Abstract

Heme is an essential biomolecule and cofactor involved in a myriad of biological processes. In this review, we focus on how heme binding to heme regulatory motifs (HRMs), catalytic sites, and gas signaling molecules as well as how changes in the heme redox state regulate protein structure, function, and degradation. We also relate these heme-dependent changes to the affected metabolic processes. We center our discussion on two HRM-containing proteins: human heme oxygenase-2, a protein that binds and degrades heme (releasing Fe²⁺ and CO) in its catalytic core and binds Fe³⁺-heme at HRMs located within an unstructured region of the enzyme, and the transcriptional regulator Rev-erbβ, a protein that binds Fe³⁺-heme at an HRM and is involved in CO sensing. We will discuss these and other proteins as they relate to cellular heme composition, homeostasis, and trafficking. In addition, we will discuss the HRM-containing family of proteins and how the stability and activity of these proteins are regulated in a dependent manner through the HRMs. Then, after reviewing CO-mediated protein regulation of heme proteins, we turn our attention to the involvement of heme, HRMs, and CO in circadian rhythms. In sum, we stress the importance of understanding the various roles of heme and the distribution of the different heme pools as they relate to the heme redox state, CO, and heme binding affinities.

摘要

血红素是参与无数生物过程的重要生物分子和辅助因子。在这篇综述中，我们关注血红素如何与血红素调节基序 (HRM)、催化位点和气体信号分子结合，以及血红素氧化还原状态的变化如何调节蛋白质的结构、功能和降解。我们还将这些血红素依赖性变化与受影响的代谢过程联系起来。我们将讨论集中在两种含 HRM 的蛋白质上：人血红素加氧酶 2，一种在其催化核心结合和降解血红素（释放 Fe ²⁺和 CO）并在位于非结构化区域内的 HRM 处结合 Fe ³⁺血红素的蛋白质酶和转录调节因子 Rev-erbβ，一种结合 Fe ^{3+的蛋白质}-HRM 的血红素，参与 CO 传感。我们将讨论这些和其他蛋白质，因为它们与细胞血红素组成、体内平衡和运输有关。此外，我们将讨论含有 HRM 的蛋白质家族，以及这些蛋白质的稳定性和活性如何通过 HRM 以依赖的方式进行调节。然后，在回顾了 CO 介导的血红素蛋白调节后，我们将注意力转向血红素、HRM 和 CO 在昼夜节律中的参与。总之，我们强调了解血红素的各种作用以及不同血红素池的分布的重要性，因为它们与血红素氧化还原状态、CO 和血红素结合亲和力有关。