bims-polyam Biomed News
on Polyamines
Issue of 2023‒07‒30
six papers selected by
Sebastian J. Hofer
University of Graz
  1. Putrescine Detected in Strains of Staphylococcus aureus.
  2. Structural and Kinetic Characterization of the SpeG Spermidine/Spermine N-acetyltransferase from Methicillin-Resistant Staphylococcus aureus USA300.
  3. Exploration of Bis-Cinnamido-Polyamines as Intrinsic Antimicrobial Agents and Antibiotic Enhancers.
  4. As Verified with the Aid of Biotinylated Spermine, the Brain Cannot Take up Polyamines from the Bloodstream Leaving It Solely Dependent on Local Biosynthesis.
  5. Dynamics of Polyamines, Proline, and Ethylene Metabolism under Increasing Cold in Winter Oilseed Rape.
  6. Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy.
  1. Pathogens. 2023 Jun 27. pii: 881. [Epub ahead of print]12(7):
    Putrescine Detected in Strains of Staphylococcus aureus.
    Javier Seravalli, Frank Portugal.
      Most forms of life, including the archaea, bacteria, and eukaryotes synthesize the polyamine putrescine. Although putrescine is widely distributed, several Gram-positive bacteria, including Staphylococcus aureus (S. aureus), appear to be the exceptions. We report here that strains of S. aureus can produce the polyamine putrescine, as well as the derivative N-acetyl-putrescine. Three strains of S. aureus from the American Type Culture Collection (ATCC), one strain listed in the National Center for Biotechnology Information (NCBI) database, whose genomic sequence is well defined, and well as eight strains from S. aureus-induced brain abscesses of individual patients from multiple geographic locations were evaluated. Each strain was grown in complete chemically defined medium (CDM) under stringent conditions, after which the partially purified conditioned medium (CM) was analyzed by mass spectroscopy (MS), and the data were reported as the ratio of experimental results to controls. We confirmed the synthesis of putrescine by S. aureus by using 13C/15N-labeled arginine as a tracer. We found that agmatine, N-acetyl-putrescine, ornithine, citrulline, proline, and NH3 were all labeled with heavy isotope derived from 13C/15N-labeled arginine. None of the strains examined produced spermine or spermidine, but strains from either ATCC or human brain abscesses produced putrescine and/or its derivative N-acetyl-putrescine.
    Keywords:  N-acetyl-putrescine; Staphylococcus aureus; bacterial pathogen; mass spectrometry; multiple reaction monitoring (MRM); putrescine
    DOI:  https://doi.org/10.3390/pathogens12070881
  2. Cells. 2023 Jul 12. pii: 1829. [Epub ahead of print]12(14):
    Structural and Kinetic Characterization of the SpeG Spermidine/Spermine N-acetyltransferase from Methicillin-Resistant Staphylococcus aureus USA300.
    Sofiya Tsimbalyuk, Aleksander Shornikov, Parul Srivastava, Van Thi Bich Le, Imani Warren, Yogesh B Khandokar, Misty L Kuhn, Jade K Forwood.
      Polyamines are simple yet critical molecules with diverse roles in numerous pathogenic and non-pathogenic organisms. Regulating polyamine concentrations affects the transcription and translation of genes and proteins important for cell growth, stress, and toxicity. One way polyamine concentrations are maintained within the cell is via spermidine/spermine N-acetyltransferases (SSATs) that acetylate intracellular polyamines so they can be exported. The bacterial SpeG enzyme is an SSAT that exhibits a unique dodecameric structure and allosteric site compared to other SSATs that have been previously characterized. While its overall 3D structure is conserved, its presence and role in different bacterial pathogens are inconsistent. For example, not all bacteria have speG encoded in their genomes; in some bacteria, the speG gene is present but has become silenced, and in other bacteria, it has been acquired on mobile genetic elements. The latter is the case for methicillin-resistant Staphylococcus aureus (MRSA) USA300, where it appears to aid pathogenesis. To gain a greater understanding of the structure/function relationship of SpeG from the MRSA USA300 strain (SaSpeG), we determined its X-ray crystal structure in the presence and absence of spermine. Additionally, we showed the oligomeric state of SaSpeG is dynamic, and its homogeneity is affected by polyamines and AcCoA. Enzyme kinetic assays showed that pre-incubation with polyamines significantly affected the positive cooperativity toward spermine and spermidine and the catalytic efficiency of the enzyme. Furthermore, we showed bacterial SpeG enzymes do not have equivalent capabilities to acetylate aminopropyl versus aminbutyl ends of spermidine. Overall, this study provides new insight that will assist in understanding the SpeG enzyme and its role in pathogenic and non-pathogenic bacteria at a molecular level.
