bims-polyam Biomed News
on Polyamines
Issue of 2019‒11‒17
thirteen papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

  1. Int J Mol Sci. 2019 Nov 15. pii: E5746. [Epub ahead of print]20(22):
    Tajti J, Hamow KÁ, Majláth I, Gierczik K, Németh E, Janda T, Pál M.
      Polyamines are multifaceted compounds which play a role in regulating plant growth and stress tolerance in interactions with plant hormones. The aim of the present study was to reveal how exogenous polyamines influence the synthesis of salicylic acid, with a special emphasis on the effect of salicylic acid deficiency on the polyamine metabolism and polyamine-induced changes in other plant hormone contents. Our hypothesis was that the individual polyamines induced different changes in the polyamine and salicylic acid metabolism of the wild type and salicylic acid-deficient Arabidopsis mutants, which in turn influenced other hormones. To our knowledge, such a side-by-side comparison of the influence of eds5-1 and sid2-2 mutations on polyamines has not been reported yet. To achieve our goals, wild and mutant genotypes were tested after putrescine, spermidine or spermine treatments. Polyamine and plant hormone metabolism was investigated at metabolite and gene expression levels. Individual polyamines induced different changes in the Arabidopsis plants, and the responses were also genotype-dependent. Polyamines upregulated the polyamine synthesis and catabolism, and remarkable changes in hormone synthesis were found especially after spermidine or spermine treatments. The sid2-2 mutant showed pronounced differences compared to Col-0. Interactions between plant hormones may also be responsible for the observed differences.
    Keywords:  Arabidopsis; eds5-1; plant hormone; polyamine; salicylic acid; sid2-2
  2. Chemosphere. 2019 Nov 06. pii: S0045-6535(19)32548-2. [Epub ahead of print]243 125308
    Shah AA, Ahmed S, Ali A, Yasin NA.
      Cadmium level is continuously increasing in agricultural soils mainly due to anthropogenic activities. Cadmium is one of the most phytotoxic metals in the soils. The present study investigates the possible role of 2-hydroxymelatonin (2-OHMT) in assuagement of Cd-toxicity in cucumber (Cucumis sativus L.) plants. 2-OHMT is an important metabolite produced through interaction of melatonin with oxygenated compounds. Cadmium stress decreased the activity of antioxidant enzymes and polyamines. However, exogenously applied 2-OHMT enhanced plant growth attributes including photosynthetic rate, intercellular CO2 concentration, stomatal conductance and transpiration rate in treated plants. In addition, 2-OHMT induced enhancement of the activity of PAs biosynthesizing enzymes (putrescine, spermidine and spermine) in conjunction with reduction in activity of polyamine oxidase (PAO). 2-OHMT mitigated Cd stress through up-regulation in expression of stress related CS-ERS gene along with the amplified activity of superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) in treated seedlings. The improved activity of antioxidant scavengers played central role in reduction of hydrogen peroxide (H2O2), electrolyte leakage (EL) and malondialdehyde (MDA) in plants under Cd stress. Recent findings also advocate the positive correlation between PAs and ethylene, as both possess common precursor. The current study reveals that priming seeds with 2-OHMT reduces Cd-toxicity and makes it possible to cultivate cucumber in Cd-contaminated areas. Future experiments will perhaps help in elucidation of 2-OHMT intervened stress mitigation procedure in C. sativus crop. Furthermore, research with reference to potential of 2-OHMT for stress alleviation in other horticultural and agronomic crops will assist in enhancement of crop productivity.
    Keywords:  Cadmium; Cucumis sativus; Phytotoxic; Putrescine; Spermidine; Spermine
  3. Aging Cell. 2019 Nov 13. e13043
    Tain LS, Jain C, Nespital T, Froehlich J, Hinze Y, Grönke S, Partridge L.
