bims-polyam 2022-05-29 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–05–29
ten papers selected by
Sebastian J. Hofer, University of Graz

Role of Spermidine in Photosynthesis and Polyamine Metabolism in Lettuce Seedlings under High-Temperature Stress.
The importance of the urea cycle and its relationships to polyamine metabolism during ammonium stress in Medicago truncatula.
Inferring the Significance of the Polyamine Metabolism in the Phytopathogenic Bacteria Pseudomonas syringae: A Meta-Analysis Approach.
Consecutive action of two BAHD acyltransferases promotes tetracoumaroyl spermine accumulation in chicory.
Metabolic control of arginine and ornithine levels paces the progression of leaf senescence.
First fluorescent acetylspermidine deacetylation assay for HDAC10 identifies selective inhibitors with cellular target engagement.
Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: A Randomized Clinical Trial.
Oxygen level regulates N-terminal translation elongation of selected proteins through deoxyhypusine hydroxylation.
Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.
Role of Promising Secondary Metabolites to Confer Resistance Against Environmental Stresses in Crop Plants: Current Scenario and Future Perspectives.

Plants (Basel). 2022 May 23. pii: 1385. [Epub ahead of print]11(10):

Role of Spermidine in Photosynthesis and Polyamine Metabolism in Lettuce Seedlings under High-Temperature Stress.

Xin He, Jinghong Hao, Shuangxi Fan, Chaojie Liu, Yingyan Han.

  High temperature is a huge threat to lettuce production in the world, and spermidine (Spd) has been shown to improve heat tolerance in lettuce, but the action mechanism of Spd and the role of polyamine metabolism are still unclear. The effects of Spd and D-arginine (D-arg) on hydroponic lettuce seedlings under high-temperature stress by foliar spraying of Spd and D-arg were investigated. The results showed that high-temperature stress significantly inhibited the growth of lettuce seedlings, with a 33% decrease in total fresh weight and total dry weight; photosynthesis of lettuce seedlings was inhibited by high-temperature stress, and the inhibition was greater in the D-arg treatment, while the Spd recovery treatment increased net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr), stomatal limit value (Ls), and intercellular CO2 concentration (Ci). High-temperature stress significantly reduced the maximum photochemical efficiency (Fv/Fm), photochemical quenching coefficient (qP), electron transport rate (ETR), and photochemical efficiency of PSII (ΦPSII), increased the non-photochemical burst coefficient (NPQ) and reduced the use of light energy, which was alleviated by exogenous Spd. The increase in polyamine content may be due to an increase in polyamine synthase activity and a decrease in polyamine oxidase activity, as evidenced by changes in the expression levels of genes related to polyamine synthesis and metabolism enzymes. This evidence suggested that D-arg suppressed endogenous polyamine levels in lettuce and reduced its tolerance, whereas exogenous Spd promoted the synthesis and accumulation of polyamines in lettuce and increased its photosynthetic and oxidative stress levels, which had an impact on the tolerance of lettuce seedlings.

Keywords:  high-temperature stress; photosynthesis; polyamine inhibitor; polyamine metabolism

DOI:  https://doi.org/10.3390/plants11101385
J Exp Bot. 2022 May 24. pii: erac235. [Epub ahead of print]

The importance of the urea cycle and its relationships to polyamine metabolism during ammonium stress in Medicago truncatula.

M Urra, J Buezo, B Royo, A Cornejo, P López-Gómez, D Cerdán, R Esteban, V Martínez-Merino, Y Gogorcena, P Tavladoraki, J F Moran.

  The ornithine-urea cycle (urea cycle) makes a significant contribution to the metabolic responses of lower photosynthetic eukaryotes to episodes of high nitrogen availability. We therefore compared the role of the plant urea cycle and its relationships to polyamine metabolism in ammonium-fed and nitrate-fed Medicago truncatula plants. High ammonium resulted in the accumulation of ammonium and pathway intermediates, particularly glutamine, arginine, ornithine, and putrescine. Arginine decarboxylase activity was decreased in roots, suggesting that the ornithine decarboxylase-dependent production of putrescine was important in situations of ammonium stress. The activity of copper-amine oxidase, which releases ammonium from putrescine, was significantly decreased in both shoots and roots. In addition, physiological concentrations of ammonium inhibited copper-amine oxidase activity in in vitro assays, supporting the conclusion that high ammonium accumulation favors putrescine synthesis. Moreover, putrescine early supplemented to plants avoided ammonium toxicity. The levels of transcripts encoding urea cycle-related proteins were increased and transcripts involved in polyamine catabolism were decreased under high ammonium. We conclude that the urea cycle and associated polyamine metabolism function as important protective mechanisms limiting ammonium toxicity in M. truncatula. These findings demonstrate the relevance of the urea cycle to polyamine metabolism in higher plants.

Keywords:  amine oxidase; ammonium stress; nitrogen nutrition; polyamine; putrescine; urea cycle

DOI:  https://doi.org/10.1093/jxb/erac235
Front Microbiol. 2022 ;13 893626

Inferring the Significance of the Polyamine Metabolism in the Phytopathogenic Bacteria Pseudomonas syringae: A Meta-Analysis Approach.