    Keywords:  Gcn5-related N-acetyltransferase (GNAT); MRSA USA300; Staphylococcus aureus; acetylation; polyamine; spermidine/spermine N-acetyltransferase (SSAT)
    DOI:  https://doi.org/10.3390/cells12141829
  3. Biomolecules. 2023 Jul 07. pii: 1087. [Epub ahead of print]13(7):
    Exploration of Bis-Cinnamido-Polyamines as Intrinsic Antimicrobial Agents and Antibiotic Enhancers.
    Melissa M Cadelis, Jisoo Kim, Florent Rouvier, Evangelene S Gill, Kyle Fraser, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel, Brent R Copp.
      The marine natural product ianthelliformisamine C is a bis-cinnamido substituted spermine derivative that exhibits intrinsic antimicrobial properties and can enhance the action of doxycycline towards the Gram-negative bacterium Pseudomonas aeruginosa. As part of a study to explore the structure-activity requirements of these activities, we have synthesized a set of analogues that vary in the presence/absence of methoxyl group and bromine atoms and in the polyamine chain length. Intrinsic antimicrobial activity towards Staphylococcus aureus, methicillin-resistant S. aureus (MRSA) and the fungus Cryptococcus neoformans was observed for only the longest polyamine chain examples of non-brominated analogues while all examples bearing either one or two bromine atoms were active. Weak to no activity was typically observed towards Gram-negative bacteria, with exceptions being the longest polyamine chain examples 13f, 14f and 16f against Escherichia coli (MIC 1.56, 7.2 and 5.3 µM, respectively). Many of these longer polyamine-chain analogues also exhibited cytotoxic and/or red blood cell hemolytic properties, diminishing their potential as antimicrobial lead compounds. Two of the non-toxic, non-halogenated analogues, 13b and 13d, exhibited a strong ability to enhance the action of doxycycline against P. aeruginosa, with >64-fold and >32-fold enhancement, respectively. These results suggest that any future efforts to optimize the antibiotic-enhancing properties of cinnamido-polyamines should explore a wider range of aromatic ring substituents that do not include bromine or methoxyl groups.
    Keywords:  antibiotics; antifungal agents; antimicrobial; indole; polyamine; potentiator; structure-activity relationships
    DOI:  https://doi.org/10.3390/biom13071087
  4. Biomolecules. 2023 Jul 13. pii: 1114. [Epub ahead of print]13(7):
    As Verified with the Aid of Biotinylated Spermine, the Brain Cannot Take up Polyamines from the Bloodstream Leaving It Solely Dependent on Local Biosynthesis.
    Torsten Weiss, René Bernard, Gregor Laube, Julian Rieck, Misty J Eaton, Serguei N Skatchkov, Rüdiger W Veh.
      The importance of polyamines (PAs) for the central nervous system (CNS) is well known. Less clear, however, is where PAs in the brain are derived from. Principally, there are three possibilities: (i) intake by nutrition, release into the bloodstream, and subsequent uptake from CNS capillaries, (ii) production by parenchymatous organs, such as the liver, and again uptake from CNS capillaries, and (iii) uptake of precursors, such as arginine, from the blood and subsequent local biosynthesis of PAs within the CNS. The present investigation aimed to unequivocally answer the question of whether PAs, especially the higher ones like spermidine (SPD) and spermine (SPM), can or cannot be taken up into the brain from the bloodstream. For this purpose, a biotin-labelled analogue of spermine (B-X-SPM) was synthesized, characterized, and used to visualize its uptake into brain cells following application to acute brain slices, to the intraventricular space, or to the bloodstream. In acute brain slices there is strong uptake of B-X-SPM into protoplasmic and none in fibrous-type astrocytes. It is also taken up by neurons but to a lesser degree. Under in vivo conditions, astrocyte uptake of B-X-SPM from the brain interstitial fluid is also intense after intraventricular application. In contrast, following intracardial injection, there is no uptake from the bloodstream, indicating that the brain is completely dependent on the local synthesis of polyamines.