      Reduced insulin/IGF signaling (IIS) extends lifespan in multiple organisms. Different processes in different tissues mediate this lifespan extension, with a set of interplays that remain unclear. We here show that, in Drosophila, reduced IIS activity modulates methionine metabolism, through tissue-specific regulation of glycine N-methyltransferase (Gnmt), and that this regulation is required for full IIS-mediated longevity. Furthermore, fat body-specific expression of Gnmt was sufficient to extend lifespan. Targeted metabolomics showed that reducing IIS activity led to a Gnmt-dependent increase in spermidine levels. We also show that both spermidine treatment and reduced IIS activity are sufficient to extend the lifespan of Drosophila, but only in the presence of Gnmt. This extension of lifespan was associated with increased levels of autophagy. Finally, we found that increased expression of Gnmt occurs in the liver of liver-specific IRS1 KO mice and is thus an evolutionarily conserved response to reduced IIS. The discovery of Gnmt and spermidine as tissue-specific modulators of IIS-mediated longevity may aid in developing future therapeutic treatments to ameliorate aging and prevent disease.
    Keywords:  IGF; aging; autophagy; insulin; lifespan; metabolism; polyamine
  4. Metabolites. 2019 Nov 12. pii: E275. [Epub ahead of print]9(11):
    Baruteau J, Khalil Y, Grunewald S, Zancolli M, Chakrapani A, Cleary M, Davison J, Footitt E, Waddington SN, Gissen P, Mills P.
      BACKGROUND: Dried bloodspots are easy to collect and to transport to assess various metabolites, such as amino acids. Dried bloodspots are routinely used for diagnosis and monitoring of some inherited metabolic diseases.METHODS: Measurement of amino acids from dried blood spots by liquid chromatography-tandem mass spectrometry.
    RESULTS: We describe a novel rapid method to measure underivatised urea cycle related amino acids. Application of this method enabled accurate monitoring of these amino acids to assess the efficacy of therapies in argininosuccinate lyase deficient mice and monitoring of these metabolites in patients with urea cycle defects.
    CONCLUSION: Measuring urea cycle related amino acids in urea cycle defects from dried blood spots is a reliable tool in animal research and will be of benefit in the clinic, facilitating optimisation of protein-restricted diet and preventing amino acid deprivation.
    Keywords:  amino acids; argininosuccinate lyase; dried blood spots; tandem mass spectrometry; urea cycle
  5. BMC Plant Biol. 2019 Nov 15. 19(1): 502
    Luo H, Du B, He L, Zheng A, Pan S, Tang X.
      BACKGROUND: Selenium (Se) is a beneficial element for higher plants and essential for mammals. To study the effect of the foliar application of sodium selenate on fragrant rice performance, a pot experiment was conducted in Guangdong, China. At the initial heading stage, one-time foliar application of sodium selenate with concentrations of 0, 10, 20, 30, 40 and 50 μmol·L- 1 (named CK, Se1, Se2, Se3, Se4 and Se5, respectively) were foliar applied on two fragrant rice varieties, 'Meixiangzhan-2' and 'Xiangyaxiangzhan'.RESULTS: Selenate application at the initial heading stage not only improved the grain yield of fragrant rice by increasing the seed-setting rate and grain weight, but also promoted the grain quality by increasing crude protein contents and lowering the chalky rice rate. Furthermore, Se applications enhanced the biosynthesis of 2-acetyl-1- pyrroline (2-AP), the main aromatic compound, by increasing the contents of precursors (△1- pyrroline, proline and pyrroline-5-carboxylic acid (P5C)) and the activities of enzymes (proline dehydrogenase (PRODH), △1-pyrroline-5-carboxylic acid synthetase (P5CS), and ornithine aminotransferase (OAT)) in fragrant rice. The results also showed that foliar application of sodium selenate enhanced the antioxidant system of both varieties by promoting the activities of peroxidase (POD), superoxide dismutase (SOD), catalase (CAT) and reducing the contents of malondialdehyde (MDA). Furthermore, the real-time PCR analyses depicted that foliar application of selenate up-regulated the GPX1, GPX4 and CATC transcripts. The higher antioxidative enzymatic activities might strength the stress resistant to ensure the stability of yield in fragrant rice form abiotic stress.
    CONCLUSIONS: Foliar applications of sodium selenate at the initial heading stage increased the grain 2-AP content by enhancing the biosynthesis-related enzymes and precursors. The grain yield and quality of fragrant rice also increased due to selenate application. Furthermore, foliar application of selenate promoted the activities of enzymes such as POD, SOD and CAT and up-regulated the expression of gene GPX4, GPX1 and CATC.
