bims-polyam Biomed News
on Polyamines
Issue of 2019‒11‒24
eleven papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

  1. Biochemistry. 2019 Nov 20.
    Herbst-Gervasoni CJ, Christianson DW.
      Eukaryotic histone deacetylase 10 (HDAC10) is a Zn2+-dependent hydrolase that exhibits catalytic specificity for the hydrolysis of the polyamine N8-acetylspermidine. The recently determined crystal structure of HDAC10 from Danio rerio (zebrafish) reveals a narrow active site cleft and a negatively charged "gatekeeper" (E274) that favors the binding of the slender cationic substrate. Since HDAC10 expression is upregulated in advanced-stage neuroblastoma and induces autophagy, the selective inhibition of HDAC10 suppresses the autophagic response and renders cancer cells more susceptible to cytotoxic chemotherapeutic drugs. Here, we describe X-ray crystal structures of zebrafish HDAC10 complexed with eight different analogues of N8-acetylspermidine. These analogues contain different Zn2+-binding groups, such as hydroxamate, thiolate, and the tetrahedral gem-diolate resulting from the addition of a Zn2+-bound water molecule to a ketone carbonyl group. Notably, the chemistry that accompanies the binding of ketonic substrate analogues is identical to the chemistry involved in the first step of catalysis, i.e., nucleophilic attack of a Zn2+-bound water molecule at the scissile carbonyl group of N8-acetylspermidine. The most potent inhibitor studied contains a thiolate Zn2+-binding group. These structures reveal interesting geometric changes in the metal coordination polyhedron that accommodate inhibitor binding. Additional interactions in the active site highlight features contributing to substrate specificity. These interactions are likely to contribute to inhibitor binding selectivity and will inform the future design of compounds selective for HDAC10 inhibition.
  2. Front Plant Sci. 2019 ;10 1331
    Seo SY, Kim YJ, Park KY.
      The diamine putrescine and the polyamines (PAs), spermidine (Spd) and spermine (Spm), are ubiquitously occurring polycations associated with several important cellular functions, especially antisenescence. Numerous studies have reported increased levels of PA in plant cells under conditions of abiotic and biotic stress such as drought, high salt concentrations, and pathogen attack. However, the physiological mechanism of elevated PA levels in response to abiotic and biotic stresses remains undetermined. Transgenic plants having overexpression of SAMDC complementary DNA and increased levels of putrescine (1.4-fold), Spd (2.3-fold), and Spm (1.8-fold) under unstressed conditions were compared to wild-type (WT) plants in the current study. The most abundant PA in transgenic plants was Spd. Under salt stress conditions, enhancement of endogenous PAs due to overexpression of the SAMDC gene and exogenous treatment with Spd considerably reduces the reactive oxygen species (ROS) accumulation in intra- and extracellular compartments. Conversely, as compared to the WT, PA oxidase transcription rapidly increases in the S16-S-4 transgenic strain subsequent to salt stress. Furthermore, transcription levels of ROS detoxifying enzymes are elevated in transgenic plants as compared to the WT. Our findings with OxyBlot analysis indicate that upregulated amounts of endogenous PAs in transgenic tobacco plants show antioxidative effects for protein homeostasis against stress-induced protein oxidation. These results imply that the increased PAs induce transcription of PA oxidases, which oxidize PAs, which in turn trigger signal antioxidative responses resulting to lower the ROS load. Furthermore, total proteins from leaves with exogenously supplemented Spd and Spm upregulate the chaperone activity. These effects of PAs for antioxidative properties and antiaggregation of proteins contribute towards maintaining the physiological cellular functions against abiotic stresses. It is suggested that these functions of PAs are beneficial for protein homeostasis during abiotic stresses. Taken together, these results indicate that PA molecules function as antisenescence regulators through inducing ROS detoxification, antioxidative properties, and molecular chaperone activity under stress conditions, thereby providing broad-spectrum tolerance against a variety of stresses.
    Keywords:  S-adenosylmethionine decarboxylase; chaperone activity; polyamines; reactive oxygen species; spermidine
  3. Int J Mol Med. 2019 Nov 11.
    Baroli G, Sanchez JR, Agostinelli E, Mariottini P, Cervelli M.
