Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder.

Deoxyhypusine hydroxylase (DOHH) is the enzyme catalyzing the second step in the post-translational synthesis of hypusine [N-(4-amino-2-hydroxybutyl)lysine] in the eukaryotic initiation factor 5A (eIF5A). Hypusine is formed exclusively in eIF5A by two sequential enzymatic steps catalyzed by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Hypusinated eIF5A is essential for translation and cell proliferation in eukaryotes, and all three genes encoding eIF5A, DHPS, and DOHH are highly conserved throughout eukaryotes.

Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice.

Eukaryotic initiation factor 5A (eIF5A) is an essential protein that requires a unique amino acid, hypusine, for its activity. Hypusine is formed exclusively in eIF5A post-translationally via two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase. Each of the genes encoding these proteins, Eif5a, Dhps, and Dohh, is required for mouse embryonic development.

Elevation of cellular Mg levels by the Mg transporter, Alr1, supports growth of polyamine-deficient cells.

The polyamines putrescine, spermidine, and spermine are required for normal eukaryotic cellular functions. However, the minimum requirement for polyamines varies widely, ranging from very high concentrations (mm) in mammalian cells to extremely low in the yeast Yeast strains deficient in polyamine biosynthesis (Δ, lacking ornithine decarboxylase, and Δ, lacking SAM decarboxylase) require externally supplied polyamines, but supplementation with as little as 10 m spermidine restores their growth. Here, we report that culturing a Δ mutant or a Δ mutant in a standard polyamine-free minimal medium (SDC) leads to marked increases in cellular Mg content.

The Yeast Heterochromatin Protein Sir3 Experienced Functional Changes in the AAA+ Domain After Gene Duplication and Subfunctionalization.

A key unresolved issue in molecular evolution is how paralogs diverge after gene duplication. For multifunctional genes, duplication is often followed by subfunctionalization. Subsequently, new or optimized molecular properties may evolve once the protein is no longer constrained to achieve multiple functions.