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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure and reactivity of hydroxypropylphosphonic acid epoxidase in fosfomycin biosynthesis by a cation- and flavin-dependent mechanism
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Structure and reactivity of hydroxypropylphosphonic acid epoxidase in fosfomycin biosynthesis by a cation- and flavin-dependent mechanism

机译：磷霉素依赖阳离子和黄素的机理在磷霉素生物合成中的结构和羟丙基膦酸环氧酶的反应性

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摘要

The biosynthesis of fosfomycin, an oxirane antibiotic in clinical use, involves a unique epoxidation catalyzed by (S)-2-hydroxypropylphosphonic acid epoxidase (HPPE). The reaction is essentially dehydrogenation of a secondary alcohol. A high-resolution crystallographic analysis reveals that the HPPE subunit displays a two-domain combination. The C-terminal or catalytic domain has the cupin fold that binds a divalent cation, whereas the N-terminal domain carries a helix-turn-helix motif with putative DNA-binding helices positioned 34 A apart. The structure of HPPE serves as a model for numerous proteins, of ill-defined function, predicted to be transcription factors but carrying a cupin domain at the C terminus. Structure-reactivity analyses reveal conformational changes near the catalytic center driven by the presence or absence of ligand, that HPPE is a Zn2+/Fe2+-dependent epoxidase, proof that flavin mononucleotide is required for catalysis, and allow us to propose a simple mechanism that is compatible with previous experimental data. The participation of the redox inert Zn2+ in the mechanism is surprising and indicates that Lewis acid properties of the metal ions are sufficient to polarize the substrate and, aided by flavin mononucleotide reduction, facilitate the epoxidation.
机译：磷霉素是一种临床上使用的环氧乙烷抗生素，其生物合成涉及由（S）-2-羟丙基膦酸环氧化酶（HPPE）催化的独特环氧化。该反应基本上是仲醇的脱氢。高分辨率晶体学分析表明，HPPE亚基显示出两个域的组合。 C-末端或催化结构域具有结合二价阳离子的cupin折叠，而N-末端结构域带有螺旋-转-螺旋基序，推定的DNA结合螺旋位相距34A。 HPPE的结构可作为多种蛋白质的模型，这些蛋白质功能不明确，预计是转录因子，但在C末端带有铜结构域。结构反应性分析揭示了由配体的存在或不存在驱动的催化中心附近的构象变化，HPPE是依赖Zn2 + / Fe2 +的环氧化酶，证明黄素单核苷酸是催化所必需的，并允许我们提出一个简单的机理，即与以前的实验数据兼容。氧化还原惰性Zn2 +参与该机理是令人惊讶的，表明金属离子的路易斯酸性质足以使底物极化，并在黄素单核苷酸还原的辅助下促进环氧化。

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