      Polyamines are small positively charged alkylamines that are essential in a number of crucial eukaryotic processes, like normal cell growth and development. In normal physiological conditions, intracellular polyamine content is tightly regulated through a fine regulated network of biosynthetic and catabolic enzymes and a transport system. The dysregulation of this network is frequently associated to different tumors, where high levels of polyamines has been detected. Polyamines also modulate ion channels and ionotropic glutamate receptors and altered levels of polyamines have been observed in different brain diseases, including mental disorders and epilepsy. The goal of this article is to review the role of polyamines in mental disorders and epilepsy within a frame of the possible link between these two brain pathologies. The high comorbidity between these two neurological illnesses is strongly suggestive that they share a common background in the central nervous system. This review proposes an additional association between the noradrenalin/serotonin and glutamatergic neuronal circuits with polyamines. Polyamines can be considered supplementary defensive shielding molecules, important to protect the brain from the development of epilepsy and mental illnesses that are caused by different types of neurons. In this contest, the modulation of polyamine metabolism may be a novel important target for the prevention and therapeutic treatment of these diseases that have a high impact on the costs of public health and considerably affect quality of life.
  4. Mol Plant Microbe Interact. 2019 Nov 19.
    Liu Y, Feng H, Chen L, Zhang H, Dong X, Xiong Q, Zhang R.
      The signal molecules in root exudates that are sensed by plant growth-promoting rhizobacteria (PGPRs) are critical to regulate their root colonization. Phosphorylated Spo0A is an important global transcriptional regulator that controls colonization and sporulation in Bacillus species. In this study, we found that deletion of kinD from PGPR strain Bacillus amyloliquefaciens SQR9, encoding an original phosphate donor of Spo0A, resulted in reduced biofilm formation in root exudates compared with the wild type strain, indicating that KinD is responsible for sensing root exudates. Ligands of B. amyloliquefaciens SQR9 KinD in cucumber root exudates were determined by both the non-targeted ligand fishing method and the targeted surface plasmon resonance (SPR) detection method. In total, we screened 80 compounds in root exudates for binding to KinD and found that spermine and guanosine could bind to KinD with KD values of 213 μM and 51 μΜ, respectively. In addition, calcium L-threonate, N-acetyl-L-aspartic acid, sodium decanoic acid and parabanic acid could also bind to KinD weakly. Then, the 3-dimensional binding models were constructed to demonstrate the interactions between the root secreted signals and KinD. It was observed that exogenous spermine reduced the wrinkles of biofilm when kinD was defected, indicating that KinD might be involved in sensing root-secreted spermine and stabilizing biofilm in response to this negative effector. This study provided a new insight of interaction between rhizobacterial sensor and root secreted signals.
  5. Environ Sci Pollut Res Int. 2019 Nov 16.
    Banerjee A, Singh A, Roychoudhury A.
      The manuscript illustrates the ameliorative effects of exogenously applied higher polyamine (PA), spermidine (Spd) in the susceptible indica rice cultivar IR-64 subjected to prolonged fluoride stress. The Spd treatment drastically reduced fluoride bioaccumulation by restricting entry of the anions through chloride channels and enabled better maintenance of the proton gradient via accumulation of P-H+/ATPase, thereby improving the root and shoot lengths, fresh and dry weights, RWC, chlorophyll content and activities of pyruvate dehydrogenase (PyrDH), α-amylase, and nitrate reductase (NR) in the Spd-treated, stressed plants. Expression of RuBisCo, PyrDH, α-amylase, and NR was stimulated. Spd supplementation reduced the molecular damage indices like malondialdehyde, lipoxygenase, protease activity, electrolyte leakage, protein carbonylation, H2O2, and methylglyoxal (detoxified by glyoxalase II). Mitigation of oxidative damage was facilitated by the accumulation and utilization of proline, glycine-betaine, total amino acids, higher PAs, anthocyanin, flavonoids, β-carotene, xanthophyll, and phenolics as verified from the expression of genes like P5CS, BADH1, SAMDC, SPDS, SPMS, DAO, PAO, and PAL. Spd treatment activated the ascorbate-glutathione cycle in the stressed seedlings. Expression and activities of enzymatic antioxidants showed that GPOX, APX, GPX, and GST were the chief ROS scavengers. Exogenous Spd promoted ABA accumulation by upregulating NCED3 and suppressing ABA8ox1 expression. ABA-dependent osmotic stress-responsive genes like Osem, WRKY71, and TRAB1 as well as ABA-independent transcription factor encoding gene DREB2A were induced by Spd. Thus, Spd treatment ameliorated fluoride-mediated injuries in IR-64 by restricting fluoride uptake, refining the defense machinery and activating the ABA-dependent as well as ABA-independent stress-responsive genes.
    Keywords:  Abscisic acid; Antioxidants; Exogenous spermidine; Fluoride stress; Gene expression; Osmolytes; Rice physiology
  6. Gene. 2019 Nov 16. pii: S0378-1119(19)30889-3. [Epub ahead of print] 144230
    Tsaniklidis G, Pappi P, Tsafouros A, Charova SN, Nikoloudakis N, Roussos PA, Paschalidis KA, Delis C.
