The nature of the key reactive intermediates in heme catalysis

血红素催化中关键反应中间体的性质

• 批准号: BB/K015656/1
• 负责人: Peter Moody
• 金额: $ 53.65万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK015656%2F1
• 关键词: nature; key; reactive; intermediates; heme

The involvement of the metallic element iron in various biological systems is well known. In many cases, iron is employed in the form of a heme group, most famously in hemoglobin. The family of catalytic heme proteins is vast, and the majority of these catalytic heme enzymes react with oxygen in an activation process that generates oxidised forms of the heme. These oxidised forms of heme are called Compound I (oxidised by two electrons) and Compound II (oxidised by one electron). They are such crucial intermediates in so many catalytic heme proteins - including many involved in drug metabolism and other biological oxidations - that the elucidation of their structure has become a fundamental question for all those in the field. Numerous attempts to establish the structure of Compound I and Compound II have, however, failed because of flaws in the methodology and the transient nature of the species. With improvements in methodology for neutron diffraction and for examination of iron-oxygen stretching frequencies for protein bands in crystallo (using on-line resonance Raman), it now becomes possible to take an alternative approach. We intend to use these new methods to establish, finally, the structures of these crucial intermediates.

金属元素铁参与各种生物系统是众所周知的。在许多情况下，铁以血红素基团的形式存在，最著名的是在血红蛋白中。催化血红素蛋白的家族很多，这些催化血红素酶中的大多数在激活过程中与氧气反应，产生氧化形式的血红素。这些被氧化的亚铁血红素称为化合物I(被两个电子氧化)和化合物II(被一个电子氧化)。它们是许多催化血红素蛋白的关键中间体-包括许多参与药物代谢和其他生物氧化的蛋白质-以至于对该领域的所有人来说，阐明它们的结构已经成为一个基本问题。然而，由于方法上的缺陷和物种的暂时性，确定化合物I和化合物II的结构的多次尝试都以失败告终。随着中子衍射方法的改进和晶体中蛋白质带铁氧伸展频率的检测(使用在线共振拉曼)，现在有可能采取另一种方法。我们打算使用这些新方法来最终确定这些关键中间体的结构。

项目成果

The rise of neutron cryo-crystallography.

• DOI: 10.1107/s205979831800640x
• 发表时间: 2018-08-01
• 期刊: Acta crystallographica. Section D, Structural biology
• 作者: Kwon H;Langan PS;Coates L;Raven EL;Moody PCE
• 通讯作者: Moody PCE

Combining X-ray and neutron crystallography with spectroscopy.

• DOI: 10.1107/s2059798316016314
• 发表时间: 2017-02-01
• 期刊: Acta crystallographica. Section D, Structural biology
• 作者: Kwon H;Smith O;Raven EL;Moody PC
• 通讯作者: Moody PC

Direct visualization of a Fe(IV)-OH intermediate in a heme enzyme.

• DOI: 10.1038/ncomms13445
• 发表时间: 2016-11-29
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Kwon, Hanna;Basran, Jaswir;Casadei, Cecilia M.;Fielding, Alistair J.;Schrader, Tobias E.;Ostermann, Andreas;Devos, Juliette M.;Aller, Pierre;Blakeley, Matthew P.;Moody, Peter C. E.;Raven, Emma L.
• 通讯作者: Raven, Emma L.

Neutron scattering in the biological sciences: progress and prospects

• DOI: 10.1107/s2059798318017503
• 发表时间: 2018-12-01
• 期刊: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
• 影响因子: 2.2
• 作者: Ashkar, Rana;Bilheux, Hassina Z.;Smith, Jeremy C.
• 通讯作者: Smith, Jeremy C.

The role of Ala134 in controlling substrate binding and reactivity in ascorbate peroxidase.

• DOI: 10.1016/j.jinorgbio.2017.12.018
• 发表时间: 2017-12
• 期刊: Journal of inorganic biochemistry
• 影响因子: 3.9
• 作者: D. Turner;L. Lad;H. Kwon;J. Basran;K. Carr;P. Moody;E. Raven