Aliphatic polyamines in physiology and diseases

doi:10.1016/j.clnu.2013.09.019

Clinical Nutrition

Volume 33, Issue 1, February 2014, Pages 14-22

https://doi.org/10.1016/j.clnu.2013.09.019 Get rights and content

Summary

Aliphatic polyamines are a family of polycationic molecules derived from decarboxylation of the amino acid ornithine that classically comprise three molecules: putrescine, spermidine and spermine. In-cell polyamine homeostasis is tightly controlled at key steps of cell metabolism. Polyamines are involved in an array of cellular functions from DNA stabilization, and regulation of gene expression to ion channel function and, particularly, cell proliferation. As such, aliphatic polyamines play an essential role in rapidly dividing cells such as in the immune system and digestive tract. Because of their role in cell proliferation, polyamines are also involved in carcinogenesis, prompting intensive research into polyamine metabolism as a target in cancer therapy. More recently, another aliphatic polyamine, agmatine, the decarboxylated derivative of arginine, has been identified as a neurotransmitter in mammals, and investigations have focused on its effects in the CNS, notably as a neuroprotector in brain injury.

Introduction

Aliphatic polyamines (simply quoted as polyamines throughout this paper) classically refer to three molecules: putrescine, spermidine and spermine. They are found ubiquitously in the body. They are the focus of intensive research due to their involvement in many physiological functions such as immunity and intestinal function, but especially due to their involvement in carcinogenesis. Agmatine, the decarboxylated derivative of arginine, was recently found in mammals, and several studies have investigated its potential functions, especially in the CNS.

Section snippets

Structure and metabolism

Polyamines are ornithine derivatives that form a small family of three members: putrescine, spermidine and spermine. Their chemical structure is shown in Fig. 1. Polyamine metabolic pathways (synthesis, interconversion and catabolism) are shown in Fig. 2. The first step of polyamine synthesis is the enzymatic decarboxylation of ornithine into putrescine by ornithine decarboxylase (ODC). Spermidine is derived from putrescine by addition of an aminopropyl group via spermidine synthase. Spermine

Biological functions of polyamines

Polyamines are small water-soluble polycationic molecules at physiological pH; in the cell, they are usually bound to polyanionic molecules like DNA, RNA and phospholipids. These interactions are essential for their biological roles.⁹ Polyamines are involved in multiple aspects of cell physiology (Table 1).

Physiological importance of polyamines

The role of polyamines in cell cycle progression makes them essential for cell proliferation. As a result they are heavily involved in the physiology of tissues that play host to high rates of cell division, such as the digestive, immune and reproductive systems. The different roles of polyamines in tissue physiology are summarized in Table 2.

Congenital disorders of polyamine metabolism

Given their multiple roles in cell proliferation and differentiation, defective polyamine synthesis heavily impacts normal development.

Knocking out ODC and SAMdc in mice is lethal at very early embryonic stages. In gyro mice, a model of spermine synthase inactivation, the very low tissue spermine content is associated with a striking phenotype including neurological abnormalities (such as circling behavior pattern), deafness, sterility, profound postnatal growth retardation, and a short

Structure and metabolism

Agmatine (Fig. 1) is the decarboxylated derivative of arginine and a well-known intermediate of polyamine metabolism in plants, bacteria, fungi and invertebrates. It was first identified in bovine brain in 1994 as a substance able to displace clonidine from imidazoline receptors.⁴⁵ Agmatine has since been found in many tissues and organs, for example in rats, where the highest concentrations are found in the stomach, aorta and small intestine.^S68

Agmatine is endogenously synthesized from

Conclusion

Classical polyamines (putrescine, spermidine and spermine) are involved in multiple aspects of cell physiology, interacting with cell components such as nucleic acids, cytoskeleton proteins and membranes, and are involved in functions such as regulation of gene expression, ion channel function and cell cycle progression. Polyamines levels in cells are tightly controlled by strict regulation of key enzymes of their synthesis and catabolism and by regulation of their transport but could also be

