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Archives of Biochemistry and Biophysics Jun 2022The roles and molecular interactions of polyamines (PAs) in the nucleus are not fully understood. Here their effect on nucleosome stability, a key regulatory factor in...
The roles and molecular interactions of polyamines (PAs) in the nucleus are not fully understood. Here their effect on nucleosome stability, a key regulatory factor in eukaryotic gene control, is reported, as measured in agarose embedded nuclei of H2B-GFP expressor HeLa cells. Nucleosome stability was assessed by quantitative microscopy [1,2] in situ, in close to native state of chromatin, preserving the nucleosome constrained topology of the genomic DNA. A robust destabilizing effect was observed in the millimolar concentration range in the case of spermine, spermidine as well as putrescine, which was strongly pH and salt concentration-dependent, and remained significant also at neutral pH. The integrity of genomic DNA was not affected by PA treatment, excluding DNA break-elicited topological relaxation as a factor in destabilization. The binding of PAs to DNA was demonstrated by the displacement of ethidium bromide, both from deproteinized nuclear halos and from plasmid DNA. The possibility that DNA methylation patterns may be influenced by PA levels is contemplated in the context of gene expression and DNA methylation correlations identified in the NCI-60 panel-based CellMiner database: methylated loci in subsets of high-ODC1 cell lines and the dependence of PER3 DNA methylation on PA metabolism.
Topics: DNA; HeLa Cells; Humans; Nucleosomes; Polyamines; Putrescine; Spermidine
PubMed: 35395253
DOI: 10.1016/j.abb.2022.109184 -
Molecules (Basel, Switzerland) Nov 2023Polyamines participate in the processes of cell growth and development. The degradation branch of their metabolism involves amine oxidases. The oxidation of spermine,... (Review)
Review
Polyamines participate in the processes of cell growth and development. The degradation branch of their metabolism involves amine oxidases. The oxidation of spermine, spermidine and putrescine releases hydrogen peroxide and the corresponding aminoaldehyde. Polyamine-derived aminoaldehydes have been found to be cytotoxic, and they represent the subject of this review. 3-aminopropanal disrupts the lysosomal membrane and triggers apoptosis or necrosis in the damaged cells. It is implicated in the pathogenesis of cerebral ischemia. Furthermore, 3-aminopropanal yields acrolein through the elimination of ammonia. This reactive aldehyde is also generated by the decomposition of aminoaldehydes produced in the reaction of serum amine oxidase with spermidine or spermine. In addition, acrolein is a common environmental pollutant. It causes covalent modifications of proteins, including carbonylation, the production of Michael-type adducts and cross-linking, and it has been associated with inflammation-related diseases. APAL and acrolein are detoxified by aldehyde dehydrogenases and other mechanisms. High-performance liquid chromatography, immunochemistry and mass spectrometry have been largely used to analyze the presence of polyamine-derived aminoaldehydes and protein modifications elicited by their effect. However, the main and still open challenge is to find clues for discovering clear linkages between aldehyde-induced modifications of specific proteins and the development of various diseases.
Topics: Polyamines; Acrolein; Spermidine; Spermine; Aldehydes
PubMed: 37959847
DOI: 10.3390/molecules28217429 -
International Journal of Molecular... Jun 2023Autophagy dysregulation is commonplace in the pathogenesis of several invalidating diseases, such as musculoskeletal diseases. Polyamines, as spermidine and spermine,... (Review)
Review
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.
Topics: Aged; Mice; Humans; Animals; Polyamines; Spermidine; Spermine; Sarcopenia; Muscular Atrophy; Musculoskeletal Diseases
PubMed: 37372945
DOI: 10.3390/ijms24129798 -
Proceedings of the National Academy of... Nov 2022Group 3 innate lymphoid cells (ILC3s) are RORγT lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate...
Group 3 innate lymphoid cells (ILC3s) are RORγT lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17 cells. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that ILC3-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as exacerbates autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.
Topics: Mice; Animals; Nuclear Receptor Subfamily 1, Group F, Member 3; Interleukin-17; Ornithine Decarboxylase; Immunity, Innate; Putrescine; Colitis; Enterobacteriaceae Infections; Th17 Cells; Ornithine; Anti-Bacterial Agents; Interleukin-22
PubMed: 36279426
DOI: 10.1073/pnas.2214900119 -
Molecules (Basel, Switzerland) Dec 2016Natural products represent a straightforward source for molecular structures bearing a vast array of chemical features and potentially useful for biomedical purposes.... (Review)
Review
Natural products represent a straightforward source for molecular structures bearing a vast array of chemical features and potentially useful for biomedical purposes. Recent examples of this type include the discovery of the coumarins and the polyamine natural products as atypical chemotypes for the inhibition of the metalloenzymes carbonic anhydrases (CAs; EC 4.2.2.1). CA enzymes are established pharmacological targets for important pathologies, which, among others, include glaucoma, hypoxic tumors, and central nervous system (CNS)-affecting diseases. Moreover, they are expressed in many bacteria, fungi and helminths which are the etiological agents of the majority of infectious diseases. In this context, natural products represent the ideal source of new and selective druggable CA modulators for biomedical purposes. Herein we report the state of the art on polyamines of natural origin as well as of synthetic derivatives as inhibitors of human CAs.