      Adverse conditions and biotic strain can lead to significant losses and impose limitations on plant yield. Polyamines (PAs) serve as regulatory molecules for both abiotic/biotic stress responses and cell protection in unfavourable environments. In this work, the transcription pattern of 24 genes orchestrating PA metabolism was investigated in Cucumber Mosaic Virus or Potato Virus Y infected and cold stressed tomato plants. Expression analysis revealed a differential/pleiotropic pattern of gene regulation in PA homeostasis upon biotic, abiotic or combined stress stimuli, thus revealing a discrete response specific to diverse stimuli: (i) biotic stress-influenced genes, (ii) abiotic stress-influenced genes, and (iii) concurrent biotic/abiotic stress-regulated genes. The results support different roles for PAs against abiotic and biotic stress. The expression of several genes, significantly induced under cold stress conditions, is mitigated by a previous viral infection, indicating a possible priming-like mechanism in tomato plants pointing to crosstalk among stress signalling. Several genes and resulting enzymes of PA catabolism were stimulated upon viral infection. Hence, we suggest that PA catabolism resulting in elevated H2O2 levels could mediate defence against viral infection. However, after chilling, the activities of enzymes implicated in PA catabolism remained relatively stable or slightly reduced. This correlates to an increase in free PA content, designating a per se protective role of these compounds against abiotic stress.
    Keywords:  CMV; Cold stress; Homeostasis; PVY; Polyamines; Solanum lycopersicum
  7. Cell Rep. 2019 Nov 19. pii: S2211-1247(19)31357-9. [Epub ahead of print]29(8): 2144-2153.e7
    Lerner S, Anderzhanova E, Verbitsky S, Eilam R, Kuperman Y, Tsoory M, Kuznetsov Y, Brandis A, Mehlman T, Mazkereth R, , McCarter R, Segal M, Nagamani SCS, Chen A, Erez A.
      Patients with germline mutations in the urea-cycle enzyme argininosuccinate lyase (ASL) are at risk for developing neurobehavioral and cognitive deficits. We find that ASL is prominently expressed in the nucleus locus coeruleus (LC), the central source of norepinephrine. Using natural history data, we show that individuals with ASL deficiency are at risk for developing attention deficits. By generating LC-ASL-conditional knockout (cKO) mice, we further demonstrate altered response to stressful stimuli with increased seizure reactivity in LC-ASL-cKO mice. Depletion of ASL in LC neurons leads to reduced amount and activity of tyrosine hydroxylase (TH) and to decreased catecholamines synthesis, due to decreased nitric oxide (NO) signaling. NO donors normalize catecholamine levels in the LC, seizure sensitivity, and the stress response in LC-ASL-cKO mice. Our data emphasize ASL importance for the metabolic regulation of LC function with translational relevance for ASL deficiency (ASLD) patients as well as for LC-related pathologies.
    Keywords:  ASL; locus coeruleus; nitric oxide; stress response; tyrosine hydroxylase; urea cycle disorders
  8. Front Plant Sci. 2019 ;10 1415
    Menéndez AB, Calzadilla PI, Sansberro PA, Espasandin FD, Gazquez A, Bordenave CD, Maiale SJ, Rodríguez AA, Maguire VG, Campestre MP, Garriz A, Rossi FR, Romero FM, Solmi L, Salloum MS, Monteoliva MI, Debat JH, Ruiz OA.
      Polyamines (PAs) are natural aliphatic amines involved in many physiological processes in almost all living organisms, including responses to abiotic stresses and microbial interactions. On other hand, the family Leguminosae constitutes an economically and ecologically key botanical group for humans, being also regarded as the most important protein source for livestock. This review presents the profuse evidence that relates changes in PAs levels during responses to biotic and abiotic stresses in model and cultivable species within Leguminosae and examines the unreviewed information regarding their potential roles in the functioning of symbiotic interactions with nitrogen-fixing bacteria and arbuscular mycorrhizae in this family. As linking plant physiological behavior with "big data" available in "omics" is an essential step to improve our understanding of legumes responses to global change, we also examined integrative MultiOmics approaches available to decrypt the interface legumes-PAs-abiotic and biotic stress interactions. These approaches are expected to accelerate the identification of stress tolerant phenotypes and the design of new biotechnological strategies to increase their yield and adaptation to marginal environments, making better use of available plant genetic resources.
