bims-polyam Biomed News
on Polyamines
Issue of 2020‒06‒07
eight papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology
  1. Spermidine Enhanced Free Polyamine Levels and Expression of Polyamine Biosynthesis Enzyme Gene in Rice Spikelets under Heat Tolerance before Heading.
  2. Mycolicibacterium smegmatis possesses operational agmatinase but contains no detectable polyamines.
  3. Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology.
  4. Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N-Acetyltransferase NAT2.
  5. Computational Insights Into Voltage Dependence of Polyamine Block in a Strong Inwardly Rectifying K+ Channel.
  6. Brain Gene Expression-DNA Methylation Correlation in Suicide Completers: Preliminary Results.
  7. Neuroprotective action of agmatine in rotenone-induced model of Parkinson's disease: Role of BDNF/cREB and ERK pathway.
  8. Metabolic regulation of polyamines and γ-aminobutyric acid in relation to spermidine-induced heat tolerance in white clover.
  1. Sci Rep. 2020 Jun 02. 10(1): 8976
    Spermidine Enhanced Free Polyamine Levels and Expression of Polyamine Biosynthesis Enzyme Gene in Rice Spikelets under Heat Tolerance before Heading.
    Rong Zhou, Qijuan Hu, Qiong Pu, Moxian Chen, Xiuru Zhu, Cong Gao, Guixiang Zhou, Lijun Liu, Zhiqing Wang, Jianchang Yang, Jianhua Zhang, Yunying Cao.
      High temperatures (HT) before heading strongly inhibit the development of spikelets in rice. Spermidine (Spd) can improve rice's resistance to HT stress; however, the mechanism underlying this effect has not been elucidated. This study investigated several parameters, including yield, superoxide anion (O2.-), protective enzyme activities, and polyamine content, in a heat-sensitive genotype, Shuanggui 1. The yield and yield components decreased dramatically when subjected to HT stress, while this reduction could be partially recovered by exogenous Spd. Spd also slowed the generation rate of O2.- and increased protective enzyme, superoxide dismutase (SOD) and catalase (CAT) activities both under normal and high temperatures, which suggested that Spd may participate in the antioxidant system. Furthermore, genes involved in polyamine synthesis were analyzed. The results show that HT before heading significantly increased the expression of arginine decarboxylase OsADC1, Spd synthase OsSPDS1 and OsSPDS3 and had little effect on the expression of the S-adenosylmethionine decarboxylase OsSAMDC2 and ornithine decarboxylase OsODC1. In addition, exogenous Spd considerably reduced the expression of OsSAMDC2, OsSPDS1 and OsSPDS3 under HT but not the expression of OsADC1. The above mentioned results indicate that the exogenous Spd could help young rice spikelets to resist HT stress by reducing the expression of OsSAMDC2, OsSPDS1 and OsSPDS3, resulting in higher levels of endogenous Spd and Spm, which were also positively correlated with yield. In conclusion, the adverse effect of HT stress on young spikelets seems to be alleviated by increasing the amounts of Spd and Spm, which provides guidance for adaptation to heat stress during rice production.
    DOI:  https://doi.org/10.1038/s41598-020-64978-2
  2. Int J Mycobacteriol. 2020 Apr-Jun;9(2):9(2): 138-143
    Mycolicibacterium smegmatis possesses operational agmatinase but contains no detectable polyamines.
    Mikhail Zamakhaev, Ivan Tsyganov, Larisa Nesterova, Anna Akhova, Artem Grigorov, Julia Bespyatykh, Tatyana Azhikina, Alexander Tkachenko, Mikhail Shumkov.
      Background: Polyamines are widespread intracellular molecules able to influence antibiotic susceptibility, but almost nothing is known on their occurrence and physiological role in mycobacteria.Methods: here, we analyzed transcriptomic, proteomic and biochemical data and obtained the first evidence for the post-transcriptional expression of some genes attributed to polyamine metabolism and polyamine transport in Mycolicibacterium smegmatis (basionym Mycobacterium smegmatis).
    Results: in our experiments, exponentially growing cells demonstrated transcription of 21 polyamine-associated genes and possessed 7 enzymes of polyamine metabolism and 2 polyamine transport proteins.
    Conclusion: Mycolicibacterium smegmatis putrescine synthesizing enzyme agmatinase SpeB was originally shown to catalyze agmatine conversion to putrescine in vitro. Nevertheless, we have not found any polyamines in mycobacterial cells.