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Obesity is a non-communicable chronic disease that continues to increase around the world. Recently, it has been shown that curcumin positively affects lipid, energy metabolism, and body weight change. Moreover, polyamines are aliphatic polycations, which can be found in all mammalian cells and foods and have been shown to prevent obesity through many different mechanisms. However, whether the co-administration of curcumin and polyamines has synergistic effects has yet to be clarified. Our study aimed to examine the effects of curcumin and polyamines on obesity and to assess the changes in serum polyamine levels and tissue parameters. 28 Sprague-Dawley male rats were fed a high-fat diet for 10 weeks to develop obesity, and then they were randomly divided into 4 groups as the control group (CONT), curcumin group (CUR), polyamine group (POL), curcumin and polyamine group (CUR+POL) and supplements were administered for 6 weeks. As a result, the lowest feed consumption in rats was recorded in the CUR+POL group, and the group with the lowest weight after supplements was the POL group, then the CUR+POL, CONT, and CUR groups, respectively. N-acetyl putrescine and GABA levels increased significantly after obesity development. The total histopathological score in fat, liver, and kidney tissues increased significantly in the CONT group. In the CUR+POL group, damage to the tissues was in the direction of recovery compared to the other groups, and the expression of NF-κB was significantly low. These results suggest that combined curcumin and polyamines may have protective effects.
Putrescine adsorption on pristine and Cu-decorated B<inf>12</inf>N<inf>12</inf> nanocages: A density functional theory study
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Putrescine (Put) adsorption on pure B₁₂N₁₂ and Cu-decorated (Cu– B₁₂N₁₂) nanocages was evaluated using density functional theory (DFT) calculations. Adsorption of copper on B₁₂N₁₂ results in two optimized geometries, named Cu@b₆₆ and Cu@b₆₄, with adsorption energies of approximately −2.01 and −2.07 eV, respectively. The results revealed that adsorption was a chemical process and adsorption energy decreased as follows: B₁₂N₁₂ > Cu@b₆₄ > Cu@b₆₆. DFT calculations indicated that the changes in gap energy (ΔE_gap) of Cu@b₆₆ (+16.28%) and Cu@b₆₄ (+24.17%) were larger than that of B₁₂N₁₂ (−1.37%); so, Cu@b₆₆ and Cu@b₆₄ were more sensitive toward Put than pure B₁₂N₁₂. The changes in work function (Δ $Φ$ ) of the nanocages after interacting with Put increased as follows: B₁₂N₁₂ (23.33%) < Cu@b₆₆ (34.21%) < Cu@b₆₄ (41.97%), indicating that Put can be detected by the increase in electron current density of the nanocage–Put complexes. Quantum molecular dynamic reveal one interconversion from Cu@b₆₆ to Cu@b₆₄ with and without putrescine, implying that only Cu@b₆₄ should be employed as potential conductometric and work function-type sensor for detecting of putrescine.
The endocytic pathway taken by cationic substances requires Rab14 but not Rab5 and Rab7
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This indicates that HDs follow a Rab5-independent, Rab14-dependent endosomal maturation pathway. Polyamines are small signaling molecules involved in several cellular processes (gene regulation, cell proliferation, cell survival, and cell death) (Arruabarrena-Aristorena et al., 2018; Handa et al., 2018; Miller-Fleming et al., 2015; Minois et al., 2011; Ramani et al., 2014). In mammalian cells polyamines enter cells through endocytosis (Soulet et al., 2002; Soulet et al., 2004; Uemura et al., 2010; van Veen et al., 2020), and possibly also through a polyamine specific transporter (Soulet et al., 2004).
Endocytosis and endosome dynamics are controlled by proteins of the small GTPase Rab family. Besides possible recycling routes to the plasma membrane and various organelles, previously described endocytic pathways (e.g., clathrin-mediated endocytosis, macropinocytosis, CLIC/GEEC pathway) all appear to funnel the endocytosed material to Rab5-positive early endosomes that then mature into Rab7-positive late endosomes/lysosomes. By studying the uptake of a series of cell-penetrating peptides (CPPs), we identify an endocytic pathway that moves material to nonacidic Lamp1-positive late endosomes. Trafficking via this endocytic route is fully independent of Rab5 and Rab7 but requires the Rab14 protein. The pathway taken by CPPs differs from the conventional Rab5-dependent endocytosis at the stage of vesicle formation already, as it is not affected by a series of compounds that inhibit macropinocytosis or clathrin-mediated endocytosis. The Rab14-dependent pathway is also used by physiological cationic molecules such as polyamines and homeodomains found in homeoproteins.
Hypoxia-induced antizyme inhibitors 2 regulates cisplatin resistance through epithelia-mesenchymal transition pathway in non-small cell lung cancer
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Antizyme inhibitors (AZINs) are antizyme antagonists and play important functions in the activation of ODC and the regulation of polyamines level [12]. AZINs are homologous to ODC without catalytic activity but have higher affinities to antizymes than ODC [13,14]. AZINs release ODC from antizymes to form active dimers.
