Sreekumar Parameswaran G, Hinton David R, Kannan Ram
Parameswaran G Sreekumar, David R Hinton, Ram Kannan, Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, CA 90033, United States.
World J Biol Chem. 2011 Aug 26;2(8):184-92. doi: 10.4331/wjbc.v2.i8.184.
Methionine is a highly susceptible amino acid that can be oxidized to S and R diastereomeric forms of methionine sulfoxide by many of the reactive oxygen species generated in biological systems. Methionine sulfoxide reductases (Msrs) are thioredoxin-linked enzymes involved in the enzymatic conversion of methionine sulfoxide to methionine. Although MsrA and MsrB have the same function of methionine reduction, they differ in substrate specificity, active site composition, subcellular localization, and evolution. MsrA has been localized in different ocular regions and is abundantly expressed in the retina and in retinal pigment epithelial (RPE) cells. MsrA protects cells from oxidative stress. Overexpression of MsrA increases resistance to cell death, while silencing or knocking down MsrA decreases cell survival; events that are mediated by mitochondria. MsrA participates in protein-protein interaction with several other cellular proteins. The interaction of MsrA with α-crystallins is of utmost importance given the known functions of the latter in protein folding, neuroprotection, and cell survival. Oxidation of methionine residues in α-crystallins results in loss of chaperone function and possibly its antiapoptotic properties. Recent work from our laboratory has shown that MsrA is co-localized with αA and αB crystallins in the retinal samples of patients with age-related macular degeneration. We have also found that chemically induced hypoxia regulates the expression of MsrA and MsrB2 in human RPE cells. Thus, MsrA is a critical enzyme that participates in cell and tissue protection, and its interaction with other proteins/growth factors may provide a target for therapeutic strategies to prevent degenerative diseases.
甲硫氨酸是一种高度易被氧化的氨基酸，在生物系统中产生的许多活性氧可将其氧化为甲硫氨酸亚砜的S型和R型非对映体形式。甲硫氨酸亚砜还原酶（Msrs）是与硫氧还蛋白相关的酶，参与甲硫氨酸亚砜向甲硫氨酸的酶促转化。尽管MsrA和MsrB具有相同的甲硫氨酸还原功能，但它们在底物特异性、活性位点组成、亚细胞定位和进化方面存在差异。MsrA已定位在不同的眼部区域，并在视网膜和视网膜色素上皮（RPE）细胞中大量表达。MsrA保护细胞免受氧化应激。MsrA的过表达增加对细胞死亡的抗性，而MsrA的沉默或敲低则降低细胞存活率；这些事件由线粒体介导。MsrA参与与其他几种细胞蛋白的蛋白质-蛋白质相互作用。鉴于α-晶体蛋白在蛋白质折叠、神经保护和细胞存活方面的已知功能，MsrA与α-晶体蛋白的相互作用至关重要。α-晶体蛋白中甲硫氨酸残基的氧化导致伴侣功能丧失，并可能导致其抗凋亡特性丧失。我们实验室最近的研究表明，在年龄相关性黄斑变性患者的视网膜样本中，MsrA与αA和αB晶体蛋白共定位。我们还发现，化学诱导的缺氧调节人RPE细胞中MsrA和MsrB2的表达。因此，MsrA是一种参与细胞和组织保护的关键酶，其与其他蛋白质/生长因子的相互作用可能为预防退行性疾病的治疗策略提供靶点。
