bims-polyam Biomed News
on Polyamines
Issue of 2019‒08‒11
eleven papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology


  1. Oncogene. 2019 Aug 09.
    Thakur VS, Aguila B, Brett-Morris A, Creighton CJ, Welford SM.
      Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism, has broad regulatory roles due to near ubiquitous polyamine binding. We describe a novel function of SAT1 as a gene-specific transcriptional regulator through local polyamine acetylation. SAT1 expression is elevated in aggressive brain tumors and promotes resistance to radiotherapy. Expression profiling in glioma cells identified SAT1 target genes that distinguish high- and low-grade tumors, in support of the prognostic utility of SAT1 expression. We further discovered mechanisms of SAT1-driven tumor aggressiveness through promotion of expression of both DNA damage response pathways as well as cell cycle regulatory genes. Mechanistically, SAT1 associates specifically with the promoter of the MELK gene, which functionally controls other SAT1 targets, and leads biologically to maintenance of neurosphere stemness in conjunction with FOXM1 and EZH2. CRISPR knockin mutants demonstrate the essentiality of the polyamine acetyltransferase activity of SAT1 for its function as a transcriptional regulator. Together, the data demonstrate that gene-specific polyamine removal is a major transcriptional regulatory mechanism active in high-grade gliomas that drives poor outcomes.
    DOI:  https://doi.org/10.1038/s41388-019-0917-0
  2. Front Plant Sci. 2019 ;10 894
    Liu C, Atanasov KE, Tiburcio AF, Alcázar R.
      Polyamines are involved in defense against pathogenic microorganisms in plants. However, the role of the polyamine putrescine (Put) during plant defense has remained elusive. In this work, we studied the implication of polyamines during pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) in the model species Arabidopsis thaliana. Our data indicate that polyamines, particularly Put, accumulate in response to non-pathogenic Pseudomonas syringae pv. tomato DC3000 hrcC and in response to the purified PAMP flagellin22. Exogenously supplied Put to Arabidopsis seedlings induces defense responses compatible with PTI activation, such as callose deposition and transcriptional up-regulation of several PTI marker genes. Consistent with this, we show that Put primes for resistance against pathogenic bacteria. Through chemical and genetic approaches, we find that PTI-related transcriptional responses induced by Put are hydrogen peroxide and NADPH oxidase (RBOHD and RBOHF) dependent, thus suggesting that apoplastic ROS mediates Put signaling. Overall, our data indicate that Put amplifies PTI responses through ROS production, leading to enhanced disease resistance against bacterial pathogens.
    Keywords:  PAMP-triggered immunity; defense; pathogen-associated molecular pattern; polyamines; putrescine; reactive oxygen species
    DOI:  https://doi.org/10.3389/fpls.2019.00894
  3. Plants (Basel). 2019 Aug 06. pii: E269. [Epub ahead of print]8(8):
    Miyamoto M, Shimao S, Tong W, Motose H, Takahashi T.
      A mutant defective in the biosynthesis of thermospermine, acaulis5 (acl5), shows a dwarf phenotype with excess xylem vessels in Arabidopsis thaliana. Exogenous supply of thermospermine remarkably represses xylem differentiation in the root of seedlings, indicating the role of thermospermine in proper repression of xylem differentiation. However, the effect of thermospermine has rarely been investigated in other plant species. In this paper, we examined its effect on the growth and gene expression in rice seedlings. When grown with thermospermine, rice seedlings had no clearly enlarged metaxylem vessels in the root. Expression of OsACL5 was reduced in response to thermospermine, suggesting a negative feedback control of thermospermine biosynthesis like in Arabidopsis. Unlike Arabidopsis, however, rice showed up-regulation of phloem-expressed genes, OsHB5 and OsYSL16, by one-day treatment with thermospermine. Furthermore, expression of OsPAO2 and OsPAO6, encoding extracellular polyamine oxidase whose orthologs are not present in Arabidopsis, was induced by both thermospermine and spermine. These results suggest that thermospermine affects the expression of a subset of genes in rice different from those affected in Arabidopsis.
    Keywords:  Arabidopsis; phloem; rice; spermine; thermospermine; xylem
    DOI:  https://doi.org/10.3390/plants8080269
  4. Food Chem. 2019 Jul 31. pii: S0308-8146(19)31415-3. [Epub ahead of print]301 125303
    Li Y, Ma Y, Zhang T, Bi Y, Wang Y, Prusky D.
