Interdisciplinary Program in Bioinformatics, College of Natural Sciences, Seoul National University, Seoul, South Korea.
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea.
Arch Biochem Biophys. 2022 Nov 15;730:109426. doi: 10.1016/j.abb.2022.109426. Epub 2022 Oct 4.
Selenophosphate synthetase (SEPHS) was originally discovered in prokaryotes as an enzyme that catalyzes selenophosphate synthesis using inorganic selenium and ATP as substrates. However, in contrast to prokaryotes, two paralogs, SEPHS1 and SEPHS2, occur in many eukaryotes. Prokaryotic SEPHS, also known as SelD, contains either cysteine (Cys) or selenocysteine (Sec) in the catalytic domain. In eukaryotes, only SEPHS2 carries out selenophosphate synthesis and contains Sec at the active site. However, SEPHS1 contains amino acids other than Sec or Cys at the catalytic position. Phylogenetic analysis of SEPHSs reveals that the ancestral SEPHS contains both selenophosphate synthesis and another unknown activity, and that SEPHS1 lost the selenophosphate synthesis activity. The three-dimensional structure of SEPHS1 suggests that its homodimer is unable to form selenophosphate, but retains ATPase activity to produce ADP and inorganic phosphate. The most prominent function of SEPHS1 is that it is implicated in the regulation of cellular redox homeostasis. Deficiency of SEPHS1 leads to the disturbance in the expression of genes involved in redox homeostasis. Different types of reactive oxygen species (ROS) are accumulated in response to SEPHS deficiency depending on cell or tissue types. The accumulation of ROS causes pleiotropic effects such as growth retardation, apoptosis, DNA damage, and embryonic lethality. SEPHS1 deficiency in mouse embryos affects retinoic signaling and other related signaling pathways depending on the embryonal stage until the embryo dies at E11.5. Dysregulated SEPHS1 is associated with the pathogenesis of various diseases including cancer, Crohn's disease, and osteoarthritis.
硒磷酸合成酶（SEPHS）最初在原核生物中被发现，是一种使用无机硒和 ATP 作为底物催化硒磷酸合成的酶。然而，与原核生物不同的是，许多真核生物中存在两个同源物，SEPHS1 和 SEPHS2。原核生物 SEPHS，也称为 SelD，在催化结构域中含有半胱氨酸（Cys）或硒代半胱氨酸（Sec）。在真核生物中，只有 SEPHS2 进行硒磷酸合成，并且在活性位点含有 Sec。然而，SEPHS1 在催化位置含有除 Sec 或 Cys 以外的氨基酸。SEPHS 的系统发育分析表明，原始 SEPHS 含有硒磷酸合成和另一种未知活性，而 SEPHS1 失去了硒磷酸合成活性。SEPHS1 的三维结构表明，其同源二聚体无法形成硒磷酸，但保留 ATPase 活性以产生 ADP 和无机磷酸盐。SEPHS1 的最突出功能是它参与调节细胞氧化还原稳态。SEPHS1 的缺乏会导致涉及氧化还原稳态的基因表达紊乱。根据细胞或组织类型的不同，SEPHS 缺乏会导致不同类型的活性氧（ROS）的积累。ROS 的积累会导致生长迟缓、细胞凋亡、DNA 损伤和胚胎致死等多种表型效应。小鼠胚胎中 SEPHS1 的缺乏会影响视黄酸信号转导和其他相关信号通路，具体取决于胚胎发育阶段，直到胚胎在 E11.5 死亡。失调的 SEPHS1 与各种疾病的发病机制有关，包括癌症、克罗恩病和骨关节炎。
