Regulated O2 Activation in Flavin-Dependent Monooxygenases
Regulated O2 Activation in Flavin-Dependent Monooxygenases
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DOI：
10.1021/ja203397s
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发表时间：
2011-08-17
影响因子：
15
通讯作者：
DuBois, Jennifer L.
中科院分区：
文献类型：
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作者：
Frederick, Rosanne E.;Mayfield, Jeffery A.;DuBois, Jennifer L.
黄素依赖性单加氧酶 (FMO) 参与多种生物体的重要生物合成途径，包括产生用于输入和储存严重病原体中必需铁的铁载体。我们已经证明，来自烟曲霉的 FMO（一种鸟氨酸单加氧酶 (Af-OMO)）在机制上与其经过充分研究的来自哺乳动物肝脏的远缘同源物相似。后者在底物的选择上高度混杂，而 Af-OMO 则异常具体。这就提出了一个难题：Af-OMO 和其他生物合成类别的 FMO 如何实现这种特异性？我们发现，在 L-精氨酸（作为小分子调节剂）存在的情况下，Af-OMO 中 O-2 的激活速率显着提高。这种蛋白质水平的调节可以帮助解释这种和相关的生物合成 FMO 如何设法将 O-2 活化和底物羟基化相互耦合以及与适当的细胞条件耦合。鉴于 Fe 对 Af 的重要性以及 Af-OMO 基因敲除的无毒力，Af-OMO 抑制剂可能成为对抗这种医学上难以治愈的病原体的药物靶标。
Flavin-dependent monooxygenases (FMOs) are involved in important biosynthetic pathways in diverse organisms, including production of the siderophores used for the import and storage of essential iron in serious pathogens. We have shown that the FMO from Aspergillus fumigatus, an ornithine monooxygenase (Af-OMO), is mechanistically similar to its well-studied distant homologues from mammalian liver. The latter are highly promiscuous in their choice of substrates, while Af-OMO is unusually specific. This presents a puzzle: how do Af-OMO and other FMOs of the biosynthetic classes achieve such specificity? We have discovered substantial enhancement in the rate of O-2 activation in Af-OMO in the presence of L-arginine, which acts as a small molecule regulator. Such protein-level regulation could help explain how this and related biosynthetic FMOs manage to couple O-2 activation and substrate hydroxylation to each other and to the appropriate cellular conditions. Given the essentiality of Fe to Af and the avirulence of the Af-OMO gene knock out, inhibitors of Af-OMO are likely to be drug targets against this medically intractable pathogen.