Understanding supply and demand for heme in cells

血红素是一种中心含铁的有机小分子。没有真核生物已经确定，可以生存没有血红素。有成千上万种不同的血红素蛋白，负责氧运输，电子转移，氧化应激反应，呼吸和各种催化等过程。如此简单的分子可以如此多才多艺，这是自然界的一个惊人壮举，但最近出现的情况是，这只是一个更大的冰山一角。除了上述这些作用，血红素已被确定为在细胞信号传导和调节中重要。这意味着必须有血红素的供应，除了已经致力于上述血红素蛋白之外，可以用于调节用途，并可以响应细胞中的瞬时需求。因此，细胞需要机制将血红素从其合成位置（线粒体）移动到其他相关位置。这就造成了供应和需求的后勤问题。开始，血红素不溶于水，所以它需要通过结合（可逆地）其他东西（可能是蛋白质）来溶解。由于其与氧的反应性，高浓度的它对细胞也是有毒的。所以细胞不能简单地囤积血红素，然后让它以不受控制的浓度释放。但是，虽然血红素合成（一个8步生物合成途径）和血红素降解（通过血红素加氧酶）的机制是已知的，但在这之间发生的事情-血红素动员和细胞如何管理供应-与40年前提出的基本模型相比几乎没有变化。我们想了解这一点。血红素在细胞中的位置？血红素的局部浓度是什么？它们在不同条件下会变化吗？血红素何时以及如何移动？我们已经开发出监测细胞中血红素浓度的新技术，我们将用它来回答这些问题。我们将建立一个详细的细胞血红素动态和动员的图片。它将改变我们对血红素在生物学中如何使用的思考方式，并且它将在生物技术应用中具有高度相关性，因为已知细胞血红素浓度的不足或过量与健康和疾病有关。

Heme is a small organic molecule containing iron at the centre. No eukaryote has been identified that can survive without heme. There are thousands of different heme proteins, responsible for processes such as oxygen transport, electron transfer, oxidative stress response, respiration, and all kinds of catalysis. It is an amazing feat of Nature that such a simple molecule can be so versatile, but it has emerged recently that this is just the tip of a much bigger iceberg. In addition to these roles above, heme has been identified as important in cell signalling and regulation. This means that there has to be a supply of heme, above and beyond that which is already committed to the aforementioned heme proteins, that can deployed for regulatory use and can respond to transient demands in the cell. Cells thus needs mechanisms to move heme from its place of synthesis (mitochondria) to other relevant locations. This presents logistical problems of supply and demand. To begin with, heme is insoluble in water, so it needs to be solubilised by binding (reversibly) to something else (probably a protein). It is also toxic to cells in high concentrations by virtue of its reactivity with oxygen. So cells cannot simply hoard supplies of heme then let it loose in uncontrolled concentrations. But while the machinery for heme synthesis (an 8-step biosynthetic pathway) and heme degradation (by heme oxygenase) is known, what happens in between - heme mobilisation and how cells manage supplies - has hardly changed from basic models proposed 40 years ago. We want to understand this. Where is heme located in cells? What are local concentrations of heme and do they vary under different conditions? When and how is heme moved? We have developed new technology for monitoring heme concentration in cells, and we will use it to answer these questions. We will build a detailed picture of cellular-heme dynamics and mobilisation. It will change the way we think about how heme is used in biology and it will be of high relevance in biotechnology applications, because deficiencies or excesses in cellular heme concentration are known to be relevant in health and disease.