Leandro Solmi, Hernán G Rosli, Marina A Pombo, Santiago Stalder, Franco R Rossi, Fernando M Romero, Oscar A Ruiz, Andrés Gárriz.

  To succeed in plant invasion, phytopathogenic bacteria rely on virulence mechanisms to subvert plant immunity and create favorable conditions for growth. This process requires a precise regulation in the production of important proteins and metabolites. Among them, the family of compounds known as polyamines have attracted considerable attention as they are involved in important cellular processes, but it is not known yet how phytopathogenic bacteria regulate polyamine homeostasis in the plant environment. In the present study, we performed a meta-analysis of publicly available transcriptomic data from experiments conducted on bacteria to begin delving into this topic and better understand the regulation of polyamine metabolism and its links to pathogenicity. We focused our research on Pseudomonas syringae, an important phytopathogen that causes disease in many economically valuable plant species. Our analysis discovered that polyamine synthesis, as well as general gene expression activation and energy production are induced in the early stages of the disease. On the contrary, synthesis of these compounds is inhibited whereas its transport is upregulated later in the process, which correlates with the induction of virulence genes and the metabolism of nitrogen and carboxylic acids. We also found that activation of plant defense mechanisms affects bacterial polyamine synthesis to some extent, which could reduce bacterial cell fitness in the plant environment. Furthermore, data suggest that a proper bacterial response to oxidative conditions requires a decrease in polyamine production. The implications of these findings are discussed.

Keywords:  Pseudomonas syringae; plant pathogen; putrescine; secondary metabolism; spermidine

DOI:  https://doi.org/10.3389/fmicb.2022.893626
Plant Physiol. 2022 May 23. pii: kiac234. [Epub ahead of print]

Consecutive action of two BAHD acyltransferases promotes tetracoumaroyl spermine accumulation in chicory.

Guillaume Bernard, Julie Buges, Marianne Delporte, Molinié Roland, Sébastien Besseau, Alain Bouchereau, Amandine Watrin, Jean-Xavier Fontaine, David Mathiron, Solenne Berardocco, Solène Bassard, Anthony Quéro, Jean-Louis Hilbert, Caroline Rambaud, David Gagneul.

  Fully substituted phenolamide accumulation in the pollen coat of Eudicotyledons is a conserved evolutionary chemical trait. Interestingly, spermidine derivatives are replaced by spermine derivatives as the main phenolamide accumulated in the Asteraceae family. Here, we show that the full substitution of spermine in chicory (Cichorium intybus) requires the successive action of two enzymes, i.e. CiSHT1 and CiSHT2 (spermidine hydroxycinnamoyl transferase-like protein 1 and 2), two members of the BAHD enzyme family. Deletion of these genes in chicory using CRISPR/Cas9 gene editing technology evidenced that CiSHT2 catalyzes the first N-acylation steps whereas CiSHT1 fulfills the substitution to give rise to tetracoumaroyl spermine. Additional experiments using Nicotiana benthamiana confirmed these findings. Expression of CiSHT2 alone promoted partially substituted spermine accumulation, and coexpression of CiSHT2 and CiSHT1 promoted synthesis and accumulation of the fully substituted spermine. Structural characterization of the main product of CiSHT2 using NMR revealed that CiSHT2 preferentially catalyzed N-acylation of secondary amines to form N5,N10-dicoumaroyl spermine, whereas CiSHT1 used this substrate to synthesize tetracoumaroyl spermine. We showed that spermine availability may be a key determinant towards preferential accumulation of spermine derivatives over spermidine derivatives in chicory. Our results reveal a subfunctionalization among the SHTs that was accompanied by a modification of free polyamine metabolism that has resulted in the accumulation of this new phenolamide in chicory and most probably in all Asteraceae. Finally, genetically engineered yeast (Saccharomyces cerevisiae) was shown to be a promising host platform to produce these compounds.

Keywords:   Cichorium intybus ; BAHD acyltransferases; SHTs; metabolic diversification; subfunctionalization; tetracoumaroyl spermine

DOI:  https://doi.org/10.1093/plphys/kiac234
Plant Physiol. 2022 May 23. pii: kiac244. [Epub ahead of print]

Metabolic control of arginine and ornithine levels paces the progression of leaf senescence.

Daniela Liebsch, Marta Juvany, Zhonghai Li, Hou-Ling Wang, Agnieszka Ziolkowska, Daria Chrobok, Clément Boussardon, Xing Wen, Simon R Law, Helena Janečková, Bastiaan Brouwer, Pernilla Lindén, Nicolas Delhomme, Hans Stenlund, Thomas Moritz, Per Gardeström, Hongwei Guo, Olivier Keech.