    Keywords:  2-acetyl-1-pyrroline; Fragrant rice; Grain quality; Sodium selenate; Yield
  6. Mol Genet Metab Rep. 2019 Dec;21 100525
    Ali EZ, Yakob Y, Ngu LH.
      Argininosuccinate lyase (ASL) deficiency impairs the function of the urea cycle that detoxifies blood ammonia in the body. Mutation that occurs in the ASL gene is the cause of occurrence of ASL deficiency (ASLD). This deficiency causes hyperammonemia, hepatopathy and neurodevelopmental delay in patients. In this study, the clinical characteristics and molecular analysis of 10 ASLD patients were presented. 8 patients were associated with severe neonatal onset, while the other 2 were associated with late onset. Molecular analysis of ASL gene identified four new missense variants, which were c.778C>T, p.(Leu260Arg), c.1340G>C, p.(Ser447Thr), c.436C>G, p.(Arg146Gly) and c.595C>G, p.(Leu199Val) and four reported missense variants, which were c.638G>A, p.(Arg213Gln); c.556C>T, p.(Arg186Trp), c.578G>A, p.(Arg193Gln) and c.436C>G, p.(Arg146Trp). In silico servers predicted all new and reported variants as disease-causing. Structural examination exhibited that all pathogenic variants affected the stability of the tetrameric ASL structure by disturbing the bonding pattern with the neighboring residues.Conclusion: This study revealed the genetic heterogeneity among Malaysian ASL patients. This study has also expanded the mutational spectrum of the ASL.
    Keywords:  ASLD; Argininosucinate lyase deficiency; Autosomal recessive; Hyperammonemia; Mutation
  7. Food Chem. 2019 Nov 06. pii: S0308-8146(19)31890-4. [Epub ahead of print] 125759
    Zhou T, Wang P, Gu Z, Ma M, Yang R.
      The effects of exogenous spermidine and dicyclohexylamine (DCHA, spermidine synthesis inhibitor) on the antioxidative system and energy status of germinating mung bean were investigated. Results showed that exogenous spermidine increased the content of total phenolic and ascorbic acid and the antioxidative activity, but reduced activities and gene expressions of peroxidase (POD) and catalase (CAT). These changes might be explained by increased H2O2 content and activities of succinic dehydrogenase (SDH), adenosine triphosphatases (ATPases), and cytochrome c oxidase (CCO), resulting in higher adenosine triphosphate (ATP) and energy charge (EC). Interestingly, spermidine down-regulated expressions of SDH, H+-ATPase, Ca2+-ATPase and CCO whilst DCHA reduced energy metabolism and induced the opposite effects to spermidine, except for ascorbic acid content. Inhibition was reversed by exogenous spermidine. In conclusion, spermidine induced the accumulation of H2O2, enhanced the antioxidative system and improved the energy metabolism to enhance the functional quality of mung bean sprouts.
    Keywords:  Adenosine triphosphate; Antioxidant activity; Dicyclohexylamine; Energy status; Germinating mung bean; Spermidine
  8. J Hepatol. 2019 Nov 11. pii: S0168-8278(19)30667-1. [Epub ahead of print]
    Ding Z, Ericksen RE, Escande-Beillard N, Lee QY, Loh A, Denil S, Steckel M, Haegebarth A, Wai Ho TS, Chow P, Toh HC, Reversade B, Gruenewald S, Han W.
      BACKGROUND AIM: Under the regulation of various oncogenic pathways, cancer cells undergo adaptive metabolic programming to maintain specific metabolic states that support their uncontrolled proliferation. As it has been difficult to directly and effectively inhibit oncogenic signaling cascades with pharmaceutical compounds, focusing on the downstream metabolic pathways that enable indefinite growth may provide therapeutic opportunities. Thus, we sought to characterize metabolic changes in hepatocellular carcinoma (HCC) development and identify metabolic targets required for tumorigenesis.METHODS: We compared gene expression profiles of Morris Hepatoma (MH3924a) and DEN (Diethylnitrosamine)-induced HCC models to those of liver tissues from normal and rapidly regenerating liver models, and performed gain- and loss-of-function studies of the identified gene targets for their roles in cancer cell proliferation in vitro and in vivo.
