Tsiftsoglou Stefanos A
Laboratory of Pharmacology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Curr Issues Mol Biol. 2023 Jun 16;45(6):5198-5214. doi: 10.3390/cimb45060330.
Heme (Fe-protoporphyrin IX) is a pigment of life, and as a prosthetic group in several hemoproteins, it contributes to diverse critical cellular processes. While its intracellular levels are tightly regulated by networks of heme-binding proteins (HeBPs), labile heme can be hazardous through oxidative processes. In blood plasma, heme is scavenged by hemopexin (HPX), albumin and several other proteins, while it also interacts directly with complement components C1q, C3 and factor I. These direct interactions block the classical pathway (CP) and distort the alternative pathway (AP). Errors or flaws in heme metabolism, causing uncontrolled intracellular oxidative stress, can lead to several severe hematological disorders. Direct interactions of extracellular heme with alternative pathway complement components (APCCs) may be implicated molecularly in diverse conditions at sites of abnormal cell damage and vascular injury. In such disorders, a deregulated AP could be associated with the heme-mediated disruption of the physiological heparan sulphate-CFH coat of stressed cells and the induction of local hemostatic responses. Within this conceptual frame, a computational evaluation of HBMs (heme-binding motifs) aimed to determine how heme interacts with APCCs and whether these interactions are affected by genetic variation within putative HBMs. Combined computational analysis and database mining identified putative HBMs in all of the 16 APCCs examined, with 10 exhibiting disease-associated genetic (SNPs) and/or epigenetic variation (PTMs). Overall, this article indicates that among the pleiotropic roles of heme reviewed, the interactions of heme with APCCs could induce differential AP-mediated hemostasis-driven pathologies in certain individuals.
血红素（铁 - 原卟啉IX）是生命的一种色素，作为几种血红蛋白的辅基，它参与多种关键的细胞过程。虽然其细胞内水平受到血红素结合蛋白（HeBPs）网络的严格调控，但不稳定的血红素可通过氧化过程产生危害。在血浆中，血红素被血红素结合蛋白（HPX）、白蛋白和其他几种蛋白质清除，同时它也直接与补体成分C1q、C3和因子I相互作用。这些直接相互作用阻断经典途径（CP）并扭曲替代途径（AP）。血红素代谢中的错误或缺陷，导致不受控制的细胞内氧化应激，可引发多种严重的血液学疾病。细胞外血红素与替代途径补体成分（APCCs）的直接相互作用可能在分子水平上与异常细胞损伤和血管损伤部位的多种病症有关。在这些疾病中，失调的AP可能与血红素介导的应激细胞生理性硫酸乙酰肝素 - CFH包膜破坏以及局部止血反应的诱导有关。在这个概念框架内，对血红素结合基序（HBMs）进行了计算评估，旨在确定血红素如何与APCCs相互作用以及这些相互作用是否受到假定HBMs内遗传变异的影响。综合计算分析和数据库挖掘在所有16种检测的APCCs中鉴定出假定的HBMs，其中10种表现出与疾病相关的遗传（单核苷酸多态性，SNPs）和/或表观遗传变异（翻译后修饰，PTMs）。总体而言，本文表明，在所综述的血红素的多效性作用中，血红素与APCCs的相互作用可能在某些个体中诱导由AP介导的、止血驱动的不同病理变化。
