Remaining Mysteries of Molecular Biology: The Role of Polyamines in the Cell

Abstract

The polyamines (PAs) spermidine, spermine, putrescine and cadaverine are an essential class of metabolites found throughout all kingdoms of life. In this comprehensive review, we discuss their metabolism, their various intracellular functions and their unusual and conserved regulatory features. These include the regulation of translation via upstream open reading frames, the over-reading of stop codons via ribosomal frameshifting, the existence of an antizyme and an antizyme inhibitor, ubiquitin-independent proteasomal degradation, a complex bi-directional membrane transport system and a unique posttranslational modification-hypusination-that is believed to occur on a single protein only (eIF-5A). Many of these features are broadly conserved indicating that PA metabolism is both concentration critical and evolutionary ancient. When PA metabolism is disrupted, a plethora of cellular processes are affected, including transcription, translation, gene expression regulation, autophagy and stress resistance. As a result, the role of PAs has been associated with cell growth, aging, memory performance, neurodegenerative diseases, metabolic disorders and cancer. Despite comprehensive studies addressing PAs, a unifying concept to interpret their molecular role is missing. The precise biochemical function of polyamines is thus one of the remaining mysteries of molecular cell biology.

Trace Amines and Their Receptors

“…Like the archetypal trace amines, polyamines are found in all species (Miller-Fleming et al, 2015). They are traditionally viewed as consisting of cadaverine, putrescine, spermidine, and spermine.…”

“…They are traditionally viewed as consisting of cadaverine, putrescine, spermidine, and spermine. Polyamine metabolism is complex, not least because of their ability to interconvert, and this has been detailed fully in numerous review articles (Miller-Fleming et al, 2015;Pegg, 2016). Putrescine is primarily derived from L-ornithine by the action of ornithine decarboxylase (EC 4.1.1.17; Table 1).…”

The effects of putrescine are partly overlapping with osmotic stress processes in wheat

“…In a recent review it was suggested that a group of genes that increase their translation in the presence of PAs, so called "PA modulon" [19] The beneficial effect of putrescine (PUT) pre-treatment, added to the hydroponic solution, against PEG-induced osmotic stress has been demonstrated earlier in wheat and maize plants [11]. The results demonstrated that fine tuning in the PA pool is important for PA signalling, which influences the hormonal balance required.…”

Transglutaminase 2, a double face enzyme

“…Alternatively, beside arising from direct interventions of the main enzymatic and scaffolding activities of Tgase2, they might depend on the expression of mutant forms of Tgase with altered sensitivity to effectors (Lai and Greenberg 2013) or through the modification of intracellular proteins that trigger differential responses as in the case of the control of NFκB activity by polymerization of IkB (Mann et al 2006). On the other side, the opposing effects of Tgase on cell functions might relate also to cellular "receptivity", e.g., through the modulation of cellular metabolites like polyamines which are known to influence cellular responses (notably proliferation) (Miller-Fleming et al 2015), as well as to accumulate inside the cells as protein-polyamine adducts (Folk et al 1980;Haddox and Russell 1981;Lentini et al 2004). In addition, in several cell types overexpression of Tgase2 and alternatively its suppression alter features of the cell cycle and these effects are apparently triggered by both native and transamidation inactive mutants as reviewed by Nurminskaya and Belkin (2012) suggesting that the likelihood that these effects are linked directly to protein-protein interaction or alternatively to G-protein activity rather than to the transamidation required to modify the activity of transcription factors like NFκB or Sp1 or the signaling through the TGFβ pathway.…”