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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 -
Molecules (Basel, Switzerland) May 2024Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected... (Review)
Review
Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for and viability.
Topics: NADH, NADPH Oxidoreductases; Humans; Amide Synthases; Trypanosoma; Glutathione; Animals; Spermidine; Leishmania; Trypanocidal Agents; Leishmaniasis; Trypanosomatina; Protozoan Proteins; Chagas Disease
PubMed: 38792079
DOI: 10.3390/molecules29102214 -
Pathogens (Basel, Switzerland) Jan 2024Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or... (Review)
Review
Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field.
PubMed: 38251386
DOI: 10.3390/pathogens13010079 -
Science Advances Oct 2023Spermidine, a ubiquitous polyamine, is known to be required for critical physiological functions in bacteria. Two principal pathways are known for spermidine...
Spermidine, a ubiquitous polyamine, is known to be required for critical physiological functions in bacteria. Two principal pathways are known for spermidine biosynthesis, both of which involve aminopropylation of putrescine. Here, we identified a spermidine biosynthetic pathway via a previously unknown metabolite, carboxyaminopropylagmatine (CAPA), in a model cyanobacterium sp. PCC 6803 through an approach combining C and N tracers, metabolomics, and genetic and biochemical characterization. The CAPA pathway starts with reductive condensation of agmatine and l-aspartate-β-semialdehyde into CAPA by a previously unknown CAPA dehydrogenase, followed by decarboxylation of CAPA to form aminopropylagmatine, and ends with conversion of aminopropylagmatine to spermidine by an aminopropylagmatine ureohydrolase. Thus, the pathway does not involve putrescine and depends on l-aspartate-β-semialdehyde as the aminopropyl group donor. Genomic, biochemical, and metagenomic analyses showed that the CAPA-pathway genes are widespread in 15 different phyla of bacteria distributed in marine, freshwater, and other ecosystems.
Topics: Spermidine; Putrescine; Biosynthetic Pathways; Aspartic Acid; Ecosystem; Cyanobacteria
PubMed: 37878710
DOI: 10.1126/sciadv.adj9075 -
Nature Communications Oct 2023The broad bioactivities of nonribosomal peptides rely on increasing structural diversity. Genome mining of the Burkholderiales strain Schlegelella brevitalea DSM 7029...
The broad bioactivities of nonribosomal peptides rely on increasing structural diversity. Genome mining of the Burkholderiales strain Schlegelella brevitalea DSM 7029 leads to the identification of a class of dodecapeptides, glidonins, that feature diverse N-terminal modifications and a uniform putrescine moiety at the C-terminus. The N-terminal diversity originates from the wide substrate selectivity of the initiation module. The C-terminal putrescine moiety is introduced by the unusual termination module 13, the condensation domain directly catalyzes the assembly of putrescine into the peptidyl backbone, and other domains are essential for stabilizing the protein structure. Swapping of this module to another two nonribosomal peptide synthetases leads to the addition of a putrescine to the C-terminus of related nonribosomal peptides, improving their hydrophilicity and bioactivity. This study elucidates the mechanism for putrescine addition and provides further insights to generate diverse and improved nonribosomal peptides by introducing a C-terminal putrescine.
Topics: Putrescine; Peptides; Peptide Synthases
PubMed: 37857663
DOI: 10.1038/s41467-023-42387-z -
Foods (Basel, Switzerland) Dec 2023is a broth derived from cassava roots which is produced after the spontaneous fermentation of (the liquid portion obtained by pressing cassava roots), followed by...
is a broth derived from cassava roots which is produced after the spontaneous fermentation of (the liquid portion obtained by pressing cassava roots), followed by cooking. This product is widely consumed along with traditional dishes in the Brazilian Amazonia and is already used in different places worldwide. In this study, obtained from the markets of Belém (Pará, Brazil) and produced using agroindustrial (11 samples) and non-agroindustrial (11 samples) units were investigated to determine their physicochemical characteristics, total and free HCN contents, and free bioactive amine profiles. Most of the samples showed significant variations ( ≤ 0.05) in pH (2.82-4.67), total acidity (0.14-1.36 g lactic acid/100 mL), reducing sugars (up to 2.33 g/100 mL), and total sugars (up to 4.35 g/100 mL). Regarding the amines, four biogenic amines (0.5-4.2 mg/L tyramine, 1.0-23.1 mg/L putrescine, 0.5-66.8 mg/L histamine, and 0.6-2.9 mg/L tryptamine) and one polyamine (0.4-1.7 mg/L spermidine) were identified in the samples. Even in the produced using the agroindustrial units, which had quality seals provided by the local regulatory agency, high levels of biogenic amines (4.4-78.2 mg/L) were observed, as well as high dosages of total (8.87-114.66 mg/L) and free (0.80-38.38 mg/L) HCN. These facts highlight the need for better knowledge regarding the product manufacturing process to establish standardization and high-quality conditions for processing since high contents of biogenic amines and HCN are commonly associated with adverse health effects.