      The effects of exogenous polyamines treatment on reactive oxygen species (ROS) metabolism in apricot fruits were systematically analyzed through the investigation of their curative and preventive effects on black spot disease. Results showed that 1.5 mM spermine (Spm), 1.5 mM spermidine (Spd) and 10 mM putrescine (Put) treatment significantly inhibited black spot development, additionally, the efficacy of this control was dependent upon the type of polyamines used and concentration level applied. Further studies have shown that exogenous polyamines treatments significantly improved production of O2- and H2O2, and increased the activities and gene expression levels of NADPH oxidase (NOX), super oxide dismutase (SOD), catalase (CAT) ascorbate peroxidase (AXP) and glutathione reductase (GR) in apricot fruit. Increased ascorbic acid (AsA) and reduced glutathione (GSH) content were also observed after exogenous polyamines treatment. These results have revealed that postharvest polyamines treatment effectively enhanced disease resistance through the maintenance of homeostasis in apricot fruits.
    Keywords:  Apricot fruit; Black spot; Exogenous polyamines; Induced resistance; ROS metabolism
    DOI:  https://doi.org/10.1016/j.foodchem.2019.125303
  5. Plant Signal Behav. 2019 Aug 05. 1-4
    Canales FJ, Montilla-Bascón G, Rispail N, Prats E.
      Salicylic acid (SA) is involved in several plant processes including responses to abiotic stresses. Although SA is thought to interact with other regulatory molecules in a complex way, currently, little information is available regarding its molecular mechanisms of action in response to abiotic stresses. In a previous work, we observed that drought-resistant oat plants significantly increased their SA levels as compared with a susceptible cultivar. Furthermore, exogenous SA treatment alleviated drought symptoms. Here, we investigated the interaction between SA and polyamine biosynthesis during drought responses in oat and revealed that SA regulated polyamine biosynthesis through changes in polyamine gene expression. Overall, SA treatment decreased the levels of putrescine under drought conditions while increased those of spermine. This correlates with the downregulation of the ADC gene and upregulation of the AdoMetDC gene. Based on the presented results, we propose that SA modulates drought responses in oat by regulating polyamine content and biosynthesis.
    Keywords:  Drought; oat; polyamine; salicylic acid
    DOI:  https://doi.org/10.1080/15592324.2019.1651183
  6. Antimicrob Agents Chemother. 2019 Aug 05. pii: AAC.01044-19. [Epub ahead of print]
    Bolard A, Schniederjans M, Haussler S, Triponney P, Valot B, Plesiat P, Jeannot K.
      Emergence of resistance to polymyxins in Pseudomonas aeruginosa is mainly due to mutations in two-components systems, that promote addition of 4-amino-4-deoxy-L-arabinose to the lipopolysaccharide (LPS) through upregulation of operon arnBCADTEF-ugd (arn) expression. Here, we demonstrate that mutations occurring in different domains of histidine kinase PmrB or in response regulator PmrA result in coresistance to aminoglycosides and colistin. All seventeen clinical strains tested exhibiting such a cross-resistance phenotype were found to be pmrAB mutants. As shown by gene deletion experiments, the decreased susceptibility of the mutants to aminoglycosides was independent from operon arn but required the efflux system MexXY(OprM) and the products of three genes, PA4773-PA4774-PA4775, that are cotranscribed and activated with genes pmrAB Gene PA4773 (annotated as speD2 in PAO1 genome) and PA4774 (speE2) are predicted to encode enzymes involved in biosynthesis of polyamines. Comparative analysis of cell surface extracts of an in vitro selected pmrAB mutant, called AB16.2, and derivatives lacking PA4773, PA4774 and PA4775, respectively revealed that these genes were needed for norspermidine production via a pathway that likely uses 1,3-diaminoprane, a precursor of polyamines. Altogether, our results suggest that norspermidine decreases the self-promoted uptake pathway of aminoglycosides across the outer membrane and thereby potentiates the activity of efflux pump MexXY(OprM).
    DOI:  https://doi.org/10.1128/AAC.01044-19
  7. Nat Commun. 2019 Aug 07. 10(1): 3546
    Chen J, Ni H, Meng Z, Wang J, Huang X, Dong Y, Sun C, Zhang Y, Cui L, Li J, Jia X, Meng Q, Li C.