    Keywords:  blood–brain barrier; fibrous astrocytes; local biosynthesis; metabolism; polyamines; protoplasmic astrocytes
    DOI:  https://doi.org/10.3390/biom13071114
  5. Int J Mol Sci. 2023 Jul 13. pii: 11402. [Epub ahead of print]24(14):
    Dynamics of Polyamines, Proline, and Ethylene Metabolism under Increasing Cold in Winter Oilseed Rape.
    Elžbieta Jankovska-Bortkevič, Sigita Jurkonienė, Virgilija Gavelienė, Vaidevutis Šveikauskas, Rima Mockevičiūtė, Irina Vaseva, Dessislava Todorova, Marija Žižytė-Eidetienė, Donatas Šneideris, Petras Prakas.
      Cold stress is among the most important environmental factors reducing the yield of crops. The present study aimed to investigate the impact of increasing cold stress conditions on winter oilseed rape polyamines, proline, and ethylene metabolism in acclimated and non-acclimated winter oilseed rape. This study was carried out under controlled conditions in the laboratory. The winter oilseed rape hybrid 'Visby' was used in the experiment. Acclimated and non-acclimated plants were subjected to a two-day-long increasing cold (from -1 °C to -3 °C) treatment. HPTLC, RT-qPCR, spectral analysis, and gas chromatography methods were used to analyse the levels of polyamines, gene expression, proline, and ethylene, respectively. This study showed a decrease in putrescine, spermidine, and spermine content during cold acclimation and a decrease in putrescine and spermidine levels at sub-zero temperatures. There were intensive changes in ADC2 gene expression, proline, and ethylene levels in non-acclimated plants: a substantial increase after exposure to -1 °C temperature and a sharp decrease after exposure to -3 °C temperature. The changes in these parameters were lower or absent in acclimated plants. The phenomena observed in this study add new insights to the knowledge about the plant stress response and suggest questions to be answered in the future.
    Keywords:  Brassica napus; cold stress; ethylene; oilseed rape; polyamines; proline; stress markers
    DOI:  https://doi.org/10.3390/ijms241411402
  6. Cancers (Basel). 2023 Jul 21. pii: 3708. [Epub ahead of print]15(14):
    Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy.
    Maysa Vilbert, Erica C Koch, April A N Rose, Rob C Laister, Diana Gray, Valentin Sotov, Susanne Penny, Anna Spreafico, Devanand M Pinto, Marcus O Butler, Samuel D Saibil.
      Cutaneous melanoma (CM) patients respond better to immune checkpoint inhibitors (ICI) than mucosal and uveal melanoma patients (MM/UM). Aiming to explore these differences and understand the distinct response to ICI, we evaluated the serum metabolome of advanced CM, MM, and UM patients. Levels of 115 metabolites were analyzed in samples collected before ICI, using a targeted metabolomics platform. In our analysis, molecules involved in the tryptophan-kynurenine axis distinguished UM/MM from CM. UM/MM patients had higher levels of 3-hydroxykynurenine (3-HKyn), whilst patients with CM were found to have higher levels of kynurenic acid (KA). The KA/3-HKyn ratio was significantly higher in CM versus the other subtypes. UM, the most ICI-resistant subtype, was also associated with higher levels of sphingomyelin-d18:1/22:1 and the polyamine spermine (SPM). Overall survival was prolonged in a cohort of CM patients with lower SPM levels, suggesting there are also conserved metabolic factors promoting ICI resistance across melanoma subtypes. Our study revealed a distinct metabolomic profile between the most resistant melanoma subtypes, UM and MM, compared to CM. Alterations within the kynurenine pathway, polyamine metabolism, and sphingolipid metabolic pathway may contribute to the poor response to ICI. Understanding the different metabolomic profiles introduces opportunities for novel therapies with potential synergic activity to ICI, to improve responses of UM/MM.
    Keywords:  cutaneous melanoma; immune-checkpoint inhibitors; kynurenine; melanoma; metabolomics; mucosal melanoma; spermine; tryptophan; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers15143708
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