bims-polyam 2020-01-19 papers

on Polyamines

Issue of 2020–01–19
eight papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Polyamines produced by Sinorhizobium meliloti Rm8530 contribute to symbiotically relevant phenotypes ex planta and to nodulation efficiency on alfalfa.
Role of genes and metabolites involved in polyamines synthesis pathways and nitric oxide synthase in stomatal closure on Rosa damascena Mill. under drought stress.
The Molecular and Physiological Effects of Protein-Derived Polyamines in the Intestine.
Sex-related differences in urinary immune-related metabolic profiling of alopecia areata patients.
Engineering tropane alkaloid production based on metabolic characterization of ornithine decarboxylase in Atropa belladonna.
Understanding the role of key amino acids in regulation of proline dehydrogenase/proline oxidase (prodh/pox)-dependent apoptosis/autophagy as an approach to targeted cancer therapy.
Towards a Rational Design of Polyamine-based Zinc Chelating Agents for Cancer Therapies.
Virus-Induced Interferon Regulates the Urea Cycle.

Microbiology. 2020 Jan 14.

Polyamines produced by Sinorhizobium meliloti Rm8530 contribute to symbiotically relevant phenotypes ex planta and to nodulation efficiency on alfalfa.

Victor A Becerra-Rivera, Alejandra Arteaga, Alfonso Leija, Georgina Hernández, Michael F Dunn.

  In nitrogen-fixing rhizobia, emerging evidence shows significant roles for polyamines in growth and abiotic stress resistance. In this work we show that a polyamine-deficient ornithine decarboxylase null mutant (odc2) derived from Sinorhizobium meliloti Rm8530 had significant phenotypic differences from the wild-type, including greatly reduced production of exopolysaccharides (EPS; ostensibly both succinoglycan and galactoglucan), increased sensitivity to oxidative stress and decreased swimming motility. The introduction of the odc2 gene borne on a plasmid into the odc2 mutant restored wild-type phenotypes for EPS production, growth under oxidative stress and swimming. The production of calcofluor-binding EPS (succinoglycan) by the odc2 mutant was also completely or mostly restored in the presence of exogenous spermidine (Spd), norspermidine (NSpd) or spermine (Spm). The odc2 mutant formed about 25 % more biofilm than the wild-type, and its ability to form biofilm was significantly inhibited by exogenous Spd, NSpd or Spm. The odc2 mutant formed a less efficient symbiosis with alfalfa, resulting in plants with significantly less biomass and height, more nodules but less nodule biomass, and 25 % less nitrogen-fixing activity. Exogenously supplied Put was not able to revert these phenotypes and caused a similar increase in plant height and dry weight in uninoculated plants and in those inoculated with the wild-type or odc2 mutant. We discuss ways in which polyamines might affect the phenotypes of the odc2 mutant.

Keywords:  homospermidine; ornithine decarboxylase; putrescine; rhizobia–legume symbiosis; spermidine

DOI:  https://doi.org/10.1099/mic.0.000886
Plant Physiol Biochem. 2020 Jan 03. pii: S0981-9428(19)30549-2. [Epub ahead of print]148 53-61

Role of genes and metabolites involved in polyamines synthesis pathways and nitric oxide synthase in stomatal closure on Rosa damascena Mill. under drought stress.

Nader Adamipour, Morteza Khosh-Khui, Hassan Salehi, Hooman Razi, Akbar Karami, Ali Moghadam.

  In order to evaluate the genes involved in polyamines synthesis pathway and the role of nitric oxide synthase (NOS) and H2O2 in stomatal closure under drought stress, a research conducted with three irrigation levels (100, 50 and 25% field capacity) at 1, 3, 6 and 12 days on Rosa damascena Mill. HPLC and qPCR results showed that putrescine (Put) accumulation occurred at first day in both 50 and 25% of field capacity and then decreased the other days. Furthermore, Put accumulation in the indirect pathway (ADC, AIH and CPA) was more effective related to the direct pathway (ODC) under severe stress. Increased expression of genes involved in production of spermidine (Spd) and spermine (Spm) i.e., SAMDC, SPDS and SPMS correlated with the highest accumulation of Spd and Spm under 50% FC at 6 d and 25% FC at 12 d, respectively. Moreover, results showed that Put reduction simultaneously accumulated H2O2, which subsequently increased NOS expression suggesting a key signal for stomatal closure.

Keywords:  Abiotic stress; Amino acid; Gene expression; Metabolism; Osmoregulators

DOI:  https://doi.org/10.1016/j.plaphy.2019.12.033
Nutrients. 2020 Jan 11. pii: E197. [Epub ahead of print]12(1):

The Molecular and Physiological Effects of Protein-Derived Polyamines in the Intestine.

