bims-polyam 2021-06-06 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2021–06–06
ten papers selected by
Sebastian J. Hofer, University of Graz

The autophagy inducer spermidine protects against metabolic dysfunction during overnutrition.
Polyamine Homeostasis in Development and Disease.
The Role of Spermidine Synthase (SpdS) and Spermine Synthase (Sms) in Regulating Triglyceride Storage in Drosophila.
Characterising the Response of Human Breast Cancer Cells to Polyamine Modulation.
α-Difluoromethylornithine-Induced Cytostasis is Reversed by Exogenous Polyamines, Not by Thymidine Supplementation.
Polyamine Metabolism in Scots Pine Embryogenic Cells under Potassium Deficiency.
Polyamines are required for tRNA anticodon modification in Escherichia coli.
The First Insight Into the Supramolecular System of D,L-α-Difluoromethylornithine: A New Antiviral Perspective.
Polyamine-Conjugated Nitroxides Are Efficacious Inhibitors of Oxidative Reactions Catalyzed by Endothelial-Localized Myeloperoxidase.
Plant Copper Amine Oxidases: Key Players in Hormone Signaling Leading to Stress-Induced Phenotypic Plasticity.

J Gerontol A Biol Sci Med Sci. 2021 Jun 01. pii: glab145. [Epub ahead of print]

The autophagy inducer spermidine protects against metabolic dysfunction during overnutrition.

Chen-Yu Liao, Oona M P Kummert, Amanda M Bair, Nora Alavi, Josef Alavi, Delana M Miller, Isha Bagga, Anja M Schempf, Yueh-Mei Hsu, Bruce D Woods Ii, Stephen M Brown Mayfield, Angelina N Mitchell, Gabriella Tannady, Aislinn R Talbot, Aaron M Dueck, Ricardo Barrera Ovando, Heather D Parker, Junying Wang, Jane K Schoeneweis, Brian K Kennedy.

  Autophagy, a process catabolizing intracellular components to maintain energy homeostasis, impacts aging and metabolism. Spermidine, a natural polyamine and autophagy activator, extends lifespan across a variety of species, including mice. In addition to protecting cardiac and liver tissue, spermidine also affects adipose tissue through unexplored mechanisms. Here, we examined spermidine in the links between autophagy and systemic metabolism. Consistently, daily injection of spermidine delivered even at late life is sufficient to cause a trend in lifespan extension in wild type mice. We further found that spermidine has minimal metabolic effects in young and old mice under normal nutrition. However, spermidine counteracts HFD (high-fat diet)-induced obesity by increasing lipolysis in visceral fat. Mechanistically, spermidine increases the hepatokine FGF21 expression in liver without reducing food intake. Spermidine also modulates FGF21 in adipose tissues, elevating FGF21 expression in subcutaneous fat, but reducing it in visceral fat. Despite this, FGF21 is not required for spermidine action, since Fgf21 -/- mice were still protected from HFD. Furthermore, the enhanced lipolysis by spermidine was also independent of autophagy in adipose tissue, given that adipose-specific autophagy deficient (Beclin-1 flox/+ Fabp4-cre) mice remained spermidine-responsive under HFD. Our results suggest that the metabolic effects of spermidine occurs through systemic changes in metabolism, involving multiple mechanistic pathways.

Keywords:  Aging; FGF-21; High-fat diet; Metabolism; Mice

DOI:  https://doi.org/10.1093/gerona/glab145
Med Sci (Basel). 2021 May 13. pii: 28. [Epub ahead of print]9(2):

Polyamine Homeostasis in Development and Disease.

Shima Nakanishi, John L Cleveland.

  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

DOI:  https://doi.org/10.3390/medsci9020028
Med Sci (Basel). 2021 May 02. pii: 27. [Epub ahead of print]9(2):

The Role of Spermidine Synthase (SpdS) and Spermine Synthase (Sms) in Regulating Triglyceride Storage in Drosophila.

Tahj S Morales, Erik C Avis, Elise K Paskowski, Hamza Shabar, Shannon L Nowotarski, Justin R DiAngelo.

  Polyamines are small organic cations that are important for several biological processes such as cell proliferation, cell cycle progression, and apoptosis. The dysregulation of intracellular polyamines is often associated with diseases such as cancer, diabetes, and developmental disorders. Although polyamine metabolism has been well studied, the effects of key enzymes in the polyamine pathway on lipid metabolism are not well understood. Here, we determined metabolic effects resulting from the absence of spermidine synthase (SpdS) and spermine synthase (Sms) in Drosophila. While SpdS mutants developed normally and accumulated triglycerides, Sms mutants had reduced viability and stored less triglyceride than the controls. Interestingly, when decreasing SpdS and Sms, specifically in the fat body, triglyceride storage increased. While there was no difference in triglycerides stored in heads, thoraxes and abdomen fat bodies, abdomen fat body DNA content increased, and protein/DNA decreased in both SpdS- and Sms-RNAi flies, suggesting that fat body-specific knockdown of SpdS and Sms causes the production of smaller fat body cells and triglycerides to accumulate in non-fat body tissues of the abdomen. Together, these data provide support for the role that polyamines play in the regulation of metabolism and can help enhance our understanding of polyamine function in metabolic diseases.

