Metabolic Functions of Biliverdin IXβ Reductase in Redox-Regulated Hematopoietic Cell Fate.
Metabolic Functions of Biliverdin IXβ Reductase in Redox-Regulated Hematopoietic Cell Fate.
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DOI：
10.3390/antiox12051058
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发表时间：
2023-05-07
期刊：
影响因子：
7
通讯作者：
Nesbitt, Natasha M. M.
中科院分区：
文献类型：
--
作者：
Bahou, Wadie E. F.;Marchenko, Natalia;Nesbitt, Natasha M. M.
细胞保护性血红素加氧酶使血红素衍生化以产生一氧化碳、亚铁和异构体胆绿素，随后快速NAD（P）H依赖性胆绿素还原成抗氧化剂胆红素。最近的研究表明，胆绿素IXβ还原酶（BLVRB）参与造血谱系命运的氧化还原调节机制，仅限于巨核细胞和红系细胞发育，这是一种与BLVRA（胆绿素IXα还原酶）同源物不同且不重叠的功能。在这篇综述中，我们专注于BLVRB生物化学和遗传学的最新进展，突出了人类，小鼠和基于细胞的研究，定位BLVRB调节的氧化还原功能（或ROS积累）作为一个发育调谐触发器，管理巨核细胞/红系造血干细胞产生的命运。BLVRB晶体学和热力学研究已经阐明了底物利用，氧化还原偶联和细胞保护的关键决定因素，并已确定抑制剂和底物结合的单罗斯曼倍。这些进展为开发BLVRB选择性氧化还原抑制剂作为新的细胞靶点提供了独特的机会，这些靶点保留了造血（和其他）疾病治疗适用性的潜力。
Cytoprotective heme oxygenases derivatize heme to generate carbon monoxide, ferrous iron, and isomeric biliverdins, followed by rapid NAD(P)H-dependent biliverdin reduction to the antioxidant bilirubin. Recent studies have implicated biliverdin IXβ reductase (BLVRB) in a redox-regulated mechanism of hematopoietic lineage fate restricted to megakaryocyte and erythroid development, a function distinct and non-overlapping from the BLVRA (biliverdin IXα reductase) homologue. In this review, we focus on recent progress in BLVRB biochemistry and genetics, highlighting human, murine, and cell-based studies that position BLVRB-regulated redox function (or ROS accumulation) as a developmentally tuned trigger that governs megakaryocyte/erythroid lineage fate arising from hematopoietic stem cells. BLVRB crystallographic and thermodynamic studies have elucidated critical determinants of substrate utilization, redox coupling and cytoprotection, and have established that inhibitors and substrates bind within the single-Rossmann fold. These advances provide unique opportunities for the development of BLVRB-selective redox inhibitors as novel cellular targets that retain potential for therapeutic applicability in hematopoietic (and other) disorders.
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影响因子：
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