Anna F Bekebrede, Jaap Keijer, Walter J J Gerrits, Vincent C J de Boer.

  Consumption of a high-protein diet increases protein entry into the colon. Colonic microbiota can ferment proteins, which results in the production of protein fermentation end-products, like polyamines. This review describes the effects of polyamines on biochemical, cellular and physiological processes, with a focus on the colon. Polyamines (mainly spermine, spermidine, putrescine and cadaverine) are involved in the regulation of protein translation and gene transcription. In this, the spermidine-derived hypusination modification of EIF5A plays an important role. In addition, polyamines regulate metabolic functions. Through hypusination of EIF5A, polyamines also regulate translation of mitochondrial proteins, thereby increasing their expression. They can also induce mitophagy through various pathways, which helps to remove damaged organelles and improves cell survival. In addition, polyamines increase mitochondrial substrate oxidation by increasing mitochondrial Ca2+-levels. Putrescine can even serve as an energy source for enterocytes in the small intestine. By regulating the formation of the mitochondrial permeability transition pore, polyamines help maintain mitochondrial membrane integrity. However, their catabolism may also reduce metabolic functions by depleting intracellular acetyl-CoA levels, or through production of toxic by-products. Lastly, polyamines support gut physiology, by supporting barrier function, inducing gut maturation and increasing longevity. Polyamines thus play many roles, and their impact is strongly tissue- and dose-dependent. However, whether diet-derived increases in colonic luminal polyamine levels also impact intestinal physiology has not been resolved yet.

Keywords:  hypusine; intestine; metabolism; mitochondrial function; polyamines; protein

DOI:  https://doi.org/10.3390/nu12010197
Metabolomics. 2020 Jan 16. 16(2): 15

Sex-related differences in urinary immune-related metabolic profiling of alopecia areata patients.

Yu Ra Lee, Haksoon Kim, Bark Lynn Lew, Woo Young Sim, Jeongae Lee, Han Bin Oh, Jongki Hong, Bong Chul Chung.

   INTRODUCTION: Alopecia areata is a well-known autoimmune disease affecting humans. Polyamines are closely associated with proliferation and inflammation, and steroid hormones are involved in immune responses. Additionally, bile acids play roles in immune homeostasis by activating various signaling pathways; however, the roles of these substances and their metabolites in alopecia areata remain unclear.
OBJECTIVES: In this study, we aimed to identify differences in metabolite levels in urine samples from patients with alopecia areata and healthy controls.
METHODS: To assess polyamine, androgen, and bile acid concentrations, we performed high-performance liquid chromatography-tandem mass spectrometry.
RESULTS: Our results showed that spermine and dehydroepiandrosterone levels differed significantly between male patients and controls, whereas ursodeoxycholic acid levels were significantly higher in female patients with alopecia areata than in controls.
CONCLUSION: Our findings suggested different urinary polyamine, androgen, and bile acid concentrations between alopecia areata patients and normal controls. Additionally, levels of endogenous substances varied according to sex, and this should be considered when developing appropriate treatments and diagnostic techniques. Our findings improve our understanding of polyamine, androgen, and bile acid profiles in patients with alopecia areata and highlight the need to consider sex-related differences.

Keywords:  Alopecia areata; Androgen; Bile acid; Immune; Polyamine

DOI:  https://doi.org/10.1007/s11306-020-1634-y
ACS Synth Biol. 2020 Jan 14.

Engineering tropane alkaloid production based on metabolic characterization of ornithine decarboxylase in Atropa belladonna.

Tengfei Zhao, Siqi Li, Jing Wang, Qi Zhou, Chunxian Yang, Feng Bai, Xiaozhong Lan, Min Chen, Zhihua Liao.

Ornithine decarboxylase (ODC) plays an important role in various biological processes; however, its role in plant secondary metabolism, especially in the biosynthesis of tropane alkaloids (TAs) such as pharmaceutical hyoscyamine, anisodamine and scopolamine, remains largely unknown. In this study, we characterized the physiological and metabolic functions of the ODC gene of Atropa belladonna (AbODC) and determined its role in TA production using metabolic engineering approaches. Feeding assays with enzyme inhibitors indicated that ODC, rather than arginine decarboxylase (ADC), plays a major role in TA biosynthesis. Tissue-specific AbODC expression analysis and -glucuronidase (GUS) staining assays showed that AbODC was highly expressed in secondary roots, especially in the cylinder tissue. Enzymatic assays indicated that AbODC was able to convert ornithine to putrescine, with the highest activity at pH 8.0 and 30C. Additionally, AbODC showed higher catalytic efficiency than other plant ODCs, as evident from the Km, Vmax and Kcat values of AbODC using ornithine as the substrate. In A. belladonna root cultures, suppression of AbODC greatly reduced the production of putrescine, N-methylputrescine and TAs, whereas overexpression of AbODC significantly increased the biosynthesis of putrescine, N-methylputrescine, hyoscyamine and anisodamine. Moreover, transgenic A. belladonna plants overexpressing AbODC showed a significantly higher production of hyoscyamine and anisodamine compared with control plants. These findings indicate that AbODC plays a key role in TA biosynthesis and therefore is a valuable candidate for increasing TA production in A. belladonna.

