The unusual
amino acid hypusine [N (ε) -(4-amino-2-hydroxybutyl)
lysine] is a unique component of one cellular
protein,
eukaryotic translation initiation factor 5A (eIF-5A, old terminology, eIF-4D). It is formed posttranslationally and exclusively in this
protein in two consecutive enzymatic reactions, (i) modification of a single
lysine residue of the
eIF-5A precursor
protein by the transfer of the 4-aminobutyl moiety of the
polyamine spermidine to itsε-amino group to form the intermediate,
deoxyhypusine [N (ε) -(4-aminobutyl)
lysine] and (ii) subsequent hydroxylation of this intermediate to form
hypusine. The amino acid sequences surrounding the
hypusine residue are strictly conserved in all eukaryotic species examined, suggesting the fundamental importance of this
amino acid throughout evolution.
Hypusine is required for the activity of eIF-5Ain vitro. There is strong evidence that
hypusine and
eIF-5A are vital for eukaryotic cell proliferation. Inactivation of both of the
eIF-5A genes is lethal in yeast and the
hypusine modification appears to be a requirement for yeast survival (Schnier et al., 1991 [Mol Cell Biol 11: 3105-3114]; Wöhl et al., 1993 [Mol Gen Genet 241: 305-311]). Furthermore, inhibitors of either of the
hypusine biosynthetic
enzymes,
deoxyhypusine synthase or
deoxyhypusine hydroxylase, exert strong anti-proliferative effects in mammalian cells, including many human
cancer cell lines. These inhibitors hold potential as a new class of
anticancer agents, targeting one specific eukaryotic cellular reaction,
hypusine biosynthesis.