Unravelling the remarkable synthesis and mechanisms involved in the biogenesis of heme and heme d1 from siroheme.

该项目旨在对我们理解血红素样分子相关家族的合成和进化产生重大影响，并将导致对卟啉代谢教科书部分的全面补充。血红素属于一个家庭的基本生活色素参与许多基本的呼吸过程。这个应用程序旨在通过解开导致它们合成的途径来解开一个二十年的谜团。具体来说，我们的目标是阐明血红素和血红素d1是如何在大肠杆菌和一些真细菌。血红素以前被认为是由一种叫做尿卟啉原III的化合物通过一系列酶沿着单一途径合成的，这些酶修饰酸性侧链，氧化大环并插入亚铁。然而，我们最近已经证明，血红素和结构相关的大环，血红素d1，可以通过一个全新的途径，涉及另一种改性四吡咯，一种化合物称为siroheme，亚硫酸盐和亚硝酸盐还原酶的辅基同类相食。这个项目有许多新颖的特点，使它引人注目。siroheme转化为血红素和血红素d1需要一些自由基SAM酶加上脱羧酶，涉及一些非常不寻常的步骤，是前所未有的生物化学。这个项目的目的是在分子上详细了解血红素沿着这条途径的逐步合成。虽然d1血红素仅存在于细胞色素cd1中，但这种酶的重要性变得越来越明显，因为它对于环境重要的厌氧氨氧化过程至关重要，其中氨在厌氧条件下被亚硝酸盐氧化，并且最近被认为在甲烷的厌氧氧化中发挥关键作用。据信，d1血红素已被用于呼吸亚硝酸盐还原，因为它被调整为仅允许亚硝酸盐还原到一氧化氮，而不允许由西罗血红素催化的向前还原为氨。siroheme也是d1合成的前体，这一发现引起了许多有趣的进化和调控问题。总的来说，这项研究的结果将导致一个新的血红素合成途径的分子序曲事件的组成，更清楚地解释血红素和siroheme之间的关系，并提供复杂的生物合成途径的新达尔文主义的理解。它还将有助于使英国保持在生物分子科学研究的前沿，并保持我们的团队在该领域作为世界领导者的地位。

This project aims to have a major impact on our understanding of the synthesis and evolution of a related family of heme-like molecules, and will result in a comprehensive addition to text book sections dealing with porphyrin metabolism. Hemes belong to a family of essential life pigment involved in many basic respiratory processes. This application aims to decipher a twenty-year mystery by unravelling the pathway leading to their synthesis. Specifically we aim to elucidate how heme and heme d1 are made in the Archaea and a number of eubacteria. Heme was previously thought to be synthesized along a single pathway from a compound called uroporphyrinogen III by a series of enzymes that modify the acidic side chains, oxidize the macrocycle and insert ferrous iron. However, we have recently demonstrated that heme and a structurally related macrocycle, heme d1, can be made by a completely novel pathway that involves the cannibalism of another modified tetrapyrrole, a compound called siroheme, the prosthetic group of sulphite and nitrite reductase. There are many novel features to this project that make it compelling. The transformation of siroheme into heme and heme d1 requires a number of radical SAM enzymes coupled with a decarboxylase, involving some highly unusual steps that are unprecedented in biological chemistry. The aim of this project is to understand in molecular detail the step-by-step synthesis of hemes along this pathway. Although the d1 heme is only found in the cytochrome cd1, the importance of this enzyme is becoming ever more evident as it vital for the environmentally important ANAMMOX process whereby ammonia is oxidised by nitrite under anaerobic conditions and has recently been implicated in playing a key role in the anaerobic oxidation of methane. It is believed that d1 heme has been adopted for respiratory nitrite reduction because it is tuned to permit nitrite reduction only as far as nitric oxide and not to allow the onward reduction to ammonia that is catalysed by siroheme. The discovery that siroheme is also a precursor for d1 synthesis therefore raises many interesting evolutionary and regulatory questions. Overall, the outcome of this research will result in the composition of a molecular overture of events for a new heme synthesis route, explain more clearly the relationship between heme and siroheme and provide a neodarwinistic understanding of complex biosynthetic pathways. It will also help maintain the UK at the cutting edge of biomolecular science research and maintain the position our groups have as world leaders in this field.