Polyamines and Their Metabolism: From the Maintenance of Physiological Homeostasis to the Mediation of Disease

Abstract

The polyamines spermidine and spermine are positively charged aliphatic molecules. They are critical in the regulation of nucleic acid and protein structures, protein synthesis, protein and nucleic acid interactions, oxidative balance, and cell proliferation. Cellular polyamine levels are tightly controlled through their import, export, de novo synthesis, and catabolism. Enzymes and enzymatic cascades involved in polyamine metabolism have been well characterized. This knowledge has been used for the development of novel compounds for research and medical applications. Furthermore, studies have shown that disturbances in polyamine levels and their metabolic pathways, as a result of spontaneous mutations in patients, genetic engineering in mice or experimentally induced injuries in rodents, are associated with multiple maladaptive changes. The adverse effects of altered polyamine metabolism have also been demonstrated in in vitro models. These observations highlight the important role these molecules and their metabolism play in the maintenance of physiological normalcy and the mediation of injury. This review will attempt to cover the extensive and diverse knowledge of the biological role of polyamines and their metabolism in the maintenance of physiological homeostasis and the mediation of tissue injury.

The Polyamine Spermine Potentiates the Propagation of Negatively Charged Molecules through the Astrocytic Syncytium

“…PAs play a key role in brain function and cell survival [ 12 , 34 , 40 , 47 , 115 , 116 , 117 ]. Recently, it was reviewed that PAs are anti-inflammatory, antioxidant, antithrombotic, antidepressant [ 10 , 11 , 13 , 15 , 16 , 118 ], and neuroprotective [ 55 ]. Indeed, both SPM and SPD have demonstrated similar effects.…”

“…Astrocytes are connected by large diameter connexin (Cx) gap junction pores (GJs) that facilitate astrocytic communication and function [ 1 , 2 , 3 , 4 ]. Over the past decade, the interest about astrocytes [ 5 , 6 , 7 , 8 ] and polyamines (PAs) in the nervous system [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] has increased. Astrocytes have extensive communication via Cx GJ channels that make the three-dimensional astrocytic syncytium large, electrically isopotential [ 4 , 19 ], and unique [ 10 , 11 , 19 , 20 ].…”

“…Metabolites are transferred via glial Cx43 and Cx30 GJs for large distances where they may affect the neuronal environment [ 2 , 20 , 29 , 31 , 32 , 33 ]. Therefore, GJs and HCs together with transporters like SLC18B1 [ 34 ] and SLC22A [ 11 , 15 , 16 , 35 , 36 , 37 ] are PA uptake/release pathways in astrocytes and other glial cells.…”

“…PAs underlie many glial cell-involved CNS diseases and syndromes [ 3 , 10 , 11 , 15 ]. PA catabolism in brain is regulated by Spermidine/Spermine N 1-Acetyltransferase (SSAT), which catalyzes acetylation of SPD and SPM and polyamine oxidases (PAO, SMOX); these catalyze the oxidation of acetylated PAs to dangerous radicals, such as hydrogen peroxide and propyl aldehyde (3-aminopropanal) causing excitotoxicity, epilepsy, seizure, and astrogliosis [ 16 , 17 , 51 , 52 ]. There are ways to quench oxidation of PAs and to induce neuroprotection by blocking DAO, PAO, and SMOX by aminoguanidine, chloroquine [ 53 , 54 ], and probably by SPD which has a clear neuroprotective effect [ 55 ].…”

Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy

“…Dysregulation of polyamine homeostasis is implicated in a variety of disease states including neurodegenerative, infectious, and cancerous [ 13 , 14 , 15 ]. Because polyamines are absolutely required for proliferation and many oncogene-driven cancers rely on an elevated intracellular polyamine pool, both polyamine metabolism and transport are frequently dysregulated in cancer [ 16 ].…”