Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York 14642, USA.
Curr Drug Targets. 2010 Dec;11(12):1586-94. doi: 10.2174/1389450111009011586.
The range and diversity of functions of biliverdin reductase (BVR) is unmatched by any enzyme characterized to date. BVR is the sole catalyst for the conversion of biliverdin-IXα the activity product of the stress-inducible HO-1 and the constitutive HO-2, to bilirubin-IXα. Bilirubin is both cytoprotective and cytotoxic, quenches reactive oxygen species (ROS) and inhibits inflammatory and mitogen-induced ROS-mediated responses, and its elevated levels in the newborn adversely effects neuronal cells. Thus, BVR occupies a center stage in cellular defense mechanisms. As a dual specificity (serine/threonine/tyrosine) kinase the human (h) BVR influences transduction of extracellular stimuli to kinases downstream of the insulin/IGF-1(insulin-like growth factor-1)/MAPK/PI3-K signaling pathways. As a bZip-type transcription factor it binds to AP-1 (activator protein-1) and CRE (cAMP response element) sites and stimulates stress-inducible gene expression; as a scaffold protein, it is a platform for interaction of kinases; while acting as an intracellular shuttle, it transports regulatory factors to their target sites. hBVR promoter has consensus sequences with several regulatory elements. The gene is subject to negative and positive regulation, respectively, by TNF-α (tumor necrosis factor-α) and oxidative stress/hypoxia. Small human BVR-based peptides effectively duplicate polypeptide's activating influence on kinases, or mimic inhibitors of cell signaling. This, points to a realistic prospect of their use in clinical settings. The present review will briefly update cytoprotective activity and cytotoxicity of bile pigments and will focus on findings that link hBVR to cell signaling.
胆红素还原酶 (BVR) 的功能范围和多样性是迄今为止任何已鉴定的酶都无法比拟的。BVR 是唯一的催化剂，可将胆红素-IXα（应激诱导的 HO-1 和组成型 HO-2 的活性产物）转化为胆红素-IXα。胆红素具有细胞保护和细胞毒性作用，可淬灭活性氧 (ROS) 并抑制炎症和有丝分裂原诱导的 ROS 介导的反应，其在新生儿中的升高水平对神经元细胞产生不利影响。因此，BVR 在细胞防御机制中占据中心舞台。作为一种双重特异性（丝氨酸/苏氨酸/酪氨酸）激酶，人 (h) BVR 影响胰岛素/IGF-1（胰岛素样生长因子-1）/MAPK/PI3-K 信号通路下游激酶的转导。作为 bZip 型转录因子，它与 AP-1（激活蛋白-1）和 CRE（cAMP 反应元件）结合并刺激应激诱导的基因表达；作为支架蛋白，它是激酶相互作用的平台；同时作为细胞内穿梭物，它将调节因子运输到其靶位。hBVR 启动子具有与几个调节元件的共识序列。该基因分别受到 TNF-α（肿瘤坏死因子-α）和氧化应激/缺氧的负调控和正调控。基于小的人 BVR 的肽有效地复制多肽对激酶的激活作用，或模拟细胞信号转导的抑制剂。这表明它们在临床环境中的使用具有现实前景。本综述将简要更新胆色素的细胞保护活性和细胞毒性，并重点介绍将 hBVR 与细胞信号转导联系起来的发现。
