黄素化学的底物依赖性控制将通过其氧化还原性质的变化来检测。这些研究也将通过持续的 IYD 晶体学研究而得到丰富。最后，通过表达和表征“生命之树”中与哺乳动物距离越来越远的生物体的同源基因，将检查这种不寻常的脱碘作用的起源。公共健康相关性：碘化物是我们饮食的必要组成部分，用于在甲状腺中产生一种含碘激素，这是调节我们整个身体的代谢率所必需的。我们将研究从激素生物合成过程中形成的副产物中回收碘化物的过程，这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。

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.