    Keywords:  Agmatine; Mycolicibacterium smegmatis; mycobacteria; polyamines; putrescine
    DOI:  https://doi.org/10.4103/ijmy.ijmy_48_20
  3. Nat Commun. 2020 Jun 03. 11(1): 2799
    Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology.
    Madhurima Dhara, Jose A Matta, Min Lei, Daniel Knowland, Hong Yu, Shenyan Gu, David S Bredt.
      Small molecule polyamines are abundant in all life forms and participate in diverse aspects of cell growth and differentiation. Spermidine/spermine acetyltransferase (SAT1) is the rate-limiting enzyme in polyamine catabolism and a primary genetic risk factor for suicidality. Here, using genome-wide screening, we find that SAT1 selectively controls nicotinic acetylcholine receptor (nAChR) biogenesis. SAT1 specifically augments assembly of nAChRs containing α7 or α4β2, but not α6 subunits. Polyamines are classically studied as regulators of ion channel gating that engage the nAChR channel pore. In contrast, we find polyamine effects on assembly involve the nAChR cytosolic loop. Neurological studies link brain polyamines with neurodegenerative conditions. Our pharmacological and transgenic animal studies find that reducing polyamines enhances cortical neuron nAChR expression and augments nicotine-mediated neuroprotection. Taken together, we describe a most unexpected role for polyamines in regulating ion channel assembly, which provides a new avenue for nAChR neuropharmacology.
    DOI:  https://doi.org/10.1038/s41467-020-16629-3
  4. Angew Chem Int Ed Engl. 2020 Jun 04.
    Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N-Acetyltransferase NAT2.
    Louis P Conway, Veronica Rendo, Mario S P Correia, Ingvar Bergdahl, Tobias Sjöblom, Daniel Globisch.
      N-Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has previously been classified as an arylamine N-acetyltransferase that mainly converts aromatic amines, hydroxylamines and hydrazines. Here, we demonstrate that the human arylamine N-acetyltransferase NAT2 also acetylates a series of aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed significantly increased intracellular concentrations of mono- and diacetylated spermidine in human cell lines expressing the rapid compared to the slow acetylator NAT2 phenotype. The regioselective N 8 -acetylation of monoacetylated spermidine by NAT2 answers the long-standing question in polyamine metabolism of the source of diacetylspermidine. We also identified selective acetylation of structurally diverse alkylamine-containing commonly used drugs by NAT2. Such moieties are present in 21% of prescribed drugs in the US and acetylation by NAT2 may contribute to variations in patient responses. The results demonstrate a previously unknown functionality and potential regulatory role for NAT2 and we therefore suggest that this enzyme should be considered for re-classification.
    Keywords:  Metabolomics; N-acetyltransferase; drug metabolism; mass spectrometry; polyamines
    DOI:  https://doi.org/10.1002/anie.202005915
  5. Front Pharmacol. 2020 ;11 721
    Computational Insights Into Voltage Dependence of Polyamine Block in a Strong Inwardly Rectifying K+ Channel.
    Xingyu Chen, Michael Bründl, Theres Friesacher, Anna Stary-Weinzinger.
      Inwardly rectifying potassium (KIR) channels play important roles in controlling cellular excitability and K+ ion homeostasis. Under physiological conditions, KIR channels allow large K+ influx at potentials negative to the equilibrium potential of K+ but permit little outward current at potentials positive to the equilibrium potential of K+, due to voltage dependent block of outward K+ flux by cytoplasmic polyamines. These polycationic molecules enter the KIR channel pore from the intracellular side. They block K+ ion movement through the channel at depolarized potentials, thereby ensuring, for instance, the long plateau phase of the cardiac action potential. Key questions concerning how deeply these charged molecules migrate into the pore and how the steep voltage dependence arises remain unclear. Recent MD simulations on GIRK2 (=Kir3.2) crystal structures have provided unprecedented details concerning the conduction mechanism of a KIR channel. Here, we use MD simulations with applied field to provide detailed insights into voltage dependent block of putrescine, using the conductive state of the strong inwardly rectifying K+ channel GIRK2 as starting point. Our µs long simulations elucidate details about binding sites of putrescine in the pore and suggest that voltage-dependent rectification arises from a dual mechanism.
    Keywords:  Kir3.2; charge movement; inward rectification; ion displacement; molecular dynamics simulation; putrescine
    DOI:  https://doi.org/10.3389/fphar.2020.00721
  6. Rev Invest Clin. 2020 May 07. 73(3):
    Brain Gene Expression-DNA Methylation Correlation in Suicide Completers: Preliminary Results.