    RESULTS: The proline biosynthetic PYCR1 (Pyrroline-5-Carboxylate Reductase 1) was identified as a top up-regulated gene in the HCC models. Knockdown (KD) of PYCR1 potently reduced cell proliferation of multiple HCC cell lines in vitro and tumor growth in vivo. Conversely, overexpression of PYCR1 enhanced the proliferation of the HCC cell lines. Importantly, PYCR1 expression was not elevated in the regenerating liver, and KD or overexpression of PYCR1 had no effect on proliferation of non-cancerous cells. Besides PYCR1, we found that additional proline biosynthetic enzymes, such as ALDH18A1, were upregulated in HCC models and also regulated HCC cell proliferation. Clinical data demonstrated that PYCR1 expression was increased in HCC, correlated with tumor grade, and was an independent predictor of clinical outcome.
    CONCLUSION: Enhanced expression of proline biosynthetic enzymes promotes HCC cell proliferation. Inhibition of PYCR1 or ALDH18A1 may be a novel therapeutic strategy to target HCC.
    Keywords:  cancer; drug discovery; enzyme; hepatocellular carcinoma; metabolism; oncology; therapy
  9. Anim Genet. 2019 Nov 15.
    Mármol-Sánchez E, Luigi-Sierra MG, Quintanilla R, Amills M.
      The sequencing of the pig genome revealed the existence of homozygous individuals for a nonsense mutation in the argininosuccinate synthase 1 (ASS1) gene (rs81212146, c.944T>A, L315X). Paradoxically, an AA homozygous genotype for this polymorphism is expected to abolish the function of the ASS1 enzyme that participates in the urea cycle, leading to citrullinemia, hyperammonemia, coma and death. Sequencing of five Duroc boars that sired a population of 350 Duroc barrows revealed the segregation of the c.944T>A polymorphism, so we aimed to investigate its phenotypic consequences. Genotyping of this mutation in the 350 Duroc barrows revealed the existence of seven individuals homozygous (AA) for the nonsense mutation. These AA pigs had a normal weight despite the fact that mild citrullinemia often involves impaired growth. Sequencing of the region surrounding the mutation in TT, TA and AA individuals revealed that the A substitution in the second position of the codon (c.944T>A) is in complete linkage disequilibrium with a C replacement (c.943T>C) in the first position of the codon. This second mutation would compensate for the potentially damaging effect of the c.944T>A replacement. In fact, this is the most probable reason why pigs with homozygous AA genotypes at the 944 site of the ASS1 coding region are alive. Our results illustrate the complexities of predicting the consequences of nonsense mutations on gene function and phenotypes, not only because of annotation issues but also owing to the existence of genetic mechanisms that sometimes limit the penetrance of highly harmful mutations.
    Keywords:  citrullinemia; nonsense mutation; pig; premature stop codon; single nucleotide polymorphism
  10. J Inorg Biochem. 2019 Aug 26. pii: S0162-0134(19)30419-2. [Epub ahead of print]202 110812
    Uribe E, Reyes MB, Martínez I, Mella K, Salas M, Tarifeño-Saldivia E, López V, García-Robles M, Martínez-Oyanedel J, Figueroa M, Carvajal N, Schenk G.
      Ureohydrolases form a conserved family of enzymes with a strict requirement for divalent metal ions for catalytic activity. They catalyze the hydrolysis of the guanidino group and produce urea. In their active sites six highly conserved amino acid residues form a binding pocket for two catalytically essential metal ions that are needed to activate a water molecule to initiate the hydrolysis of the guanidino group in a nucleophilic attack. Focus in this review is on two members of the ureohydrolase family, the Mn2+-dependent arginase and agmatinase, which play important roles in functions related to replication and cell survival. We will focus in particular on Mn2+ binding interactions, and on how this metal ion contributes to the reaction catalyzed by these enzymes. We also include the agmatinase-like protein (ALP) because it is functionally closely related to agmatinase, also requires at least one Mn2+ ion for catalytic activity, but may possess an active site that differs significantly from all other known ureohydrolases.