Topics: Antineoplastic Agents; Biological Products; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Coumarins; Drug Design; Humans; Models, Molecular; Molecular Structure; Neoplasms; Putrescine; Spermidine; Spermine; Structure-Activity Relationship
PubMed: 27983696
DOI: 10.3390/molecules21121726 -
Journal of Bacteriology Jan 2022Pseudomonas aeruginosa, an opportunistic bacterial pathogen, can synthesize and catabolize several small cationic molecules known as polyamines. In several clades of...
Pseudomonas aeruginosa, an opportunistic bacterial pathogen, can synthesize and catabolize several small cationic molecules known as polyamines. In several clades of bacteria, polyamines regulate biofilm formation, a lifestyle-switching process that confers resistance to environmental stress. The polyamine putrescine and its biosynthetic precursors, l-arginine and agmatine, promote biofilm formation in Pseudomonas spp. However, it remains unclear whether the effect is a direct effect of polyamines or occurs through a metabolic derivative. Here, we used a genetic approach to demonstrate that putrescine accumulation, either through disruption of the spermidine biosynthesis pathway or the catabolic putrescine aminotransferase pathway, promoted biofilm formation in P. aeruginosa. Consistent with this observation, exogenous putrescine robustly induced biofilm formation in P. aeruginosa that was dependent on putrescine uptake and biosynthesis pathways. Additionally, we show that l-arginine, the biosynthetic precursor of putrescine, also promoted biofilm formation but did so by a mechanism independent of putrescine or agmatine conversion. We found that both putrescine and l-arginine induced a significant increase in the intracellular level of bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) (c-di-GMP), a bacterial second messenger widely found in that upregulates biofilm formation. Collectively these data show that putrescine and its metabolic precursor, arginine, promote biofilm and c-di-GMP synthesis in P. aeruginosa. Biofilm formation allows bacteria to physically attach to a surface, confer tolerance to antimicrobial agents, and promote resistance to host immune responses. As a result, the regulation of biofilm formation is often crucial for bacterial pathogens to establish chronic infections. A primary mechanism of biofilm promotion in bacteria is the molecule c-di-GMP, which promotes biofilm formation. The level of c-di-GMP is tightly regulated by bacterial enzymes. In this study, we found that putrescine, a small molecule ubiquitously found in eukaryotic cells, robustly enhances P. aeruginosa biofilm and c-di-GMP. We propose that P. aeruginosa may sense putrescine as a host-associated signal that triggers a lifestyle switch that favors chronic infection.
Topics: Arginine; Biofilms; Cyclic GMP; Gene Expression Regulation, Bacterial; Pseudomonas aeruginosa; Putrescine; Up-Regulation
PubMed: 34723645
DOI: 10.1128/JB.00297-21 -
Plant Biotechnology Journal Oct 2022The polyamine putrescine (1,4-diaminobutane) contributes to cellular fitness in most organisms, where it is derived from the amino acids ornithine or arginine. In the...
The polyamine putrescine (1,4-diaminobutane) contributes to cellular fitness in most organisms, where it is derived from the amino acids ornithine or arginine. In the chemical industry, putrescine serves as a versatile building block for polyamide synthesis. The green microalga Chlamydomonas reinhardtii accumulates relatively high putrescine amounts, which, together with recent advances in genetic engineering, enables the generation of a powerful green cell factory to promote sustainable biotechnology for base chemical production. Here, we report a systematic investigation of the native putrescine metabolism in C. reinhardtii, leading to the first CO -based bio-production of putrescine, by employing modern synthetic biology and metabolic engineering strategies. A CRISPR/Cas9-based knockout of key enzymes of the polyamine biosynthesis pathway identified ornithine decarboxylase 1 (ODC1) as a gatekeeper for putrescine accumulation and demonstrated that the arginine decarboxylase (ADC) route is likely inactive and that amine oxidase 2 (AMX2) is mainly responsible for putrescine degradation in C. reinhardtii. A 4.5-fold increase in cellular putrescine levels was achieved by engineered overexpression of potent candidate ornithine decarboxylases (ODCs). We identified unexpected substrate promiscuity in two bacterial ODCs, which exhibited co-production of cadaverine and 4-aminobutanol. Final pathway engineering included overexpression of recombinant arginases for improved substrate availability as well as functional knockout of putrescine degradation, which resulted in a 10-fold increase in cellular putrescine titres and yielded 200 mg/L in phototrophic high cell density cultivations after 10 days.