      Polyamines are essential for the growth of eukaryotic cells and can be dysregulated in tumors. Here we describe a strategy to deplete polyamines through host-guest encapsulation using a peptide-pillar[5]arene conjugate (P1P5A, P1 = RGDSK(N3)EEEE) as a supramolecular trap. The RGD in the peptide sequence allows the molecule to bind to integrin αvβ3-overexpressing tumor cells. The negative charged glutamic acid residues enhance the inclusion affinities between the pillar[5]arene and cationic polyamines via electrostatic interactions and facilitate the solubility of the conjugate in aqueous media. The trap P1P5A efficiently encapsulates polyamines with association constants of 105-106 M-1. We show that P1P5A has a wide spectrum of antitumor activities, and induces apoptosis via affecting the polyamine biosynthetic pathway. Experiments in vivo show that P1P5A effectively inhibits the growth of breast adenocarcinoma xenografts in female nude mice. This work reveals an approach for suppressing tumor growth by using supramolecular macrocycles to trap polyamines in tumor cells.
    DOI:  https://doi.org/10.1038/s41467-019-11553-7
  8. Front Plant Sci. 2019 ;10 921
    Parthasarathy A, Savka MA, Hudson AO.
      Most studies on amino acids are focused on the proteinogenic amino acids given their essential roles in protein synthesis among other pathways. In addition to 20 ubiquitous amino acids used in protein synthesis, plants synthesize over 250 non-proteinogenic amino acids that are involved in the synthesis of compounds that are anti-herbivory, anti-microbial, response to abiotic stresses, nitrogen storage, toxins against both vertebrates/invertebrates, and plant hormones among others. One such non-proteinogenic acid is β-alanine, which is known mainly for studies on humans. β-Alanine forms a part of pantothenate (vitamin B5), which is incorporated into the universal carbon shuttling compounds Coenzyme A and acyl carrier protein, in all organisms including plants. The focus of this review, however, is on the biosynthesis, metabolism, and the role of β-alanine in plants. There are several functions of β-alanine unique to plants. It is accumulated as a generic stress response molecule involved in protecting plants from temperature extremes, hypoxia, drought, heavy metal shock, and some biotic stresses. There is evidence of its participation in lignin biosynthesis and ethylene production in some species. It is further converted to the osmoprotective compound β-alanine betaine in some species and converted to the antioxidant homoglutathione in others. The polyamines spermine/spermidine, propionate and uracil have been shown to be precursors of β-alanine in plants. However, plants vary in terms of their biosynthetic pathways, and the primary metabolism of β-alanine is far from settled.
    Keywords:  L-alanine; amino acid; non-proteinogenic; secondary metabolites; β-alanine
    DOI:  https://doi.org/10.3389/fpls.2019.00921
  9. Int J Syst Evol Microbiol. 2019 Aug 06.
    Lee SY, Kang W, Kim PS, Kim HS, Sung H, Shin NR, Whon TW, Yun JH, Lee JY, Lee JY, Jung MJ, Jeong YS, Tak EJ, Han JE, Hyun DW, Kang MS, Lee KE, Lee BH, Bae JW.
      A novel Gram-stain-negative, non-spore-forming, obligate aerobic, motile, rod-shaped, and flagellated bacterium, designated S11R28T, was isolated from the intestinal tract of a Korean shiner, Coreoleuciscus splendidus. Based on 16S rRNA gene sequences, strain S11R28T was identified as member of the genus Undibacterium in class Betaproteobacteria, and was closely related to Undibacterium parvum DSM 23061T (98.49 %). The isolate grew at 4-25 °C, pH 6-9, with 0 % (w/v) NaCl, and grew optimally at 20 °C, pH 8, in the absence of NaCl. The main cellular fatty acids were C16 : 0 and summed features 3 (C16 : 1ω7c and/or C16 : 1ω6c). The strain possessed diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine as predominant polar lipids, and ubiquinone Q-8 as a respiratory quinone. The polyamine profile composed of 2-hydroxyputrescine, spermidine, putrescine, and benzoic acid. A genomic DNA G+C content was 51.4 mol%. The average nucleotide identity between strains S11R28T and U. parvum DSM 23061T was 78.66 %. Thus, Undibacterium piscinae can be considered a novel species within the genus Undibacterium with the type strain S11R28T (=KCTC 62668T=JCM 33224T).