    Brenda Cabrera-Mendoza, José J Martínez-Magaña, Alma D Genis-Mendoza, Nancy Monroy-Jaramillo, Consuelo Walss-Bass, Gabriel R Fries, Fernando García-Dolores, Mauro López-Armenta, Gonzalo Flores, Rubén A Vázquez-Roque, Humberto Nicolini.
      BACKGROUND: Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes.OBJECTIVE: The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides.
    METHODS: Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database.
    RESULTS: We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database.
    CONCLUSIONS: The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms.
  7. Behav Brain Res. 2020 May 29. pii: S0166-4328(20)30391-0. [Epub ahead of print] 112692
    Neuroprotective action of agmatine in rotenone-induced model of Parkinson's disease: Role of BDNF/cREB and ERK pathway.
    S Sırrı Bilge, Caner Günaydin, M Emin Önger, Ayhan Bozkurt, Bahattin Avci.
      Numerous studies have investigated the role of agmatine in the central nervous system and indicated neuroprotective properties. In addition to its potent antioxidant effects, agmatine is an endogenous neuromodulator and has wide spectrum molecular actions on different receptor subtypes (NMDA, Imidazoline 1-2, alpha-2 adrenoreceptor, 5-HT2a, 5-HT3) and cellular signaling pathways (MAPK, PKA, NO, BDNF). Although the neuroprotective effects of agmatine demonstrated in experimental Parkinson's disease model, the effects of agmatine with the aspect of neuroplasticity and possible signaling mechanisms behind agmatine actions have not been investigated. Herein, in this study, we investigated the role of the of agmatine on rotenone-induced Parkinson's disease model. Agmatine at the dose of 100 mg/kg i.p., was mitigated oxidative damage and alleviated motor impairments which were the results of the rotenone insult. Additionally, agmatine decrease in neuronal loss, tyrosine hydroxylase immunoreactivity and increased cREB, BDNF and ERK1/2 expression in the striatum, which are crucial neuroplasticity elements of striatal integrity. Taken together, the present study expands the knowledge of molecular mechanisms behind neuroprotective actions of agmatine in Parkinson's disease, and as far as we have known, this is the first study to delineate agmatine treated activation of cellular pathways which are important elements in neuronal cell survival.
    Keywords:  Agmatine; BDNF; ERK1/2; cREB; rat; rotenone
    DOI:  https://doi.org/10.1016/j.bbr.2020.112692
  8. Plant Biol (Stuttg). 2020 Jun 05.
    Metabolic regulation of polyamines and γ-aminobutyric acid in relation to spermidine-induced heat tolerance in white clover.
    L Luo, Z Li, M Y Tang, B Z Cheng, W H Zeng, Y Peng, G Nie, X Q Zhang.
      Heat stress decreases crop growth and yield worldwide. Spermidine (Spd) is small aliphatic amine and acts as ubiquitous plant growth regulator to regulate plant growth, development, and stress tolerance. Objectives of this study was to determine effects of exogenous Spd on changes of endogenous polyamines and γ-aminobutyric acid metabolism, oxidative damage, senescence response, and heat shock proteins (HSPs) expression in white clover under heat stress. Physiological and molecular methods including colorimetric assay, high performance liquid chromatography, and qRT-PCR were applied. Results showed that exogenous Spd significantly alleviated heat-induced stress damage. Spd application not only increased endogenous putrescine (Put), Spd, spermine (Spm), and total polyamine (PAs) accumulation, but also accelerated PAs oxidation and improved glutamic acid decarboxylase activity leading to GABA accumulation in leaves under heat stress. Spd-pretreated white clover maintained significantly higher chlorophyll (Chl) content than untreated plants under heat stress, which could be related to roles of Spd in up-regulating genes encoding Chl synthesis (PBGD and Mg-CHT) and maintaining lower Chl degradation (PaO and CHLASE) during heat stress. In addition, Spd up-regulated HSP70, HSP70B, and HSP70-5 expression that could have function of stabilizing denatured protein and helping proteins to folding correctly in white clover under high temperature stress. In summary, exogenous Spd treatment improves the heat tolerance of white clover by altering endogenous PAs and GABA content and metabolism, enhancing the antioxidant system and HSPs expression, and slowing down leaf senescence related to an increase in Chl biosynthesis and a decrease in Chl degradation during heat stress.
    Keywords:  Antioxidant; chlorophyll metabolism; gene expression; photosynthesis; thermotolerance; water use efficiency
    DOI:  https://doi.org/10.1111/plb.13139
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