Understanding supply and demand for heme in cells

亚铁血红素是一种中心含铁的有机小分子。目前还没有发现没有血红素就能存活的真核生物。有数千种不同的血红素蛋白，负责氧运输、电子转移、氧化应激反应、呼吸作用和各种催化等过程。如此简单的分子能够如此多功能，这是大自然的一项惊人壮举，但最近出现的情况是，这只是一个更大的冰山的一角。除了上述作用外，血红素还被认为在细胞信号传递和调控中起着重要作用。这意味着，在已经承诺使用上述血红素蛋白的基础上，必须有更多的血红素供应，这些供应可以用于调节用途，并能够对细胞中的瞬时需求做出反应。因此，细胞需要机制将血红素从其合成地点(线粒体)移动到其他相关位置。这就带来了供应和需求的后勤问题。首先，血红素不溶于水，因此需要通过(可逆地)与其他东西(可能是蛋白质)结合来溶解它。由于其与氧气的反应能力，它在高浓度时也会对细胞产生毒性。因此，细胞不能简单地囤积血红素供应，然后将其以不受控制的浓度释放。但是，尽管血红素合成(一种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，但两者之间发生的事情--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几乎没有变化。我们想要了解这一点。血红素在细胞中的位置是什么？当地的血红素浓度是多少？在不同的条件下它们是否会有所不同？亚铁血红素是什么时候以及如何移动的？我们已经开发了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。我们将构建一幅细胞-血红素动力学和动员的详细图景。它将改变我们思考血红素在生物学中的使用方式，并将在生物技术应用中具有很高的相关性，因为众所周知，细胞内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.