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Direct coordination of pterin to FeII enables neurotransmitter biosynthesis in the pterin-dependent hydroxylases [Biochemistry]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-04-13 , DOI: 10.1073/pnas.2022379118
Shyam R. Iyer, Kasper D. Tidemand, Jeffrey T. Babicz, Ariel B. Jacobs, Leland B. Gee, Lærke T. Haahr, Yoshitaka Yoda, Masayuki Kurokuzu, Shinji Kitao, Makina Saito, Makoto Seto, Hans E. M. Christensen, Günther H. J. Peters, Edward I. Solomon

The pterin-dependent nonheme iron enzymes hydroxylate aromatic amino acids to perform the biosynthesis of neurotransmitters to maintain proper brain function. These enzymes activate oxygen using a pterin cofactor and an aromatic amino acid substrate bound to the FeII active site to form a highly reactive FeIV = O species that initiates substrate oxidation. In this study, using tryptophan hydroxylase, we have kinetically generated a pre-FeIV = O intermediate and characterized its structure as a FeII-peroxy-pterin species using absorption, Mössbauer, resonance Raman, and nuclear resonance vibrational spectroscopies. From parallel characterization of the pterin cofactor and tryptophan substrate–bound ternary FeII active site before the O2 reaction (including magnetic circular dichroism spectroscopy), these studies both experimentally define the mechanism of FeIV = O formation and demonstrate that the carbonyl functional group on the pterin is directly coordinated to the FeII site in both the ternary complex and the peroxo intermediate. Reaction coordinate calculations predict a 14 kcal/mol reduction in the oxygen activation barrier due to the direct binding of the pterin carbonyl to the FeII site, as this interaction provides an orbital pathway for efficient electron transfer from the pterin cofactor to the iron center. This direct coordination of the pterin cofactor enables the biological function of the pterin-dependent hydroxylases and demonstrates a unified mechanism for oxygen activation by the cofactor-dependent nonheme iron enzymes.



中文翻译:

蝶呤与FeII的直接配位可在蝶呤依赖性羟化酶中实现神经递质的生物合成[生物化学]

依赖于蝶呤的非血红素铁酶将芳香族氨基酸羟化,以执行神经递质的生物合成,以维持适当的大脑功能。这些酶利用蝶呤辅助因子和结合到Fe II活性位点的芳香族氨基酸底物激活氧,从而形成高反应性的Fe IV = O物种,从而引发底物氧化。在这项研究中,我们使用色氨酸羟化酶动力学生成了前Fe IV = O中间体,并利用吸收,Mössbauer,共振拉曼光谱和核共振振动光谱学将其结构表征为Fe II-过氧蝶呤物种。通过对蝶呤辅因子和色氨酸底物结合的三元Fe II的平行表征O 2反应之前的活性位点(包括圆二色谱),这些研究都通过实验确定了Fe IV = O形成的机理,并证明了蝶呤上的羰基官能团直接与三元体系中的Fe II位点配位复合物和过氧中间体。反应坐标计算预测,由于蝶呤羰基与Fe II的直接结合,氧气活化势垒会降低14 kcal / mol位置,因为这种相互作用为从蝶呤辅因子到铁中心的有效电子转移提供了轨道途径。蝶呤辅因子的这种直接配位使得蝶呤依赖型羟化酶具有生物学功能,并证明了辅因子依赖型非血红素铁酶激活氧的统一机制。

更新日期:2021-04-06
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