SEPHS1: Its evolution, function and roles in development and diseases

Arch Biochem Biophys. 2022 Nov 15:730:109426. doi: 10.1016/j.abb.2022.109426. Epub 2022 Oct 4.

Abstract

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.

Keywords: Cell death; Development; Osteoarthritis; Reactive oxygen species; Selenium; Selenophosphate synthetase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Diphosphate
  • Adenosine Triphosphatases
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cysteine
  • Mice
  • Phosphates
  • Phylogeny
  • Reactive Oxygen Species
  • Selenium*
  • Selenocysteine*

Substances

  • Adenosine Diphosphate
  • Adenosine Triphosphatases
  • Adenosine Triphosphate
  • Cysteine
  • Phosphates
  • Reactive Oxygen Species
  • Selenium
  • Selenocysteine
  • selenophosphate
  • Sephs1 protein, mouse