    Keywords:  constrained environments; legume; plant polyamines; plant stress and adaptation; symbionts
  9. J Clin Lab Anal. 2019 Nov 20. e23124
    Fan L, Zhao J, Jiang L, Xie L, Ma J, Li X, Cheng M.
      BACKGROUND: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare urea cycle disorder. The aim of this study was to present the clinical findings, management, biochemical data, molecular genetic analysis, and short-term prognosis of five children with CPS1D.METHODS: The information of five CPS1D patients was retrospectively studied. We used targeted next-generation sequencing to identify carbamoyl phosphate synthetase 1 (CPS1) variants in patients suspected to have CPS1D. Candidate mutations were validated by Sanger sequencing. In silico and structure analyses were processed for the pathogenicity predictions of the identified mutations.
    RESULTS: The patients had typically clinical manifestations and biochemical data of CPS1D. Genetic analysis revealed nine mutations in the CPS1 gene, including recurrence of c.1145C > T, five of which were firstly reported. Seven mutations were missense changes, while the remaining two were predicted to create premature stop codons. In silico and structure analyses showed that these genetic lesions were predicted to affect the function or stability of the enzyme.
    CONCLUSION: We reported five cases of CPS1D. Five novel mutations of CPS1 gene were found. Mutations of CPS1 have private nature, and most of them are missense compound heterozygous. The mutation affecting residue predicted to interfere the catalytic sites, the internal tunnel, or the regulatory domain results in severe phenotype.
    Keywords:  CPS1; carbamoyl phosphate synthetase 1 deficiency; clinical presentation; hyperammonemia; urea cycle disorders
  10. Food Chem. 2019 Nov 09. pii: S0308-8146(19)32012-6. [Epub ahead of print] 125874
    Yang X, Lin S, Jia Y, Rehman F, Zeng S, Wang Y.
      The Lycium ruthenicum (Lr) fruit is a widely used nutritional food that contains various bioactive components such as anthocyanin and spermidine derivatives. In the present study, ultra-high-performance liquid chromatography with tandem mass spectrometry was utilized to profile the metabolic dynamics of four developmental stages of Lr fruit. A total of 49 compounds, including anthocyanin, alkaloids, hydroxycinnamic acid derivatives, flavonoids, and amino acids, were tentatively identified. Principal component analysis distinguished the fruit at four developmental stages using 15 (9 were tentatively identified) potential marker compounds. Pearson correlation analysis suggested that anthocyanin and spermidine derivative hexoses had a strong positive correlation coefficient. A glucosyltransferase (HG27071) was confirmed to glucosylate both anthocyanidin and spermidine derivative in vitro. Our results provide insight into the metabolic linkages among bioactive components in Lr fruits. The glucosyltransferase identified in this study will promote its potential use in functional foods and natural pigment resources.
    Keywords:  Anthocyanin; Fruit development and ripening; Glucosyltransferase; Lycium ruthenicum; Spermidine derivative hexoses
  11. Int J Biol Macromol. 2019 Nov 18. pii: S0141-8130(18)35783-0. [Epub ahead of print]
    Mohammadi M, Shareghi B, Akbar Saboury A.
      Carboxypeptidase A (CPA) (EC is one of the main members of the M14 family that release one amino acid from the C-terminal region of the polypeptides at each time. The purpose of the present study was to study the effect of spermidine (NH2(CH2)3NH-(CH2)4NH2) on the conformation, thermal stability, and activity of native CPA from bovine pancreas, by employing ultraviolet-visible (UV-Vis) spectroscopy, intrinsic fluorescence, thermal stability, circular dichroism (CD), kinetic techniques and molecular docking. It was found that the decrease in the CPA, UV-Vis absorption could be due to the formation of the CPA-spermidine complexes. The results of fluorescence spectroscopic measurements at the temperatures of 308 and 318 K also revealed that spermidine had the capability to quench the intrinsic fluorescence of CPA with the static mode. Further, the thermodynamic parameters, (Gibbs free-energy, enthalpy and entropy changes) showed that the binding process of spermidine to CPA was spontaneous and the main force in stabilizing the complex was the van der Waals and hydrogen interactions, along with the molecular docking results. In addition, CD spectra and fluorescence results revealed that spermidine had a partial effect on the CPA structure, leading to some changes in its secondary structure. The Tm studies of the CPA-spermidine complex also indicated that the Tm values were enhanced with increasing the spermidine concentration. Kinetic studies further showed that by spermidine binding, the Vmax value and activity of the enzyme were increased.
    Keywords:  Carboxypeptidase A (CPA); Docking simulations; Spectroscopic techniques; Spermidine