Antizyme inhibitors 2 (AZIN2) was found to be associated with poor prognosis of patients with rectal cancer. However, no studies have reported whether AZIN2 functions in non-small cell lung cancer (NSCLC). This study aimed to investigate the role of AZIN2 in cisplatin (DDP) resistance in NSCLC. We established DDP resistant A549 and H1299 cell lines. The transcriptional and translational expression levels were examined using quantitative real-time polymerase chain reaction and western blot. Cell apoptosis was evaluated by caspase-3 activity and nucleosome ELISA assays. Luciferase reporter assay was employed to evaluate the impact of hypoxia-inducible factor (HIF-1α) on AZIN2 transcription. AZIN2 expression was found to be associated with DDP resistance and poor prognosis in patients with NSCLC. AZIN2 overexpression promoted cell viability, colony formation, and reduced cell apoptosis in H1299 cells and A549 upon DDP treatment. Correspondingly, AZIN2 knockdown significantly inhibited cell viability and colony formation, and increased cell apoptosis upon DDP treatment. Interestingly, AZIN2 expression in NSCLC cells was significantly induced by hypoxia condition. The occupancy of HIF-1α, an important regulator of the hypoxia response, remarkably enriched at the promoter region of AZIN2 under hypoxia condition. In addition, AZIN2 overexpression resulted in epithelial–mesenchymal transition (EMT). The results suggested that hypoxia-induced AZIN2 high expression may contribute to DDP resistance development by promoting the EMT.
Radiosynthesis and evaluation of N<sup>5</sup>-(2-<sup>18</sup>F-fluoropropanyl) ornithine as a potential agent for tumor PET imaging
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Studies have confirmed that tumorigenesis is related to an imbalance of polyamine metabolism and over-expression of oncogenes resulting in the up-regulation of ornithine decarboxylase (ODC, the first rate-limiting enzyme for regulating intracellular polyamines biosynthesis), which has become a target for anti-tumor therapy. In this study, an ornithine derivative, N⁵-(2-[¹⁸F]fluoropropionyl) ornithine (N⁵-[¹⁸F]FPO), has been prepared and its potential utility for tumor PET imaging evaluated.
N⁵-[¹⁸F]FPO was successfully prepared via a nucleophilic fluorination reaction and a subsequent efficient deprotection step. The in vitro and in vivo stability were determined by HPLC conducted in fetal bovine serum, saline and rat urine. Cellular uptake studies were conducted in HepG2 cells and the biodistribution and micro-PET/CT imaging performed in normal ICR mice and three tumor-bearing mice models, respectively.
Total synthesis time of N⁵-[¹⁸F]FPO was about 80 min with a radiochemical yield of 15% ± 6% (uncorrected, based on ¹⁸F⁻, n = 6) and a high radiochemical stability can be seen in vitro and vivo. The N⁵-[¹⁸F]FPO exhibited fast uptake in HepG2 cells and the cellular uptake ability of N⁵-[¹⁸F]FPO can be inhibited by L-ornithine and DFMO, which indicated that the transport pathway of N⁵-[¹⁸F]FPO is similar to that of L-ornithine, interacting with ODC after being transported into the cell. The biodistribution and micro-PET/CT images demonstrate that N⁵-[¹⁸F]FPO was excreted by the urinary system, and excellent tumor visualization with high tumor-to-background ratios can be observed in the three tumor-bearing mice models studied.
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Mushrooms are significant sources of amino acids and bioactive amines; however, their bioaccessibility can be affected by processing and during in vitro digestion. Fresh Agaricus bisporus mushroom was submitted to cooking and canning and samples were submitted to in vitro gastric and gastric-intestinal digestions. An UHPLC method was used for the simultaneous determination of 18 free amino acids, 10 biogenic amines and ammonia in the samples. Fresh mushroom contained 14 free amino acids, with predominance of alanine and glutamic acid; spermidine was the only amine detected; and ammonia was also detected. Spermidine levels were not affected by cooking, but there was a significant loss (14%) after canning. Spermidine levels were not affected by the in vitro gastric and intestinal digestion, suggesting full bioaccessibility. There was a significant decrease on total amino acids levels after cooking and canning, with higher losses for aspartic and glutamic acids in cooked and for aspartic acid and valine in canned mushrooms. After the in vitro gastric and intestinal digestions, the total levels of amino acids increased and two additional amino acids (arginine and methionine) were detected. During in vitro digestion many of the amino acids were released mainly in the intestinal phase. After in vitro digestion, amino acids per gram of protein of mushrooms are adequate for most FAO amino acid pattern for adults. Multivariate analysis confirmed that protein hydrolysis in processed mushrooms is higher in intestinal phase. Bioaccessibility data for spermidine in A. bisporus is a novelty and increase the value of this food.

