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

该项目旨在对我们对血红素类分子相关家族的合成和进化的理解产生重大影响，并将导致在教科书中全面添加处理卟啉代谢的部分。血红素是一种重要的生命色素，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破译一个20年的谜团。具体来说，我们的目的是阐明血红素和血红素d1是如何在古细菌和一些真细菌中产生的。血红素以前被认为是由一种叫做uroporphyrinogen III的化合物沿着一条单一的途径合成的，通过一系列酶来修饰酸性侧链，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可以通过一种全新的途径产生，该途径涉及另一种修饰的四吡啶，一种称为siroheme的化合物，亚硫酸盐和亚硝酸盐还原酶的假基。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需要许多自由基SAM酶与脱羧酶结合，涉及一些生物化学中前所未有的极不寻常的步骤。该项目的目的是了解血红素沿着这条途径一步一步合成的分子细节。虽然d1血红素只存在于细胞色素cd1中，但这种酶的重要性正变得越来越明显，因为它对厌氧条件下氨被亚硝酸盐氧化的厌氧氨氧化过程至关重要，最近被认为在甲烷的厌氧氧化中起关键作用。据信，d1血红素已被用于呼吸性亚硝酸盐还原，因为它被调整为只允许亚硝酸盐还原到一氧化氮，而不允许由siroheme催化的进一步还原到氨。因此，siroheme也是d1合成的前体的发现提出了许多有趣的进化和调控问题。总的来说，这项研究的结果将为新的血红素合成途径提供分子序曲，更清楚地解释血红素和siro血红素之间的关系，并为复杂的生物合成途径提供新达尔文主义的理解。它还将有助于保持英国在生物分子科学研究的前沿地位，并保持我们的团队在该领域的世界领先地位。

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.