Keywords:  Drosophila; fat body; spermidine synthase; spermine synthase; triglyceride

DOI:  https://doi.org/10.3390/medsci9020027
Biomolecules. 2021 May 17. pii: 743. [Epub ahead of print]11(5):

Characterising the Response of Human Breast Cancer Cells to Polyamine Modulation.

Oluwaseun Akinyele, Heather M Wallace.

  Breast cancer is a complex heterogeneous disease with multiple underlying causes. The polyamines putrescine, spermidine, and spermine are polycationic molecules essential for cell proliferation. Their biosynthesis is upregulated in breast cancer and they contribute to disease progression. While elevated polyamines are linked to breast cancer cell proliferation, there is little evidence to suggest breast cancer cells of different hormone receptor status are equally dependent on polyamines. In this study, we characterized the responses of two breast cancer cells, ER+ (oestrogen receptor positive) MCF-7 and ER- MDA-MB-231 cell lines, to polyamine modulation and determined the requirement of each polyamine for cancer cell growth. The cells were exposed to DFMO (a polyamine pathway inhibitor) at various concentrations under different conditions, after which several growth parameters were determined. Exposure of both cell lines to DFMO induced differential growth responses, MCF-7 cells showed greater sensitivity to polyamine pathway inhibition at various DFMO concentrations than the MDA-MB-231 cells. Analysis of intracellular DFMO after withdrawal from growth medium showed residual DFMO in the cells with concomitant decreases in polyamine content, ODC protein level, and cell growth. Addition of exogenous polyamines reversed the cell growth inhibition, and this growth recovery appears to be partly dependent on the spermidine content of the cell. Similarly, DFMO exposure inhibits the global translation state of the cells, with spermidine addition reversing the inhibition of translation in the breast cancer cells. Taken together, these data suggest that breast cancer cells are differentially sensitive to the antitumour effects of polyamine depletion, thus, targeting polyamine metabolism might be therapeutically beneficial in breast cancer management based on their subtype.

Keywords:  DFMO; breast cancer subtypes; cell growth; polyamines

DOI:  https://doi.org/10.3390/biom11050743
Biomolecules. 2021 May 10. pii: 707. [Epub ahead of print]11(5):

α-Difluoromethylornithine-Induced Cytostasis is Reversed by Exogenous Polyamines, Not by Thymidine Supplementation.

Mervi T Hyvönen, Maxim Khomutov, Jouko Vepsäläinen, Alex R Khomutov, Tuomo A Keinänen.

  Polyamine spermidine is essential for the proliferation of eukaryotic cells. Administration of polyamine biosynthesis inhibitor α-difluoromethylornithine (DFMO) induces cytostasis that occurs in two phases; the early phase which can be reversed by spermidine, spermine, and some of their analogs, and the late phase which is characterized by practically complete depletion of cellular spermidine pool. The growth of cells at the late phase can be reversed by spermidine and by very few of its analogs, including (S)-1-methylspermidine. It was reported previously (Witherspoon et al. Cancer Discovery 3(9); 1072-81, 2013) that DFMO treatment leads to depletion of cellular thymidine pools, and that exogenous thymidine supplementation partially prevents DFMO-induced cytostasis without affecting intracellular polyamine pools in HT-29, SW480, and LoVo colorectal cancer cells. Here we show that thymidine did not prevent DFMO-induced cytostasis in DU145, LNCaP, MCF7, CaCo2, BT4C, SV40MES13, HepG2, HEK293, NIH3T3, ARPE19 or HT-29 cell lines, whereas administration of functionally active mimetic of spermidine, (S)-1-methylspermidine, did. Thus, the effect of thymidine seems to be specific only for certain cell lines. We conclude that decreased polyamine levels and possibly also distorted pools of folate-dependent metabolites mediate the anti-proliferative actions of DFMO. However, polyamines are necessary and sufficient to overcome DFMO-induced cytostasis, while thymidine is generally not.

