Polyamines: Key Players in Immunometabolism and Immune Regulation

Abstract

Polyamines are small organic molecules ubiquitously present in all living organisms and function as crucial regulators of biological processes ranging from fundamental cellular metabolism to immune regulation. Dysregulation of polyamine metabolism has been implicated in numerous diseases, including neurodegenerative disorders, inflammatory conditions, autoimmune diseases, and cancer. This review provides an overview of pathophysiology of these conditions, highlighting polyamines' role in immunometabolic alterations in the context of immune regulation. Exploring the intricate mechanisms of polyamine metabolism holds promise for advancing our understanding of disease processes and developing potential innovative therapeutic interventions.

Keywords: Cancer; HIV; Immune regulation; Immunometabolism; Polyamines; Tumorigenesis.

Figure 1.. The polyamine metabolic pathways, transport, and eIF5A hypusination.

Polyamine uptake by cells occurs through the cell surface proteoglycans heparin sulfate and glypican 1 (GPC1) system while putrescine transports through solute carrier SLC3A2. Spermidine and spermine efflux through the cells by ornithine transcarbamylase 1–3 (OCT1–3). The uptake could be inhibited by polyamine transport inhibitors (PTIs). (A) Polyamine synthesis involves two synthetic pathways either involving conversion of L-Arginine or methionine to polyamines. The first pathway involves the conversion of L-Arginine to L-Ornithine by arginase 1 with the release of urea or it is converted to nitric oxide and L-Citrulline by nitric oxide synthase (NOS). The excessive L-Citrulline acts as an allosteric inhibitor of arginase 1. Further, L-Ornithine is sequentially converted to the 3 major polyamines through a rate-limiting enzyme ornithine decarboxylase (ODC) and spermidine/spermine synthases. The ODC activity can be inhibited by difluoromethylornithine (DFMO). The proto-oncogene protein MYC functions as a trans-activator of ODC to enhance the proliferation of cancer cells and to induce tumorigenesis. The second pathway involves the conversion of methionine to polyamines through an ATP-dependent methionine adenosyl transferase 2 (MAT2) to form S-adenosylmethionine (SAMe) which is further decarboxylated to decarboxy SAMe through SAMe decarboxyalse and could be inhibited by methyl glyoxal-bis-guanidylhydrazone (MGBG) and SAM486A (CGP48664 or Sardomozide). (B) Multifaceted role of spermidine and hypusination of eIF5A. Hypusination occurs at a conserved lysine residue of eIF5A and is mediated by spermidine through the action of deoxyhypusine synthase (DHS) forming an inactive intermediate deoxyhypusine eIF5A which is further converted to an active hypusinated eIF5A by deoxyhypusine hydroxylase (DOHH). The active hypusinated eIF5A can be converted to an inactive form through acetylation at lysine 47 through P300/CBP-associated factor (PCAF) or by spermidine/spermine N’- acetyltransferase (SSAT) or back to its active form through deacetylation by histidine deacetylase 6 (HDAC6) or sirtuin-2 (SIRT2). (C) In vitro oxidative deamination of polyamines. The oxidative deamination causes release of toxic by-products such as aldehydes, ammonia, hydrogen peroxide and acrolein. Figure was generated using Microsoft^® PowerPoint.

Figure 2.. Schematic representation of pleiotropic effects of polyamine-induced immunometabolic changes and associated signaling pathways.

(A) Polyamine immunometabolism pathways impact various cellular processes and could be manipulated by either blocking the pathway with inhibitors or uptake by polyamine transport inhibitors. Upward and Downward red arrows indicate enhanced or decreased protein expression respectively. (B) Modulation of polyamine-induced signaling pathways in immune cells. TCR: T cell Receptor; HIF- 1α: Hypoxia-inducible Factor-1α; ODC: Ornithine Decarboxylase; ATG5: Autophagy-related Gene 5; mTOR: Mammalian Target of Rapamycin; Nos2: Nitric Oxide Synthase 2; eIF5A: Eukaryotic Translation Initiation Factor 5A; DC: Dendritic Cells; IDO1: Indoleamine 2,3-Ddioxygenase 1; Arg: Arginase); MDSCs: Myeloid-Derived Suppressor Cells.