    DOI:  https://doi.org/10.1099/ijsem.0.003604
  10. Hepatology. 2019 Aug 05.
    De Chiara F, Thomsen KL, Habtesion A, Jones H, Davies N, Gracia-Sancho J, Manicardi N, Hall A, Andreola F, Paish HL, Reed LH, Watson AA, Leslie J, Oakley F, Rombouts K, Mookerjee RP, Mann J, Jalan R.
      In non-alcoholic fatty liver disease (NAFLD), fibrosis is the most important factor contributing to NAFLD-associated morbidity and mortality. Prevention of progression and reduction in fibrosis is the main aim of treatment. Even in early stages of NAFLD, hepatic and systemic hyperammonaemia is evident. This is due to reduced urea synthesis and as ammonia is known to activate hepatic stellate cells, we hypothesised that ammonia may be involved in the progression of fibrosis in NAFLD. In a high-fat high-cholesterol diet induced rodent model of NAFLD, we observed a progressive step-wise reduction in the expression and activity of urea cycle enzymes resulting in hyperammonaemia, evidence of hepatic stellate cell activation and progressive fibrosis. In primary, cultured hepatocytes and precision cut liver slices we demonstrated increased gene expression of pro-fibrogenic markers after lipid and/or ammonia exposure. Lowering of ammonia with the ammonia scavenger ornithine phenylacetate (OP) prevented hepatocyte cell death and significantly reduced the development of fibrosis both in vitro in the liver slices and also in vivo in the rodent animal model. The prevention of fibrosis in the rodent model was associated with restoration of urea cycle enzyme activity and function, reduced hepatic ammonia and markers of inflammation. CONCLUSION: The results of this study suggest that hepatic steatosis results in hyperammonaemia, which is associated with progression of hepatic fibrosis. Reduction of ammonia levels prevented progression of fibrosis providing a potentially novel treatment for NAFLD. This article is protected by copyright. All rights reserved.
    Keywords:  ammonia; fibrosis; non-alcoholic fatty liver disease; urea cycle
    DOI:  https://doi.org/10.1002/hep.30890
  11. Liver Int. 2019 Aug 06.
    Eriksen PL, Vilstrup H, Rigbolt K, Suppli MP, Sørensen M, Heebøll S, Veidal SS, Knop FK, Thomsen KL.
      BACKGROUND & AIMS: We recently showed that the functional capacity for ureagenesis is deficient in NAFLD patients. The aim of this study was to assess expression of urea cycle related genes to elucidate a possible gene regulatory basis to the functional problem.METHODS: Liver mRNA expression analyses within the gene pathway governing hepatic nitrogen conversion were performed in 20 non-diabetic, biopsy-proven NAFLD patients (8 simple steatosis; 12 non-alcoholic steatohepatitis (NASH)) and 12 obese and 14 lean healthy individuals. Sixteen NAFLD patients were included for gene expression validation. Relationship between gene expressions and functional capacity for ureagenesis was described.
    RESULTS: Gene expression of most urea cycle-related enzymes were downregulated in NAFLD vs. both control groups; markedly so for the urea cycle flux-generating carbamoyl phosphate synthetase (CPS1) (~3.5-fold, p<0.0001). In NASH, CPS1 downregulation paralleled the deficit in ureagenesis (p=0.03). Additionally, expression of several genes involved in amino acid uptake and degradation, and the glucagon receptor gene, were downregulated in NAFLD. Conversely, glutamine synthetase (GS) expression increased >1.5-fold (p≤0.03), inversely related to CPS1 expression (p=0.004).
    CONCLUSIONS: NAFLD downregulated expression of urea cycle-related genes. Downregulation of urea cycle flux-generating CPS1 correlated with loss of functional capacity for ureagenesis in NASH. On gene level, these changes coincided with an increase in the major ammonia scavenging enzyme GS. The effects seemed related to a fatty liver as such rather than NASH or obesity. The findings support gene regulatory mechanisms involved in the deficient ureagenesis of NAFLD, but it remains unexplained how hepatocyte fat accumulation exerts these effects. This article is protected by copyright. All rights reserved.
    Keywords:  amino acids; ammonia; glucagon; glutamine synthetase; non-alcoholic steatohepatitis; urea
    DOI:  https://doi.org/10.1111/liv.14205