DOI: https://doi.org/10.1021/acssynbio.9b00461
Mol Cell Biochem. 2020 Jan 13.

Understanding the role of key amino acids in regulation of proline dehydrogenase/proline oxidase (prodh/pox)-dependent apoptosis/autophagy as an approach to targeted cancer therapy.

Thi Yen Ly Huynh, Ilona Zareba, Weronika Baszanowska, Sylwia Lewoniewska, Jerzy Palka.

  In stress conditions, as neoplastic transformation, amino acids serve not only as nutrients to maintain the cell survival but also as mediators of several regulatory pathways which are involved in apoptosis and autophagy. Especially, under glucose deprivation, in order to maintain the cell survival, proline and glutamine together with other glutamine-derived products such as glutamate, alpha-ketoglutarate, and ornithine serve as alternative sources of energy. They are substrates for production of pyrroline-5-carboxylate which is the product of conversion of proline by proline dehydrogenase/ proline oxidase (PRODH/POX) to produce ATP for protective autophagy or reactive oxygen species for apoptosis. Interconversion of proline, ornithine, and glutamate may therefore regulate PRODH/POX-dependent apoptosis/autophagy. The key amino acid is proline, circulating between mitochondria and cytoplasm in the proline cycle. This shuttle is known as proline cycle. It is coupled to pentose phosphate pathway producing nucleotides for DNA biosynthesis. PRODH/POX is also linked to p53 and AMP-activated protein kinase (AMPK)-dependent pathways. Proline availability for PRODH/POX-dependent apoptosis/autophagy is regulated at the level of collagen biosynthesis (proline utilizing process) and prolidase activity (proline supporting process). In this review, we suggest that amino acid metabolism linking TCA and Urea cycles affect PRODH/POX-dependent apoptosis/autophagy and the knowledge might be useful to targeted cancer therapy.

Keywords:  Apoptosis; Autophagy; Glutamine; Proline; Proline dehydrogenase/proline oxidase

DOI:  https://doi.org/10.1007/s11010-020-03685-y
J Med Chem. 2020 Jan 14.

Towards a Rational Design of Polyamine-based Zinc Chelating Agents for Cancer Therapies.

Cristina Galiana-Rosell Oacute, Clara Aceves-Luquero, Jorge González, Álvaro Martínez-Camarena, Ruth Villalonga, Silvia Fernández de Mattos, Concepción Soriano, José Llinares, Enrique García-España, Priam Villalonga, María Eugenia González-Rosende.

In vitro viability assays against a representative panel of human cancer cell lines revealed that polyamines L1a and L5a displayed remarkable activity with IC50 values in the micromolar range. Preliminary research indicated that both compounds promoted G1 cell cycle arrest followed by cellular senescence and apoptosis. The induction of apoptotic cell death involved loss of mitochondrial outer membrane permeability and activation of caspases 3/7. Interestingly, L1a and L5a failed to activate cellular DNA damage response. High intracellular zinc chelating capacity of both compounds, deduced from the metal specific Zinquin assay and ZnL2+ stability constant values in solution strongly support their cytotoxicity. These data along with quantum mechanical studies have enabled to establish a precise Structure-Activity Relationship. Moreover, L1a and L5a showed appropriate drug-likeness by in silico methods. Based on these promising results, L1a and L5a should be considered a new class of zinc-chelating anticancer agents that deserve further development.

DOI: https://doi.org/10.1021/acs.jmedchem.9b01554
Immunity. 2019 Dec 17. pii: S1074-7613(19)30493-5. [Epub ahead of print]51(6): 975-977

Virus-Induced Interferon Regulates the Urea Cycle.

Akira Nishio, Barbara Rehermann.

Integrating transcriptomic, proteomic, and metabolomic data, Lercher et al. show in a mouse model of LCMV infection that type I interferon alters the expression and function of key enzymes of the urea cycle in hepatocytes. This results in altered systemic metabolism, attenuating antiviral T cell responses and ameliorating liver injury.

DOI: https://doi.org/10.1016/j.immuni.2019.11.012