Keywords:  S-adenosyl-L-methionine; polyamines; proliferation; thymidine; α-difluoromethylornithine

DOI:  https://doi.org/10.3390/biom11050707
Cells. 2021 May 18. pii: 1244. [Epub ahead of print]10(5):

Polyamine Metabolism in Scots Pine Embryogenic Cells under Potassium Deficiency.

Riina Muilu-Mäkelä, Jaana Vuosku, Hely Häggman, Tytti Sarjala.

  Polyamines (PA) have a protective role in maintaining growth and development in Scots pine during abiotic stresses. In the present study, a controlled liquid Scots pine embryogenic cell culture was used for studying the responses of PA metabolism related to potassium deficiency. The transcription level regulation of PA metabolism led to the accumulation of putrescine (Put). Arginine decarboxylase (ADC) had an increased expression trend under potassium deficiency, whereas spermidine synthase (SPDS) expression decreased. Generally, free spermidine (Spd) and spermine (Spm)/ thermospermine (t-Spm) contents were kept relatively stable, mostly by the downregulation of polyamine oxidase (PAO) expression. The low potassium contents in the culture medium decreased the potassium content of the cells, which inhibited cell mass growth, but did not affect cell viability. The reduced growth was probably caused by repressed metabolic activity and cell division, whereas there were no signs of H2O2-induced oxidative stress or increased cell death. The low intracellular content of K+ decreased the content of Na+. The decrease in the pH of the culture medium indicated that H+ ions were pumped out of the cells. Altogether, our findings emphasize the specific role(s) of Put under potassium deficiency and strict developmental regulation of PA metabolism in Scots pine.

Keywords:  Scots pine (Pinus sylvestris L.); abiotic stress; chemical elements; liquid culture; polyamines; potassium deficiency

DOI:  https://doi.org/10.3390/cells10051244
J Mol Biol. 2021 May 28. pii: S0022-2836(21)00291-6. [Epub ahead of print] 167073

Polyamines are required for tRNA anticodon modification in Escherichia coli.

Kristoffer Skovbo Winther, Michael Askvad Sørensen, Sine Lo Svenningsen.

  Biogenic polyamines are natural aliphatic polycations formed from amino acids by biochemical pathways that are highly conserved from bacteria to humans. Their cellular concentrations are carefully regulated and dysregulation causes severe cell growth defects. Polyamines have high affinity for nucleic acids and are known to interact with mRNA, tRNA and rRNA to stimulate the translational machinery, but the exact molecular mechanism(s) for this stimulus is still unknown. Here we exploit that Escherichia coli is viable in the absence of polyamines, including the universally conserved putrescine and spermidine. Using global macromolecule labelling approaches we find that ribosome efficiency is reduced by 50-70% in the absence of polyamines and this reduction is caused by slow translation elongation speed. The low efficiency causes rRNA and multiple tRNA species to be overproduced in the absence of polyamines, suggesting an impact on the feedback regulation of stable RNA transcription. Importantly, we find that polyamine deficiency affects both tRNA levels and tRNA modification patterns. Specifically, a large fraction of tRNAhis, tRNAtyr and tRNAasn lack the queuosine modification in the anticodon "wobble" base, which can be reversed by addition of polyamines to the growth medium. In conclusion, we demonstrate that polyamines are needed for modification of specific tRNA, possibly by facilitating the interaction with modification enzymes.

Keywords:  Anticodon; Polyamine; Queuosine; Spermidine; tRNA

DOI:  https://doi.org/10.1016/j.jmb.2021.167073
Front Chem. 2021 ;9 679776

The First Insight Into the Supramolecular System of D,L-α-Difluoromethylornithine: A New Antiviral Perspective.

Joanna Bojarska, Roger New, Paweł Borowiecki, Milan Remko, Martin Breza, Izabela D Madura, Andrzej Fruziński, Anna Pietrzak, Wojciech M Wolf.

  Targeting the polyamine biosynthetic pathway by inhibiting ornithine decarboxylase (ODC) is a powerful approach in the fight against diverse viruses, including SARS-CoV-2. Difluoromethylornithine (DFMO, eflornithine) is the best-known inhibitor of ODC and a broad-spectrum, unique therapeutical agent. Nevertheless, its pharmacokinetic profile is not perfect, especially when large doses are required in antiviral treatment. This article presents a holistic study focusing on the molecular and supramolecular structure of DFMO and the design of its analogues toward the development of safer and more effective formulations. In this context, we provide the first deep insight into the supramolecular system of DFMO supplemented by a comprehensive, qualitative and quantitative survey of non-covalent interactions via Hirshfeld surface, molecular electrostatic potential, enrichment ratio and energy frameworks analysis visualizing 3-D topology of interactions in order to understand the differences in the cooperativity of interactions involved in the formation of either basic or large synthons (Long-range Synthon Aufbau Modules, LSAM) at the subsequent levels of well-organized supramolecular self-assembly, in comparison with the ornithine structure. In the light of the drug discovery, supramolecular studies of amino acids, essential constituents of proteins, are of prime importance. In brief, the same amino-carboxy synthons are observed in the bio-system containing DFMO. DFT calculations revealed that the biological environment changes the molecular structure of DFMO only slightly. The ADMET profile of structural modifications of DFMO and optimization of its analogue as a new promising drug via molecular docking are discussed in detail.