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ReviewAliphatic polyamines in physiology and diseases

Summary

Introduction

Section snippets

Structure and metabolism

Biological functions of polyamines

Physiological importance of polyamines

Congenital disorders of polyamine metabolism

Structure and metabolism

Conclusion

Clin Nutr

J Biol Chem

Int J Biochem Cell Biol

J Biol Chem

Biochem Biophys Res Commun

Dev Comp Immunol

J Nutr

Brain Res Bull

Neuroscience

J Urol

Biomed Pharmacother

Neurosci Biobehav Rev

Mammalian polyamine metabolism and function

IUBMB Life

A perspective of polyamine metabolism

Biochem J

Structural biology of S-adenosylmethionine decarboxylase

Amino Acids

Spermidine/spermine-N(1)-acetyltransferase: a key metabolic regulator

Am J Physiol Endocrinol Metab

Recent advances in the molecular biology of metazoan polyamine transport

Amino Acids

Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract

Am J Physiol Gastrointest Liver Physiol

Polyamine-dependent gene expression

Cell Mol Life Sci

Polyamine-mediated regulation of protein acetylation in murine skin and tumors

Mol Carcinog

Polyamine production is downstream and upstream of oncogenic PI3K signalling and contributes to tumour cell growth

Biochem J

Polyamines: new cues in cellular signal transduction

News Physiol Sci

Regulation of estrogenic and nuclear factor kappa B functions by polyamines and their role in polyamine analog-induced apoptosis of breast cancer cells

Oncogene

Probing tRNA interaction with biogenic polyamines

RNA

Polyamines regulate the stability of JunD mRNA by modulating the competitive binding of its 3' untranslated region to HuR and AUF1

Mol Cell Biol

Review
Aliphatic polyamines in physiology and diseases