Polyamine Homeostasis in Development and Disease

Abstract

Polycationic polyamines are present in nearly all living organisms and are essential for mammalian cell growth and survival, and for development. These positively charged molecules are involved in a variety of essential biological processes, yet their underlying mechanisms of action are not fully understood. Several studies have shown both beneficial and detrimental effects of polyamines on human health. In cancer, polyamine metabolism is frequently dysregulated, and elevated polyamines have been shown to promote tumor growth and progression, suggesting that targeting polyamines is an attractive strategy for therapeutic intervention. In contrast, polyamines have also been shown to play critical roles in lifespan, cardiac health and in the development and function of the brain. Accordingly, a detailed understanding of mechanisms that control polyamine homeostasis in human health and disease is needed to develop safe and effective strategies for polyamine-targeted therapy.

Keywords: aging; cancer; development; metabolism; polyamines.

Figure 1

Polyamine metabolism and interacting pathways. Enzymes that control central polyamine biosynthesis and catabolism are shown, as well as the metabolic circuits that feed into the control of polyamine homeostasis. Light blue, substrates and products; red, inhibitors of key enzymes. ADC, Arginine decarboxylase; AHCY, S-adenosylhomocysteine hydrolase; AMD1, Adenosylmethionine decarboxylase-1; AGMAT, Agmatinase; Arg, Arginine; ARG, Arginase; ASL, Arginosuccinate lyase; ASS1, Arginosuccinate synthase-1; AZIN1, Antizyme inhibitor-1; Ac-Spd, N¹-acetylated Spd; Ac-Spm: N¹-acetylated Spm; CBS, Cystathione β-synthase; CSE, Cystathionine γ-lyase; Cys, Cysteine; DFMO, Difluoromethylornithine; DHPS, Deoxyhypusine synthase; DOHH, Deoxyhypusine hydroxylase; eIF5A, Eukaryotic translation initiation factor 5A; GC7, N1-guanyl-1, 7-diamine-heptane; GSH, Glutathione; HS, Homocysteine; Hyp, Hypusine; MATs, Methionine adenosyltransferases -1, -2A and -2B; Met, Methionine; MTA, 5′methylthioadenosine; MTAP, MTA phosphorylase; MTDIA, Methylthio-DaDMe-Immucillin-A; MTOB, 4-Methylthio-2-oxobutanoic acid; MTR: 5′ methylthioribose; MTs, Methyltransferase; MS, Methionine synthase; nor-NOHA, Nω-hydroxy-nor-arginine; ODC, Ornithine decarboxylase; OAZs, ODC antizyme-1, -2 and -3; OTC, Ornithine transcarbamylase; PAOX, Polyamine oxidase; SAH, S-adenosylhomocysteine; SAHH. SAH hydrolase; SAM, S-adenosylmethionine; Ser, Serine; SSAT1, SPD/SPM acetyltransferase 1 (SAT1); SMOX, Spermine oxidase; SMS, Spm synthase; SRS, Spd synthase.