Defining the structure of ferryl heme

定义ferryl血红素的结构

• 批准号: BB/N015940/1
• 负责人: Peter Moody
• 金额: $ 83.31万
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN015940%2F1
• 关键词: Defining; structure; ferryl; heme

Metal-catalysed activation of oxygen is a cornerstone of biology. It is usually achieved using metal ions, typically either copper or iron. In the case of iron, there are both non-heme-containing and heme-containing enzymes which activate oxygen. This application focuses on the latter. The mechanism of activation involves formation of the iconic Compound I and Compound II intermediates, which are used across a diverse group of catalytic heme enzymes that include all the cytochrome P450s (involved in drug metabolism), the nitric oxide synthases (involved in cell signalling), and the terminal oxidases (involved in respiration), plus the heme dioxygenases (involved in formation of NAD) and heme peroxidases (involved in peroxide detoxification). Compounds I and II are such crucial intermediates in so many processes that defining their structure and understanding their reactivity, and in particular their protonation states, has been a key question in the field over several decades. We intend to use neutron crystallography to decisively advance the field in this area. We intend to obtain neutron crystal structures of Compound II, and we propose three strategies to deliver this. This will identify the locations of all the protons in the Compound II intermediate and will allow us to make mechanistic comparisons across the family of heme enzymes. These are ambitious, technically difficult and time-consuming experiments. But the likely gains are very high, because we have chance to finally resolve questions that have eluded the whole community for many years.

金属催化的氧气活化是生物学的基石。它通常使用金属离子来实现，通常是铜或铁。在铁的情况下，有两个不含血红素和含血红素的酶激活氧。本申请侧重于后者。活化的机制涉及形成标志性的化合物I和化合物II中间体，其用于包括所有细胞色素P450的催化血红素酶的不同组（参与药物代谢），一氧化氮合酶（参与细胞信号传导）和末端氧化酶（参与呼吸），加上血红素双加氧酶（参与NAD的形成）和血红素过氧化物酶（参与过氧化物解毒）。化合物I和II是如此重要的中间体，在如此多的过程中，定义它们的结构和理解它们的反应性，特别是它们的质子化状态，几十年来一直是该领域的关键问题。我们打算使用中子晶体学来决定性地推进这一领域的研究。我们打算获得化合物II的中子晶体结构，我们提出了三种策略来实现这一目标。这将确定化合物II中间体中所有质子的位置，并使我们能够在血红素酶家族中进行机理比较。这些都是雄心勃勃、技术上困难和耗时的实验。但可能的收益是非常高的，因为我们有机会最终解决多年来整个社会一直回避的问题。

项目成果

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

Visualizing the protons in a metalloenzyme electron proton transfer pathway

• DOI: 10.1073/pnas.1918936117
• 发表时间: 2020-03-24
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Kwon, Hanna;Basran, Jaswir;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.

Heme peroxidase-Trapping intermediates by cryo neutron crystallography.

通过低温中子晶体学捕获血红素过氧化物酶中间体。

• DOI: 10.1016/bs.mie.2020.01.010
• 发表时间: 2020
• 期刊: Methods in enzymology
• 作者: Kwon H

XFEL Crystal Structures of Peroxidase Compound II

过氧化物酶化合物 II 的 XFEL 晶体结构

• DOI: 10.1002/ange.202103010
• 发表时间: 2021
• 期刊: Angewandte Chemie
• 作者: Kwon H