Functions of Polyamines in Mammals

Abstract

The content of spermidine and spermine in mammalian cells has important roles in protein and nucleic acid synthesis and structure, protection from oxidative damage, activity of ion channels, cell proliferation, differentiation, and apoptosis. Spermidine is essential for viability and acts as the precursor of hypusine, a post-translational addition to eIF5A allowing the translation of mRNAs encoding proteins containing polyproline tracts. Studies with Gy mice and human patients with the very rare X-linked genetic condition Snyder-Robinson syndrome that both lack spermine synthase show clearly that the correct spermine:spermidine ratio is critical for normal growth and development.

Keywords: N-methyl-D-aspartate receptor (NMDA receptor, NMDAR); Snyder-Robinson syndrome; Spermine; eukaryotic initiation factor 5A (eIF5A); hearing; polyamine; potassium channel; spermidine.

FIGURE 1.

Polyamine structures, biosynthesis, and interconversion. APAO, acetylpolyamine oxidase.

FIGURE 2.

Polyamine interaction with ion channels. A, spermine is depicted in a deep binding site in the inner cavity of a molecular model of the Kir6.2[N160D] mutant channel, generated as a homology model based on an open conformation model of KirBac1.1 (98) with this blocker configuration generated using AutoDock as described previously (54), and selected based on functional studies of Kir6.2[N160D] and Kir2.1 channel (55). B, side view of the crystal structure of the full-length ionotropic glutamate receptor, GluA2 (Protein Data Bank (PDB) ID 3KG2), with a single spermine molecule manually positioned in the transmembrane pore region. C, view of the GluA2 transmembrane domain from the intracellular side showing a single spermine in the pore region. D, two subunits (A/C) of the Bacillus cereus NaK channel pore (PDB ID 3E86) with putrescine (left), spermidine (middle), and spermine (right) docked in the selectivity filter (66).

FIGURE 3.

Effect of transgenic spermine synthase expression in Gy mice. A, polyamine content in brain. B, spermine synthase activity in brain (note log scale). C, survival. D, size. Results in panels A and B are shown as the mean ± S.E. for at least six animals. See Ref. for details. This figure was modified from research originally published in the Journal of Biological Chemistry. Wang, X., Ikeguchi, Y., McCloskey, D. E., Nelson, P., and Pegg, A. E. Spermine synthesis is required for normal viability, growth and fertility in the mouse. J. Biol. Chem. 2004. 279, 51370–51375. © The American Society for Biochemistry and Molecular Biology.

FIGURE 4.

Mutations causing Snyder Robinson Syndrome. A monomer of human spermine synthase (13) is shown as a ribbon (left) and topology diagram (right) (PDB IDs 3C6K and 3C6M). The N-terminal, central, and C-terminal domains are shown in brown, red, and green, respectively. The loop connecting the N-terminal and central domains is in gray. Known mutations causing SRS are shown (88–94).