Topics: Amino Acids; Arginine; Cadaverine; Carbon Dioxide; Carboxy-Lyases; Nylons; Ornithine; Ornithine Decarboxylase; Oxidoreductases; Polyamines; Putrescine
PubMed: 35748533
DOI: 10.1111/pbi.13879 -
Proceedings of the National Academy of... Feb 2023Viruses produce more viruses by manipulating the metabolic and replication systems of their host cells. Many have acquired metabolic genes from ancestral hosts and use...
Viruses produce more viruses by manipulating the metabolic and replication systems of their host cells. Many have acquired metabolic genes from ancestral hosts and use the encoded enzymes to subvert host metabolism. The polyamine spermidine is required for bacteriophage and eukaryotic virus replication, and herein, we have identified and functionally characterized diverse phage- and virus-encoded polyamine metabolic enzymes and pathways. These include pyridoxal 5'-phosphate (PLP)-dependent ornithine decarboxylase (ODC), pyruvoyl-dependent ODC and arginine decarboxylase (ADC), arginase, -adenosylmethionine decarboxylase (AdoMetDC/), spermidine synthase, homospermidine synthase, spermidine -acetyltransferase, and -acetylspermidine amidohydrolase. We identified homologs of the spermidine-modified translation factor eIF5a encoded by giant viruses of the . Although AdoMetDC/ is prevalent among marine phages, some homologs have lost AdoMetDC activity and have evolved into pyruvoyl-dependent ADC or ODC. The pelagiphages that encode the pyruvoyl-dependent ADCs infect the abundant ocean bacterium , which we have found encodes a PLP-dependent ODC homolog that has evolved into an ADC, indicating that infected cells would contain both PLP- and pyruvoyl-dependent ADCs. Complete or partial spermidine or homospermidine biosynthetic pathways are found encoded in the giant viruses of the and , and in addition, some viruses of the can release spermidine from the inactive -acetylspermidine. In contrast, diverse phages encode spermidine -acetyltransferase that can sequester spermidine into its inactive -acetyl form. Together, the virome-encoded enzymes and pathways for biosynthesis and release or biochemical sequestration of spermidine or its structural analog homospermidine consolidate and expand evidence supporting an important and global role of spermidine in virus biology.
Topics: Polyamines; Spermidine; Ornithine Decarboxylase; Acetyltransferases
PubMed: 36802435
DOI: 10.1073/pnas.2214165120 -
Circulation Research Apr 2017A recent study published in reports that dietary supplementation with spermidine, a natural polyamine, extends life span and reverses aging-associated cardiac... (Review)
Review
A recent study published in reports that dietary supplementation with spermidine, a natural polyamine, extends life span and reverses aging-associated cardiac dysfunction in mice through induction of autophagy. Similar protective effects of spermidine on human cardiovascular health were also suggested by epidemiological studies.
Topics: Animals; Autophagy; Drosophila melanogaster; Longevity; Polyamines; Spermidine
PubMed: 28408448
DOI: 10.1161/CIRCRESAHA.117.310603 -
Medical Sciences (Basel, Switzerland) Jul 2022The polyamines spermidine and spermine are positively charged aliphatic molecules. They are critical in the regulation of nucleic acid and protein structures, protein... (Review)
Review
The polyamines spermidine and spermine are positively charged aliphatic molecules. They are critical in the regulation of nucleic acid and protein structures, protein synthesis, protein and nucleic acid interactions, oxidative balance, and cell proliferation. Cellular polyamine levels are tightly controlled through their import, export, synthesis, and catabolism. Enzymes and enzymatic cascades involved in polyamine metabolism have been well characterized. This knowledge has been used for the development of novel compounds for research and medical applications. Furthermore, studies have shown that disturbances in polyamine levels and their metabolic pathways, as a result of spontaneous mutations in patients, genetic engineering in mice or experimentally induced injuries in rodents, are associated with multiple maladaptive changes. The adverse effects of altered polyamine metabolism have also been demonstrated in models. These observations highlight the important role these molecules and their metabolism play in the maintenance of physiological normalcy and the mediation of injury. This review will attempt to cover the extensive and diverse knowledge of the biological role of polyamines and their metabolism in the maintenance of physiological homeostasis and the mediation of tissue injury.
Topics: Animals; Homeostasis; Mice; Nucleic Acids; Polyamines; Spermidine; Spermine
PubMed: 35893120
DOI: 10.3390/medsci10030038