Hanna David A, Martinez-Guzman Osiris, Reddi Amit R
School of Chemistry and Biochemistry and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology , Atlanta, Georgia 30332, United States.
Biochemistry. 2017 Apr 4;56(13):1815-1823. doi: 10.1021/acs.biochem.7b00007. Epub 2017 Mar 27.
Heme (iron protoporphyrin IX) is an essential protein prosthetic group and signaling molecule required for most life on Earth. All heme-dependent processes require the dynamic and rapid mobilization of heme from sites of synthesis or uptake to hemoproteins present in virtually every subcellular compartment. The cytotoxicity and hydrophobicity of heme necessitate that heme mobilization be carefully controlled to mitigate the deleterious effects of this essential toxin. Indeed, a number of disorders, including certain cancers, cardiovascular diseases, and aging and age-related neurodegenerative diseases, are tied to defects in heme homeostasis. However, the molecules and mechanisms that mediate heme transport and trafficking, and the dynamics of these processes, are poorly understood. This is in large part due to the lack of physical tools for probing cellular heme. Herein, we discuss the recent development of fluorescent probes that can monitor and image kinetically labile heme with respect to its mobilization and role in signaling. In particular, we will highlight how heme gazing with these tools can uncover new heme trafficking factors upon being integrated with genetic screens and illuminate the concentration, subcellular distribution, and dynamics of labile heme in various physiological contexts. Altogether, the monitoring of labile heme, along with recent biochemical and cell biological studies demonstrating the reversible regulation of certain cellular processes by heme, is challenging us to reconceptualize heme from being a static cofactor buried in protein active sites to a dynamic and mobile signaling molecule.
血红素（铁原卟啉IX）是地球上大多数生命所必需的蛋白质辅基和信号分子。所有依赖血红素的过程都需要将血红素从合成或摄取位点动态快速地转运到几乎存在于每个亚细胞区室的血红素蛋白中。血红素的细胞毒性和疏水性使得必须仔细控制血红素的转运，以减轻这种必需毒素的有害影响。事实上，包括某些癌症、心血管疾病以及衰老和与年龄相关的神经退行性疾病在内的许多疾病都与血红素稳态缺陷有关。然而，介导血红素运输和 trafficking 的分子和机制，以及这些过程的动态变化，目前仍知之甚少。这在很大程度上是由于缺乏用于探测细胞内血红素的物理工具。在此，我们讨论了荧光探针的最新进展，这些探针可以监测和成像动态不稳定的血红素在其转运和信号传导中的作用。特别是，我们将强调如何利用这些工具结合基因筛选来发现新的血红素运输因子，并阐明不稳定血红素在各种生理环境中的浓度、亚细胞分布和动态变化。总之，对不稳定血红素的监测，以及最近的生化和细胞生物学研究表明血红素对某些细胞过程的可逆调节，促使我们重新认识血红素，从一个埋在蛋白质活性位点的静态辅因子转变为一个动态和可移动的信号分子。
