The role of polyamine metabolism in cellular function and physiology

Abstract

Polyamines are molecules with multiple amino groups that are essential for cellular function. The major polyamines are putrescine, spermidine, spermine, and cadaverine. Polyamines are important for posttranscriptional regulation, autophagy, programmed cell death, proliferation, redox homeostasis, and ion channel function. Their levels are tightly controlled. High levels of polyamines are associated with proliferative pathologies such as cancer, whereas low polyamine levels are observed in aging, and elevated polyamine turnover enhances oxidative stress. Polyamine metabolism is implicated in several pathophysiological processes in the nervous, immune, and cardiovascular systems. Currently, manipulating polyamine levels is under investigation as a potential preventive treatment for several pathologies, including aging, ischemia/reperfusion injury, pulmonary hypertension, and cancer. Although polyamines have been implicated in many intracellular mechanisms, our understanding of these processes remains incomplete and is a topic of ongoing investigation. Here, we discuss the regulation and cellular functions of polyamines, their role in physiology and pathology, and emphasize the current gaps in knowledge and potential future research directions.

Keywords: cellular function; pathophysiology; physiology; polyamines; sex differences.

Graphical abstract

Figure 1.

The basic biochemistry of polyamines. Arginine serves as a major substrate for the nitric oxide synthases (NOS, producing NO), arginases (ARG1and ARG2), and AGAT that synthesize ornithine as a reaction byproduct. Ornithine is a direct substrate for polyamine biosynthesis, as well as for a polyamine-unrelated pathway initiated by OAT. The biosynthesis of major polyamines starts with the rate-limiting enzymes ODC1 and AMD followed by SRM and SMS. Spermidine and spermine are catabolized by the rate-limiting spermidine/spermine SSAT followed by PAOX. ADC, arginine decarboxylase; AGMAT, agmatinase; AMD1, S-adenosylmethionine decarboxylase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; dcSAM, decarboxylated S-adenosylmethionine; MAT2A, methionine adenosyltransferase 2 A; MTA, 5′-methylthioadenosine; MTAP, methylthioadenosine phosphorylase; MTR, 5-methylthioribose-1-phosphate; NO, nitric oxide; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase; PAOX, polyamine oxidase; SRM, spermidine synthase; SMS, spermine synthase; SAM, S-adenosylmethionine; SMOX, spermine oxidase; SSAT, N1-acetyltransferase 1. Created with Biorender.com.

Figure 2.

The antizyme mechanism that regulates enzymatic activity in polyamine biosynthesis. A: polyamine biosynthesis occurs when two ODC1 subunits bind and become an enzymatically active dimer; the two subunits rapidly switch between an associated and a disassociated state. B: the antizyme inhibitor, in its shorter form, has a greater affinity for the antizyme than the ODC1 subunit, thus, when both the short form of the antizyme and its inhibitor are present, they preferentially bind to each other, and the two ODC1 subunits associate unopposed by the antizyme. C: when relatively high levels of polyamines are present, this induces a frameshift in the antizyme mRNA, leading to creation of a full-length antizyme protein. The full-length antizyme has a higher affinity for ODC1 subunit and forms an ODC1/antizyme complex that inhibits polyamine synthesis. ODC, ornithine decarboxylase.

Figure 3.

An overview of the major known cellular functions of polyamines. Created with Biorender.com.

Figure 4.

A schematic highlighting the import and export proteins known to transport polyamines and the major cellular function of polyamines. Shown are ATP-binding cassette transporters; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CNG channel, cyclic nucleotide-gated channel; Kir channels, inward rectifier potassium channels; SLC transporters, solute carrier transporters; TRPC channels, transient receptor potential canonical channels; TRPM, transient receptor potential melastatin channels; TRPV channels, transient receptor potential vanilloid channels. Created with Biorender.com.

Figure 5.

An overview of alterations in the polyamine biosynthesis and catabolism pathways that contribute to cardiovascular and renal pathophysiology.