Keywords:  DFMO; SARS-CoV-2; coronavirus; difluoromethylornithine; eflornithine; fluorine theranostics; ornidyl

DOI:  https://doi.org/10.3389/fchem.2021.679776
Chem Res Toxicol. 2021 Jun 04.

Polyamine-Conjugated Nitroxides Are Efficacious Inhibitors of Oxidative Reactions Catalyzed by Endothelial-Localized Myeloperoxidase.

Sophie Maiocchi, Jacqueline Ku, Tom Hawtrey, Irene De Silvestro, Ernst Malle, Martin Rees, Shane R Thomas, Jonathan C Morris.

The heme enzyme myeloperoxidase (MPO) is a key mediator of endothelial dysfunction and a therapeutic target in cardiovascular disease. During inflammation, MPO released by circulating leukocytes is internalized by endothelial cells and transcytosed into the subendothelial extracellular matrix of diseased vessels. At this site, MPO mediates endothelial dysfunction by catalytically consuming nitric oxide (NO) and producing reactive oxidants, hypochlorous acid (HOCl) and the nitrogen dioxide radical (•NO2). Accordingly, there is interest in developing MPO inhibitors that effectively target endothelial-localized MPO. Here we studied a series of piperidine nitroxides conjugated to polyamine moieties as novel endothelial-targeted MPO inhibitors. Electron paramagnetic resonance analysis of cell lysates showed that polyamine conjugated nitroxides were efficiently internalized into endothelial cells in a heparan sulfate dependent manner. Nitroxides effectively inhibited the consumption of MPO's substrate hydrogen peroxide (H2O2) and formation of HOCl catalyzed by endothelial-localized MPO, with their efficacy dependent on both nitroxide and conjugated-polyamine structure. Nitroxides also differentially inhibited protein nitration catalyzed by both purified and endothelial-localized MPO, which was dependent on •NO2 scavenging rather than MPO inhibition. Finally, nitroxides uniformly inhibited the catalytic consumption of NO by MPO in human plasma. These studies show for the first time that nitroxides effectively inhibit local oxidative reactions catalyzed by endothelial-localized MPO. Novel polyamine-conjugated nitroxides, ethylenediamine-TEMPO and putrescine-TEMPO, emerged as efficacious nitroxides uniquely exhibiting high endothelial cell uptake and efficient inhibition of MPO-catalyzed HOCl production, protein nitration, and NO oxidation. Polyamine-conjugated nitroxides represent a versatile class of antioxidant drugs capable of targeting endothelial-localized MPO during vascular inflammation.

DOI: https://doi.org/10.1021/acs.chemrestox.1c00094
Int J Mol Sci. 2021 May 12. pii: 5136. [Epub ahead of print]22(10):

Plant Copper Amine Oxidases: Key Players in Hormone Signaling Leading to Stress-Induced Phenotypic Plasticity.

Ilaria Fraudentali, Renato A Rodrigues-Pousada, Riccardo Angelini, Sandip A Ghuge, Alessandra Cona.

  Polyamines are ubiquitous, low-molecular-weight aliphatic compounds, present in living organisms and essential for cell growth and differentiation. Copper amine oxidases (CuAOs) oxidize polyamines to aminoaldehydes releasing ammonium and hydrogen peroxide, which participates in the complex network of reactive oxygen species acting as signaling molecules involved in responses to biotic and abiotic stresses. CuAOs have been identified and characterized in different plant species, but the most extensive study on a CuAO gene family has been carried out in Arabidopsis thaliana. Growing attention has been devoted in the last years to the investigation of the CuAO expression pattern during development and in response to an array of stress and stress-related hormones, events in which recent studies have highlighted CuAOs to play a key role by modulation of a multilevel phenotypic plasticity expression. In this review, the attention will be focused on the involvement of different AtCuAOs in the IAA/JA/ABA signal transduction pathways which mediate stress-induced phenotypic plasticity events.

Keywords:  abscisic acid; auxin; copper amine oxidases; hormones; hydrogen peroxide; jasmonic acid; polyamines; root plasticity; wounding

DOI:  https://doi.org/10.3390/ijms22105136