Mammalian polyamine metabolism and function

Abstract

Polyamines are ubiquitous small basic molecules that play multiple essential roles in mammalian physiology. Their cellular content is highly regulated and there is convincing evidence that altered metabolism is involvement in many disease states. Drugs altering polyamine levels may therefore have a variety of important targets. This review will summarize the current state of understanding of polyamine metabolism and function, the regulation of polyamine content, and heritable pathological conditions that may be derived from altered polyamine metabolism.

Figure 1

Polyamine structures, biosynthesis and interconversion. Polyamine structures are shown in blue. Enzymes are shown in red italic fonts (ODC, L-ornithine decarboxylase; AdoMetDC, S-adenosylmethionine decarboxylase; SMO, spermine oxidase; SSAT, spermidine/spermine-N¹-acetyltransferase; APAO, acetylpolyamine oxidase).

Figure 2

Regulation of AdoMetDC. The transcription of the AdoMetDC gene and the translation of its message are negatively regulated by spermidine and spermine (Spd/Spm). The translational regulation involves the 5′UTR(shown in dark blue) where a small upstream ORF encoding the peptide MAGDIS (shown in red) is located. The mRNA encodes a proenzyme (π subunit) that undergoes a spontaneous processing reaction generating the pyruvoyl (shown as Py in red) prosthetic group at the amino terminus of the α subunit and a small β subunit. This processing and the activity of the final (αβ)₂ enzyme are activated by putrescine. Incorrect protonation of the pyruvate group during enzymatic reaction can lead to its transamination and conversion to Ala permanently inactivating the enzyme. Degradation of the enzyme by the proteasome requires polyubiquitination and is increased by Spd/Spm. It is possible that transamination precedes ubiquitination as shown, but details are not yet known.

Figure 3

Structure and mechanism of aminopropyltransferases. Panel A shows the homodimeric forms of spermine synthase and spermidine synthase. Panel B shows the similarity between the N-terminal domain of spermine synthase monomer and the AdoMetDC proenzyme, and the similarity between the structure formed by central- and C-terminal domains of spermine synthase and the spermidine synthase monomer. Panel C shows the general mechanism for aminopropyl transfer illustrated with spermine synthase.

Figure 4

Regulation of ODC. ODC is regulated by polyamines (PA) at the levels of transcription, translation and protein stability and probably also by transcript stability as shown. ODC translation is regulated by the 5′UTR (shown in dark blue). Only the dimeric form of ODC is active. Antizyme protein (yellow) plays a critical role in the stability of ODC since it binds to the ODC monomer and targets it for proteasomal degradation without need for ubiquitination. Antizyme is released and can recycle to produce further ODC degradation. Antizyme synthesis is increased by high polyamine levels by stimulating the frameshifting needed for correct translation past the internal stop codon, and also possibly by increased transcription. Antizyme is degraded by the proteasome after polyubiquitination and degradation is increased by low polyamine levels. Antizyme inhibitor is an inactive ODC paralog, which is monomeric and is degraded after polyubiquitination. It binds tightly to antizyme forming a stable complex and preventing ODC degradation.

Figure 5

Regulation of SSAT. Transcription of the Sat1 gene encoding SSAT, correct processing of the initial transcript and translation of its mRNA are increased by polyamines (PA). The pre-mRNA transcript can also be processed incorrectly and degraded when polyamine levels are low. The active SSAT is a homodimer and it is rapidly ubiquitinated and degraded. Polyamines inhibit this degradation.

Figure 6

Functions of polyamines. Polyamine levels affect ion channels, cell-cell interactions, the cytoskeleton, signaling via phosphorylation and other mechanisms, activity of eIF5A via the role of spermidine as a precursor for its hypusination, transcription and mRNA translation. The effects on transcription and translation (both direct and indirect) alter the cellular levels of many proteins making up the polyamine-responsive modulon as described by Igarashi and colleagues (96, 97).