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首页> 外文期刊>Biochemistry >Role of propionates in substrate binding to heme oxygenase from neisseria meningitidis: A nuclear magnetic resonance study
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Role of propionates in substrate binding to heme oxygenase from neisseria meningitidis: A nuclear magnetic resonance study

机译：丙酸酯在脑膜炎奈瑟菌血红素加氧酶结合底物中的作用：核磁共振研究

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摘要

Heme oxygenase (HO) cleaves hemin into biliverdin, iron, and CO. For mammalian HOs, both native hemin propionates are required for substrate binding and activity. The HO from the pathogenic bacterium Neisseria meningitidis (NmHO) possesses a crystallographically undetected C-terminal fragment that by solution ~1H nuclear magnetic resonance (NMR) is found to fold and interact with the active site. One of the substrate propionates has been proposed to form a salt bridge to the C-terminus rather than to the conventional buried cationic side chain in other HOs. Moreover, the C-terminal dipeptide Arg208His209 cleaves spontaneously over ～24 h at a rate dependent on substituent size. Two-dimensional ~1H NMR of NmHO azide complexes with hemins with selectively deleted or rearranged propionates shows that all bind to NmHO with a structurally conserved active site as reflected in optical spectra and NMR nuclear Overhauser effect spectroscopy cross-peak and hyperfine shift patterns. In contrast to mammalian HOs, NmHO requires only a single propionate interacting with the buried terminus of Lys16 to exhibit full activity and tolerates the existence of a propionate at the exposed 8-position. The structure of the C-terminus is qualitatively retained upon deletion of the 7-propionate, but a dramatic change in the 7-propionate carboxylate ~(13)C chemical shift upon C-terminal cleavage confirms its role in the interaction with the C-terminus. The stronger hydrophobic contacts between pyrroles A and B with NmHO contribute more substantially to the substrate binding free energy than in mammalian HOs, "liberating" one propionate to stabilize the C-terminus. The functional implications of the C-terminus in product release are discussed.
机译：血红素加氧酶（HO）将血红素裂解为biliverdin，铁和CO。对于哺乳动物的HOs，两种天然血红素丙酸酯都需要底物结合和活性。来自病原性细菌脑膜炎奈瑟氏球菌（NmHO）的HO具有晶体学上未检测到的C末端片段，通过溶液〜1H核磁共振（NMR）发现该末端折叠并与活性位点相互作用。已经提出一种底物丙酸酯形成到C末端的盐桥，而不是形成到其他HO中的常规掩埋阳离子侧链的盐桥。此外，C端二肽Arg208His209在约24小时内以取决于取代基大小的速率自发裂解。 NmHO叠氮化物配合物的血红素的二维〜1H NMR和选择性缺失或重排的丙酸酯表明，所有这些均与NmHO结合，具有结构保守的活性位点，如光谱和NMR核Overhauser效应光谱的峰峰值和超精细位移图所示。与哺乳动物HO相比，NmHO仅需要一个丙酸酯与Lys16的掩埋末端相互作用即可发挥全部活性，并能在暴露的8位位置容忍丙酸酯的存在。删除7-丙酸酯后，C端的结构在质量上得以保留，但7-丙酸酯的羧酸酯〜（13）C化学位移在C端裂解后发生了巨大变化，证实了其在与C-丙醇相互作用中的作用总站。吡咯A和B与NmHO之间更强的疏水性接触比哺乳动物HO中更重要地促进了底物结合自由能，从而“释放”了一种丙酸酯以稳定C端。讨论了C末端在产品发布中的功能含义。

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