Wang Jun, Krizowski Sabina, Fischer-Schrader Katrin, Niks Dimitri, Tejero Jesús, Sparacino-Watkins Courtney, Wang Ling, Ragireddy Venkata, Frizzell Sheila, Kelley Eric E, Zhang Yingze, Basu Partha, Hille Russ, Schwarz Guenter, Gladwin Mark T
1 Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania.
2 Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Antioxid Redox Signal. 2015 Aug 1;23(4):283-94. doi: 10.1089/ars.2013.5397. Epub 2014 Dec 11.
Recent studies suggest that the molybdenum enzymes xanthine oxidase, aldehyde oxidase, and mARC exhibit nitrite reductase activity at low oxygen pressures. However, inhibition studies of xanthine oxidase in humans have failed to block nitrite-dependent changes in blood flow, leading to continued exploration for other candidate nitrite reductases. Another physiologically important molybdenum enzyme—sulfite oxidase (SO)—has not been extensively studied.
Using gas-phase nitric oxide (NO) detection and physiological concentrations of nitrite, SO functions as nitrite reductase in the presence of a one-electron donor, exhibiting redox coupling of substrate oxidation and nitrite reduction to form NO. With sulfite, the physiological substrate, SO only facilitates one turnover of nitrite reduction. Studies with recombinant heme and molybdenum domains of SO indicate that nitrite reduction occurs at the molybdenum center via coupled oxidation of Mo(IV) to Mo(V). Reaction rates of nitrite to NO decreased in the presence of a functional heme domain, mediated by steric and redox effects of this domain. Using knockdown of all molybdopterin enzymes and SO in fibroblasts isolated from patients with genetic deficiencies of molybdenum cofactor and SO, respectively, SO was found to significantly contribute to hypoxic nitrite signaling as demonstrated by activation of the canonical NO-sGC-cGMP pathway.
Nitrite binds to and is reduced at the molybdenum site of mammalian SO, which may be allosterically regulated by heme and molybdenum domain interactions, and contributes to the mammalian nitrate-nitrite-NO signaling pathway in human fibroblasts.
SO is a putative mammalian nitrite reductase, catalyzing nitrite reduction at the Mo(IV) center.
近期研究表明，钼酶黄嘌呤氧化酶、醛氧化酶和mARC在低氧压力下具有亚硝酸还原酶活性。然而，对人体黄嘌呤氧化酶的抑制研究未能阻断血流中依赖亚硝酸盐的变化，因此需要继续探索其他潜在的亚硝酸还原酶。另一种具有重要生理功能的钼酶——亚硫酸盐氧化酶（SO）尚未得到广泛研究。
利用气相一氧化氮（NO）检测和生理浓度的亚硝酸盐，在存在单电子供体的情况下，SO发挥亚硝酸还原酶的功能，表现出底物氧化与亚硝酸盐还原形成NO的氧化还原偶联。对于生理底物亚硫酸盐，SO仅促进亚硝酸盐还原的一轮周转。对SO的重组血红素和钼结构域的研究表明，亚硝酸盐还原通过Mo(IV)氧化为Mo(V)在钼中心发生。在功能性血红素结构域存在的情况下，亚硝酸盐向NO的反应速率降低，这是由该结构域的空间和氧化还原效应介导的。分别使用钼辅因子和SO基因缺陷患者分离的成纤维细胞中所有钼蝶呤酶和SO的敲低，发现SO对缺氧亚硝酸盐信号有显著贡献，这通过经典的NO-sGC-cGMP途径的激活得以证明。
亚硝酸盐在哺乳动物SO的钼位点结合并被还原，这可能受血红素和钼结构域相互作用的变构调节，并在人成纤维细胞中对哺乳动物硝酸盐-亚硝酸盐-NO信号通路有贡献。
SO是一种潜在的哺乳动物亚硝酸还原酶，催化Mo(IV)中心的亚硝酸盐还原。
