Deoxyhypusine hydroxylase (DOHH)

Deoxyhypusine hydroxylase is a nonheme diiron metalloenzyme that catalyzes the final, oxygen- and iron-dependent hydroxylation step in the biosynthesis of hypusine—a unique post-translationally modified amino acid—exclusively in eukaryotic initiation factor 5A (eIF5A)[1][2][3][5][6]. This two-step modification, with DOHH acting after deoxyhypusine synthase, is essential for converting a specific lysine residue in eIF5A to the fully functional hypusine residue, which is required for eIF5A’s role in translation elongation and regulation of cell proliferation[2][3][6]. DOHH features a distinctive eight HEAT-repeat α-helical structure with an internal diiron active site, coordinated by strictly conserved His-Glu motifs[3][6]. DOHH is widely conserved in eukaryotes, and loss of its activity impairs synthesis of hypusine-containing eIF5A, resulting in failure to support normal cell growth[1][2][4][5]. The biochemistry and structure of DOHH distinguish it from other protein hydroxylases, as it forms a stable μ-1,2-peroxo–diiron(III) intermediate during catalysis. There are no established clinical drugs targeting DOHH, but it is recognized as a promising target for research focused on cancer and diseases requiring modulation of cell proliferation[1][4][6].

Other names

deoxyhypusine hydroxylase/monooxygenaseHLRC1 (gene)DOHH (gene/protein)HEAT-repeat proteinhypusine synthesis enzyme

Iron chelation or disruption of Fe(II) center may inhibit DOHH activity Small molecules targeting the diiron center or impairing substrate binding/hydroxylation step Blockade of DOHH prevents formation of hypusine on eIF5A, inhibiting eIF5A activity and downstream cell proliferation[1][6]