Kryukov Gregory V, Kumar R Abhilash, Koc Ahmet, Sun Zhaohui, Gladyshev Vadim N
Department of Biochemistry, University of Nebraska, Lincoln, NE 68588-0664, USA.
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4245-50. doi: 10.1073/pnas.072603099.
Selenoprotein R (SelR) is a mammalian selenocysteine-containing protein with no known function. Here we report that cysteine homologs of SelR are present in all organisms except certain parasites and hyperthermophiles, and this pattern of occurrence closely matches that of only one protein, peptide methionine sulfoxide reductase (MsrA). Moreover, in several genomes, SelR and MsrA genes are fused or clustered, and their expression patterns suggest a role of both proteins in protection against oxidative stress. Consistent with these computational screens, growth of Saccharomyces cerevisiae SelR and MsrA mutant strains was inhibited, and the strain lacking both genes could not grow, in the presence of H2O2 and methionine sulfoxide. We found that the cysteine mutant of mouse SelR, as well as the Drosophila SelR homolog, contained zinc and reduced methionine-R-sulfoxide, but not methionine-S-sulfoxide, in in vitro assays, a function that is both distinct and complementary to the stereo-specific activity of MsrA. These findings identify a function of the conserved SelR enzyme family, define a pathway of methionine sulfoxide reduction, reveal a case of convergent evolution of similar function in structurally distinct enzymes, and suggest a previously uncharacterized redox regulatory role of selenium in mammals.
硒蛋白R（SelR）是一种哺乳动物含硒代半胱氨酸的蛋白质，其功能尚不清楚。在此我们报告，除了某些寄生虫和嗜热菌外，SelR的半胱氨酸同源物存在于所有生物体中，并且这种出现模式仅与一种蛋白质——肽甲硫氨酸亚砜还原酶（MsrA）的模式密切匹配。此外，在几个基因组中，SelR和MsrA基因融合或成簇，并且它们的表达模式表明这两种蛋白质在抵抗氧化应激中发挥作用。与这些计算筛选结果一致，在过氧化氢和甲硫氨酸亚砜存在的情况下，酿酒酵母SelR和MsrA突变株的生长受到抑制，并且缺乏这两个基因的菌株无法生长。我们发现，小鼠SelR的半胱氨酸突变体以及果蝇SelR同源物在体外试验中含有锌并能还原甲硫氨酸-R-亚砜，但不能还原甲硫氨酸-S-亚砜，该功能与MsrA的立体特异性活性既不同又互补。这些发现确定了保守的SelR酶家族的功能，定义了甲硫氨酸亚砜还原途径，揭示了结构不同的酶中相似功能的趋同进化情况，并表明硒在哺乳动物中具有以前未被表征的氧化还原调节作用