PubMed: 38231841
DOI: 10.3390/foods12234333 -
Physiology and Molecular Biology of... May 2024Polyamines play an important role in growth and differentiation by regulating numerous physiological and biochemical processes at the cellular level. In addition to...
Polyamines play an important role in growth and differentiation by regulating numerous physiological and biochemical processes at the cellular level. In addition to their roborative effect, their essential role in plant stress responses has been also reported. However, the positive effect may depend on the fine-tuning of polyamine metabolism, which influences the production of free radicals and/or signalling molecules. In the present study, 0.3 mM hydroponic putrescine treatment was tested in wheat, maize, and rice in order to reveal differences in their answers and highlight the relation of these with polyamine metabolism. In the case of wheat, the chlorophyll content and the actual quantum yield increased after putrescine treatment, and no remarkable changes were detected in the stress markers, polyamine contents, or polyamine metabolism-related gene expression. Although, in maize, the actual quantum yield decreased, and the root hydrogen peroxide content increased, no other negative effect was observed after putrescine treatment due to activation of polyamine oxidases at enzyme and gene expression levels. The results also demonstrated that after putrescine treatment, rice with a higher initial polyamine content, the balance of polyamine metabolism was disrupted and a significant amount of putrescine was accumulated, accompanied by a detrimental decrease in the level of higher polyamines. These initial differences and the putrescine-induced shift in polyamine metabolism together with the terminal catabolism or back-conversion-induced release of a substantial quantity of hydrogen peroxide could contribute to oxidative stress observed in rice.
PubMed: 38846465
DOI: 10.1007/s12298-024-01462-5 -
EMBO Molecular Medicine Nov 2023Snyder-Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males,...
Snyder-Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2-difluoromethylornithine (DFMO), an FDA-approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential.
Topics: Male; Humans; Polyamines; Spermidine; Spermine; Eflornithine; Spermine Synthase
PubMed: 37702369
DOI: 10.15252/emmm.202317833 -
The Science of the Total Environment Dec 2023The deep ocean is a rich reservoir of unique organisms with great potential for bioprospecting, ecosystem services, and the discovery of novel materials. These organisms... (Review)
Review
The deep ocean is a rich reservoir of unique organisms with great potential for bioprospecting, ecosystem services, and the discovery of novel materials. These organisms thrive in harsh environments characterized by high hydrostatic pressure, low temperature, and limited nutrients. Hydrothermal vents and cold seeps, prominent features of the deep ocean, provide a habitat for microorganisms involved in the production and filtration of methane, a potent greenhouse gas. Methanotrophs, comprising archaea and bacteria, play a crucial role in these processes. This review examines the intricate relationship between the roles, responses, and niche specialization of methanotrophs in the deep ocean ecosystem. Our findings reveal that different types of methanotrophs dominate specific zones depending on prevailing conditions. Type I methanotrophs thrive in oxygen-rich zones, while Type II methanotrophs display adaptability to diverse conditions. Verrumicrobiota and NC10 flourish in hypoxic and extreme environments. In addition to their essential role in methane regulation, methanotrophs contribute to various ecosystem functions. They participate in the degradation of foreign compounds and play a crucial role in cycling biogeochemical elements like metals, sulfur, and nitrogen. Methanotrophs also serve as a significant energy source for the oceanic food chain and drive chemosynthesis in the deep ocean. Moreover, their presence offers promising prospects for biotechnological applications, including the production of valuable compounds such as polyhydroxyalkanoates, methanobactin, exopolysaccharides, ecotines, methanol, putrescine, and biofuels. In conclusion, this review highlights the multifaceted roles of methanotrophs in the deep ocean ecosystem, underscoring their ecological significance and their potential for advancements in biotechnology. A comprehensive understanding of their niche specialization and responses will contribute to harnessing their full potential in various domains.
PubMed: 37579801
DOI: 10.1016/j.scitotenv.2023.166145 -
Science Advances Mar 2024Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm...
Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm is a microbivore that must distinguish nutritive microbes from pathogens. We characterized a neural circuit used by to rapidly discriminate between nutritive bacteria and pathogens. Distinct sensory neuron populations responded to chemical cues from nutritive and pathogenic , and these neural signals are decoded by downstream AIB interneurons. The polyamine metabolites cadaverine, putrescine, and spermidine produced by activate this neural circuit and elicit positive chemotaxis. Our study shows how polyamine odorants can be sensed by animals as proxies for microbe identity and suggests that, hence, polyamines might have widespread roles brokering host-microbe interactions.
Topics: Animals; Polyamines; Caenorhabditis elegans; Escherichia coli; Spermidine; Putrescine
PubMed: 38517971
DOI: 10.1126/sciadv.adj4387