bims-polyam 2023-07-02 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023–07–02
seven papers selected by
Sebastian J. Hofer, University of Graz

ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7.
C-Methylated Spermidine Derivatives: Convenient Syntheses and Antizyme-Related Effects.
Polyamines and Physical Activity in Musculoskeletal Diseases: A Potential Therapeutic Challenge.
Investigation of Naphthyl-Polyamine Conjugates as Antimicrobials and Antibiotic Enhancers.
Spermidine from arginine metabolism activates Nrf2 and inhibits kidney fibrosis.
A back-door insights into the modulation of Src kinase activity by the polyamine spermidine.
Characterization and Mechanism of Tea Polyphenols Inhibiting Biogenic Amine Accumulation in Marinated Spanish Mackerel.

Biomolecules. 2023 05 31. pii: 918. [Epub ahead of print]13(6):

ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7.

Sarah van Veen, Antria Kourti, Elke Ausloos, Joris Van Asselberghs, Chris Van den Haute, Veerle Baekelandt, Jan Eggermont, Peter Vangheluwe.

  Polyamine homeostasis is disturbed in several human diseases, including cancer, which is hallmarked by increased intracellular polyamine levels and an upregulated polyamine transport system (PTS). Thus far, the polyamine transporters contributing to the elevated levels of polyamines in cancer cells have not yet been described, despite the fact that polyamine transport inhibitors are considered for cancer therapy. Here, we tested whether the upregulation of candidate polyamine transporters of the P5B transport ATPase family is responsible for the increased PTS in the well-studied breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A. We found that MCF7 cells presented elevated expression of a previously uncharacterized P5B-ATPase, ATP13A4, which was responsible for the elevated polyamine uptake activity. Furthermore, MCF7 cells were more sensitive to polyamine cytotoxicity, as demonstrated by cell viability, cell death and clonogenic assays. Importantly, the overexpression of ATP13A4 WT in MCF10A cells induced a MCF7 polyamine phenotype, with significantly higher uptake of BODIPY-labeled polyamines and increased sensitivity to polyamine toxicity. In conclusion, we established ATP13A4 as a new polyamine transporter in the human PTS and showed that ATP13A4 may play a major role in the increased polyamine uptake of breast cancer cells. ATP13A4 therefore emerges as a candidate therapeutic target for anticancer drugs that block the PTS.

Keywords:  ATP13A4; P5B-type ATPases; cancer; mammalian polyamine transport system

DOI:  https://doi.org/10.3390/biom13060918
Biomolecules. 2023 05 31. pii: 916. [Epub ahead of print]13(6):

C-Methylated Spermidine Derivatives: Convenient Syntheses and Antizyme-Related Effects.

Maxim A Khomutov, Arthur I Salikhov, Vladimir A Mitkevich, Vera L Tunitskaya, Olga A Smirnova, Sergey P Korolev, Alexander O Chizhov, Marina B Gottikh, Sergey N Kochetkov, Alex R Khomutov.

  The biogenic polyamines, spermidine (Spd) and spermine (Spm), are present at millimolar concentrations in all eukaryotic cells, where they participate in the regulation of vitally important cellular functions. Polyamine analogs and derivatives are a traditional and important instrument for the investigation of the cellular functions of polyamines, enzymes of their metabolism, and the regulation of the biosynthesis of antizyme-a key downregulator of polyamine homeostasis. Here, we describe convenient gram-scale syntheses of a set of C-methylated analogs of Spd. The biochemical properties of these compounds and the possibility for the regulation of their activity by moving a methyl group along the polyamine backbone and by changing the stereochemistry of the chiral center(s) are discussed.

Keywords:  antizyme dimerization; methylated spermidine analogs; polyamines; spermidine; spermine; synthesis

DOI:  https://doi.org/10.3390/biom13060916
Int J Mol Sci. 2023 Jun 06. pii: 9798. [Epub ahead of print]24(12):

Polyamines and Physical Activity in Musculoskeletal Diseases: A Potential Therapeutic Challenge.

Letizia Galasso, Annalisa Cappella, Antonino Mulè, Lucia Castelli, Andrea Ciorciari, Alessandra Stacchiotti, Angela Montaruli.

  Autophagy dysregulation is commonplace in the pathogenesis of several invalidating diseases, such as musculoskeletal diseases. Polyamines, as spermidine and spermine, are small aliphatic cations essential for cell growth and differentiation, with multiple antioxidant, anti-inflammatory, and anti-apoptotic effects. Remarkably, they are emerging as natural autophagy regulators with strong anti-aging effects. Polyamine levels were significantly altered in the skeletal muscles of aged animals. Therefore, supplementation of spermine and spermidine may be important to prevent or treat muscle atrophy. Recent in vitro and in vivo experimental studies indicate that spermidine reverses dysfunctional autophagy and stimulates mitophagy in muscles and heart, preventing senescence. Physical exercise, as polyamines, regulates skeletal muscle mass inducing proper autophagy and mitophagy. This narrative review focuses on the latest evidence regarding the efficacy of polyamines and exercise as autophagy inducers, alone or coupled, in alleviating sarcopenia and aging-dependent musculoskeletal diseases. A comprehensive description of overall autophagic steps in muscle, polyamine metabolic pathways, and effects of the role of autophagy inducers played by both polyamines and exercise has been presented. Although literature shows few data in regard to this controversial topic, interesting effects on muscle atrophy in murine models have emerged when the two "autophagy-inducers" were combined. We hope these findings, with caution, can encourage researchers to continue investigating in this direction. In particular, if these novel insights could be confirmed in further in vivo and clinical studies, and the two synergic treatments could be optimized in terms of dose and duration, then polyamine supplementation and physical exercise might have a clinical potential in sarcopenia, and more importantly, implications for a healthy lifestyle in the elderly population.

