Probing Extradiol Dioxygenase Mechanism in NAD+ Biosynthesis by Viewing Reaction Cycle Intermediates
Probing Extradiol Dioxygenase Mechanism in NAD+ Biosynthesis by Viewing Reaction Cycle Intermediates
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通过观察反应循环中间体探讨 NAD 生物合成中的外二醇双加氧酶机制
DOI：
10.1002/9781119951438.eibc2813
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Liu, Aimin
中科院分区：
文献类型：
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作者：
Davis, Ian;Liu, Aimin
单核非血红素铁酶以其在初级和次级代谢中介导有机分子氧化的能力而闻名。一类这样的酶是催化芳族分子的氧化裂解的二醇双加氧酶。它们有两种，intradiol和extradiol，分别对称或不对称地添加分子氧。3-羟基邻氨基苯甲酸3，4-双加氧酶（HAO）是在与分解色氨酸2-硝基苯甲酸相关的代谢途径中发现的III型二醇外双加氧酶。HAO的产物是不稳定的，并且或者非酶促环化为喹啉酸（QUIN）（内源性神经毒素和NAD（P）生物合成的通用前体），或者酶促加工，最终在柠檬酸循环中完全氧化为CO2。QUIN的升高与神经退行性疾病相关，使得HAO具有生物医学相关性。本文综述了HAO生物化学的历史和现状。最近的研究，利用X-射线晶体学的晶体反应，加上各种光谱和活性测量，以阐明许多的化学机制HAO催化的突出。
Mononuclear, nonheme iron enzymes are known for their ability to mediate the oxidation of organic molecules in primary and secondary metabolism. One class of such enzymes is the diol dioxygenases that catalyze the oxidative cleavage of aromatic molecules. They come in two varieties, intradiol and extradiol, that add molecular oxygen symmetrically or asymmetrically, respectively. 3-Hydroxyanthranilate 3,4-dioxygenase (HAO) is a type III extradiol dioxygenase found in metabolic pathways related to breaking down tryptophan 2-nitrobenzoic acid. The product of HAO is unstable and either nonenzymatically cyclizes to quinolinic acid (QUIN), an endogenous neurotoxin and the universal precursor for NAD(P) biosynthesis, or is enzymatically processed, ultimately being fully oxidized to CO2 in the citric acid cycle. Elevation of QUIN is associated with neurodegenerative diseases, making HAO biomedically relevant. This article summarizes the history and current state of knowledge of the biochemistry of HAO. Recent studie that utilized X-ray crystallography of the in crystallo reactions coupled with various spectroscopies and activity measurements to elucidate much of the chemical mechanism catalyzed by HAO are highlighted.