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Molecular pharmacology of NRH:quinone oxidoreductase 2: A detoxifying enzyme acting as an undercover toxifying enzyme.
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2020-11-01 , DOI: 10.1124/molpharm.120.000105
Elzbieta Janda 1 , Françoise Nepveu 1 , Barbara Calamini 1 , Gilles Ferry 1 , Jean A Boutin 2
Affiliation  

N-ribosyldihydronicotinamide:quinone oxidoreductase 2 (NQO2/QR2, Enzyme Commission number 1.10.99.2) is a cytosolic enzyme, abundant in the liver and variably expressed in mammalian tissues. Cloned 30 years ago, it was characterized as a flavoenzyme catalyzing the reduction of quinones and pseudoquinones. To do so, it uses exclusively N-alkyl nicotinamide derivatives, without being able to recognize NADH, the reference hydrure donor compound, in contrast to its next of a kind, NAD(P)H:quinone oxidoreductase 1 (NQO1). For a long time both enzymes have been considered as key detoxifying enzymes in quinone metabolism, but more recent findings point to a more toxifying function of NQO2, particularly with respect to ortho-quinones. In fact, during the reduction of substrates, NQO2 generates fairly unstable intermediates that reoxidize immediately back to the original quinone, creating a futile cycle, the byproducts of which are deleterious reactive oxygen species. Beside this peculiarity, it is a target for numerous drugs and natural compounds such as melatonin, chloroquine, imiquimod, resveratrol, piceatannol, quercetin, and other flavonoids. Most of these enzyme-ligand interactions have been documented by numerous crystallographic studies, and now NQO2 is one of the best represented proteins in the structural biology database. Despite evidence for a causative role in several important diseases, the functional role of NQO2 remains poorly explored. In the present review, we aimed at detailing the main characteristics of NQO2 from a molecular pharmacology perspective. By drawing a clear border between facts and speculations, we hope to stimulate the future research toward a better understanding of this intriguing drug target.

中文翻译:

NRH:醌氧化还原酶2的分子药理作用:一种作为底下的毒素酶的毒素。

N-核糖二氢神经酰胺:醌氧化还原酶2(NQO2 / QR2,酶委员会编号1.10.99.2)是一种胞质酶,在肝脏中含量丰富,在哺乳动物组织中表达多样。它于30年前被克隆,其特征是一种黄酮酶,可催化还原醌和假醌。为此,它仅使用N-烷基烟酰胺衍生物,而不能识别NADH(参考水合供体化合物),而不是其下一个NAD(P)H:醌氧化还原酶1(NQO1)。长期以来,这两种酶都被认为是醌代谢中的关键排毒酶,但是最近的发现表明NQO2的排毒功能更强,尤其是对于甲醚而言。-醌。实际上,在还原底物期间,NQO2会生成相当不稳定的中间体,这些中间体会立即重新氧化回原来的醌,从而形成一个无用的循环,其副产物是有害的活性氧。除了这种特殊性,它还是许多药物和天然化合物(例如褪黑素,氯喹,咪喹莫特,白藜芦醇,苦味酚,槲皮素和其他类黄酮)的目标。大量的晶体学研究已证明了大多数这些酶-配体之间的相互作用,现在NQO2是结构生物学数据库中表现最好的蛋白质之一。尽管有证据表明在几种重要疾病中有致病作用,但对NQO2的功能性作用仍未充分探讨。在目前的评论中,我们旨在从分子药理学角度详细介绍NQO2的主要特征。通过在事实和推测之间划清界线,我们希望刺激未来的研究,以便更好地了解这个有趣的毒品目标。
更新日期:2020-10-27
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