Keywords:  aging; autophagy; exercise; mitophagy; physical activity; polyamines; sarcopenia; spermidine; spermine

DOI:  https://doi.org/10.3390/ijms24129798
Antibiotics (Basel). 2023 Jun 05. pii: 1014. [Epub ahead of print]12(6):

Investigation of Naphthyl-Polyamine Conjugates as Antimicrobials and Antibiotic Enhancers.

Melissa M Cadelis, Liam R Edmeades, Dan Chen, Evangelene S Gill, Kyle Fraser, Florent Rouvier, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel, Brent R Copp.

  As part of our search for new antimicrobials and antibiotic enhancers, a series of naphthyl- and biphenyl-substituted polyamine conjugates have been synthesized. The structurally-diverse library of compounds incorporated variation in the capping end groups and in the length of the polyamine (PA) core. Longer chain (PA-3-12-3) variants containing both 1-naphthyl and 2-naphthyl capping groups exhibited more pronounced intrinsic antimicrobial properties against methicillin-resistant Staphylococcus aureus (MRSA) (MIC ≤ 0.29 µM) and the fungus Cryptococcus neoformans (MIC ≤ 0.29 µM). Closer mechanistic study of one of these analogues, 20f, identified it as a bactericide. In contrast to previously reported diarylacyl-substituted polyamines, several examples in the current set were able to enhance the antibiotic action of doxycycline and/or erythromycin towards the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli. Two analogues (19a and 20c) were of note, exhibiting greater than 32-fold enhancement in activity. This latter result suggests that α,ω-disubstituted polyamines bearing 1-naphthyl- and 2-naphthyl-capping groups are worthy of further investigation and optimization as non-toxic antibiotic enhancers.

Keywords:  antibiotic enhancement; antimicrobial activities; polyamine conjugates

DOI:  https://doi.org/10.3390/antibiotics12061014
Commun Biol. 2023 Jun 28. 6(1): 676

Spermidine from arginine metabolism activates Nrf2 and inhibits kidney fibrosis.

Seishi Aihara, Kumiko Torisu, Yushi Uchida, Noriyuki Imazu, Toshiaki Nakano, Takanari Kitazono.

Kidney metabolism may be greatly altered in chronic kidney disease. Here we report that arginine metabolism is the most altered in unilateral ureteral obstruction (UUO)-induced fibrosis of the kidneys in metabolomic analysis. Spermidine is the most increased metabolite of arginine. In human glomerulonephritis, the amount of spermidine shown by immunostaining is associated with the amount of fibrosis. In human proximal tubule cells, spermidine induces nuclear factor erythroid 2-related factor 2 (Nrf2). Subsequently, fibrotic signals, such as transforming growth factor β1 secretion, collagen 1 mRNA, and oxidative stress, represented by a decrease in the mitochondrial membrane potential is suppressed by spermidine. UUO kidneys of Arg2 knockout mice show less spermidine and significantly exacerbated fibrosis compared with wild-type mice. Nrf2 activation is reduced in Arg2 knockout UUO kidneys. Spermidine treatment prevents significant fibrotic progression in Arg2 knockout mice. Spermidine is increased in kidney fibrosis, but further increases in spermidine may reduce fibrosis.

DOI: https://doi.org/10.1038/s42003-023-05057-w
Elife. 2023 Jun 30. pii: e85872. [Epub ahead of print]12

A back-door insights into the modulation of Src kinase activity by the polyamine spermidine.

Sofia Rossini, Marco Gagaro, Giulia Scalisi, Elisa Bianconi, Sara Ambrosino, Eleonora Panfili, Claudia Volpi, Ciriana Orabona, Antonio Macchiarulo, Francesca Fallarino, Giada Mondanelli.

  Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration and survival signaling pathways. In conventional dendritic cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein-protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.

Keywords:  biochemistry; chemical biology; immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.85872
Foods. 2023 Jun 12. pii: 2347. [Epub ahead of print]12(12):

Characterization and Mechanism of Tea Polyphenols Inhibiting Biogenic Amine Accumulation in Marinated Spanish Mackerel.

Zhe Xu, Jiale Chang, Jiamin Zhou, Yixin Shi, Hui Chen, Lingyu Han, Maolin Tu, Tingting Li.

  Putrescine is a low-molecular-weight organic compound that is widely found in pickled foods. Although the intake of biogenic amines is beneficial to humans, an excessive intake can cause discomfort. In this study, the ornithine decarboxylase gene (ODC) was involved in putrescine biosynthesis. After cloning, expression and functional verification, it was induced and expressed in E. coli BL21 (DE3). The relative molecular mass of the recombinant soluble ODC protein was 14.87 kDa. The function of ornithine decarboxylase was analyzed by determining the amino acid and putrescine content. The results show that the ODC protein could catalyze the decarboxylation of ornithine to putrescine. Then, the three-dimensional structure of the enzyme was used as a receptor for the virtual screening of inhibitors. The binding energy of tea polyphenol ligands to the receptor was the highest at -7.2 kcal mol-1. Therefore, tea polyphenols were added to marinated fish to monitor the changes in putrescine content and were found to significantly inhibit putrescine production (p < 0.05). This study lays the foundation for further research on the enzymatic properties of ODC and provides insight into an effective inhibitor for controlling the putrescine content in pickled fish.

Keywords:  Spanish mackerel; ornithine decarboxylase; putrescine; tea polyphenols

DOI:  https://doi.org/10.3390/foods12122347