  11. PLoS One. 2019 ;14(11): e0224765
    Gu W, Zhang A, Sun H, Gu Y, Chao J, Tian R, Duan JA.
      Selaginella tamariscina (Beauv.) spring, a primitive vascular resurrection plant, can survive extreme drought and recover when water becomes available. To identify drought-inducible genes and to clarify the molecular mechanism of drought tolerance, a comparative transcriptional pattern analysis was conducted between S. tamariscina and Selaginella moellendorffii Hieron (drought sensitive). 133 drought related genes were identified, including 72 functional genes and 61 regulatory genes. And several drought responsive reactions, such as antioxidant activity, osmotic balance, cuticle defense and signal transduction were highlighted in S. tamariscina under drought. Notably, besides peroxidase, catalase and L-ascorbate oxidase genes, DEGs associated with phenylalanine metabolism and polyamine catabolism could be alternative ways to enhance antioxidant ability in S. tamariscina. DEGs related to soluble carbohydrate metabolism, late embryogenesis abundant protein (LEA) and aquaporin protein (AQP) confirmed that osmotic adjustment could resist drought during desiccation. DEGs involved in xyloglucan metabolic process, pectin metabolic process and cutin biosynthesis may also contribute to drought tolerance of S. tamariscina by cuticle defense. Drought-responsive genes encoding protein kinases, calcium sensors, transcription factors (TFs) and plant hormones also help to drought resistance of S. tamariscina. The preliminary validation experiments were performed and the results were consistent with our hypothetical integrated regulatory network. The results of this study provide candidate resurrection genes and an integrated regulatory network for further studies on the molecular mechanisms of stress tolerance in S. tamariscina.
  12. Mol Neurobiol. 2019 Nov 09.
    Seminotti B, da Silva JC, Ribeiro RT, Leipnitz G, Wajner M.
      Tissue accumulation and high urinary excretion of argininosuccinate (ASA) is the biochemical hallmark of argininosuccinate lyase deficiency (ASLD), a urea cycle disorder mainly characterized by neurologic abnormalities, whose pathogenesis is still unknown. Thus, in the present work, we evaluated the in vitro and in vivo effects of ASA on a large spectrum of oxidative stress parameters in brain of adolescent rats in order to test whether disruption of redox homeostasis could be involved in neurodegeneration of this disorder. ASA provoked in vitro lipid and protein oxidation, decreased reduced glutathione (GSH) concentrations, and increased reactive oxygen species generation in cerebral cortex and striatum. Furthermore, these effects were totally prevented or attenuated by the antioxidants melatonin and GSH. Similar results were obtained by intrastriatal administration of ASA, in addition to increased reactive nitrogen species generation and decreased activities of superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. It was also observed that melatonin and N-acetylcysteine prevented most of ASA-induced in vivo pro-oxidant effects in striatum. Taken together, these data indicate that disturbance of redox homeostasis induced at least in part by high brain ASA concentrations per se may potentially represent an important pathomechanism of neurodegeneration in patients with ASLD and that therapeutic trials with appropriate antioxidants may be an adjuvant treatment for these patients.
    Keywords:  Antioxidants; Argininosuccinate; Argininosuccinate lyase deficiency; Brain; Oxidative stress
  13. Sci Rep. 2019 Nov 14. 9(1): 16881
    Perez M, Calles-Enríquez M, Del Rio B, Redruello B, de Jong A, Kuipers OP, Kok J, Martin MC, Ladero V, Fernandez M, Alvarez MA.
      Enterococcus faecalis is a lactic acid bacterium characterized by its tolerance of very diverse environmental conditions, a property that allows it to colonize many different habitats. This species can be found in food products, especially in fermented foods where it plays an important role as a biopreservative and influences the development of organoleptic characteristics. However, E. faecalis also produces the biogenic amines tyramine and putrescine. The consumption of food with high concentrations of these compounds can cause health problems. The present work reports the construction, via homologous recombination, of a double mutant of E. faecalis in which the clusters involved in tyramine and putrescine synthesis (which are located in different regions of the chromosome) are no longer present. Analyses showed the double mutant to grow and adhere to intestinal cells normally, and that the elimination of genes involved in the production of tyramine and putrescine has no effect on the expression of other genes.