Leaf senescence can be induced by stress or aging, sometimes in a synergistic manner. It is generally acknowledged that the ability to withstand senescence-inducing conditions can provide plants with stress resilience. Although the signaling and transcriptional networks responsible for a delayed senescence phenotype, often referred to as a functional stay-green trait, have been actively investigated, very little is known about the subsequent metabolic adjustments conferring this aptitude to survival. First, using the individually-darkened leaf (IDL) experimental setup, we compared IDLs of wild-type (WT) Arabidopsis (Arabidopsis thaliana) to several stay-green contexts, i.e., IDLs of two functional stay-green mutant lines, oresara1-2 (ore1-2) and an allele of phytochrome-interacting factor 5 (pif5), as well as to leaves from a WT plant entirely darkened (DP). We provide compelling evidence that arginine and ornithine, which accumulate in all stay-green contexts - likely due to the lack of induction of amino acids transport - can delay the progression of senescence by fueling the Krebs cycle or the production of polyamines (PAs). Secondly, we show that the conversion of putrescine to spermidine is controlled in an age-dependent manner. Thirdly, we demonstrate that spermidine represses senescence via interference with ethylene signaling by stabilizing the ETHYLENE BINDING FACTOR1 and 2 (EBF1/2) complex. Taken together, our results identify arginine and ornithine as central metabolites influencing the stress- and age-dependent progression of leaf senescence. We propose that the regulatory loop between the pace of the amino acid export and the progression of leaf senescence provides the plant with a mechanism to fine-tune the induction of cell death in leaves, which, if triggered unnecessarily, can impede nutrient remobilization and thus plant growth and survival.

DOI: https://doi.org/10.1093/plphys/kiac244
Chembiochem. 2022 May 24.

First fluorescent acetylspermidine deacetylation assay for HDAC10 identifies selective inhibitors with cellular target engagement.

Daniel Herp, Johannes Ridinger, Dina Robaa, Stephen A Shinsky, Karin Schmidtkunz, Talha Z Yesiloglu, Theresa Bayer, Raphael R Steimbach, Corey J Herbst-Gervasoni, Annika Merz, Christophe Romier, Peter Sehr, Nikolas Gunkel, Aubry K Miller, David W Christianson, Ina Oehme, Wolfgang Sippl, Manfred Jung.

  Histone deacetylases (HDACs) are key epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved as drugs and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e.g., in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. HDAC10 has strong preferences for deacetylation of oligoamine substrates like acetyl-putrescine or -spermidine. Hence, it is also termed as a polyamine deacetylase (PDAC). Here, we present the first fluorescent conversion assay for HDAC10 using an aminocoumarin-labelled acetyl-spermidine derivative to measure its PDAC activity. Using this assay, we identified potent inhibitors of HDAC10-mediated spermidine deacetylation in vitro. Based on the oligoamine preference of HDAC10, we also designed inhibitors with a basic moiety in appropriate distance to the zinc binding hydroxamate that showed potent inhibition of HDAC10 with high selectivity, and we solved a HDAC10-inhibitor structure using X-ray crystallography. We could demonstrate selective cellular target engagement for HDAC10 but a lysosomal phenotype in neuroblastoma cells that was previously associated with HDAC10 inhibition was not observed. Thus, we have developed new chemical probes for HDAC10 that allow further clarification of the biological role of this enzyme.

Keywords:  HDAC; HDAC10; histone deacetylases; inhibitors; polyamine

DOI:  https://doi.org/10.1002/cbic.202200180
JAMA Netw Open. 2022 May 02. 5(5): e2213875

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: A Randomized Clinical Trial.

Claudia Schwarz, Gloria S Benson, Nora Horn, Katharina Wurdack, Ulrike Grittner, Ralph Schilling, Stefanie Märschenz, Theresa Köbe, Sebastian J Hofer, Christoph Magnes, Slaven Stekovic, Tobias Eisenberg, Stephan J Sigrist, Dietmar Schmitz, Miranka Wirth, Frank Madeo, Agnes Flöel.

Importance: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline.
Objective: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group.
Design, Setting, and Participants: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021.
Interventions: One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention.
Main Outcomes and Measures: Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed.
Results: A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups.
Conclusions and Relevance: In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage.
Trial Registration: ClinicalTrials.gov Identifier: NCT03094546.

DOI: https://doi.org/10.1001/jamanetworkopen.2022.13875
Cell Rep. 2022 May 24. pii: S2211-1247(22)00628-3. [Epub ahead of print]39(8): 110855

Oxygen level regulates N-terminal translation elongation of selected proteins through deoxyhypusine hydroxylation.

Yugang Zhang, Dan Su, Julia Zhu, Miao Wang, Yandong Zhang, Qin Fu, Sheng Zhang, Hening Lin.

  Hypusine is a post-translational modification on eukaryotic translation initiation factor 5A (eIF5A). The last step of hypusine biosynthesis, deoxyhypusine hydroxylation, is an oxygen-dependent reaction. Here we show that deletion of the deoxyhypusine hydroxylase Lia1 compromises yeast respiration through translation downregulation of selected proteins in the respiration pathway. The translation suppression, because of the lack of deoxyhypusine hydroxylation, mainly affects translation of the N termini of the proteins, independent of the presence of proline residues but likely dependent on the interaction between the N-terminal nascent peptide and the ribosomal peptide exit tunnel. Proteomics and biochemical studies reveal that Lia1 deletion decreases N-terminal translation of proteins involved in mitochondrial respiration, oxidative stress response, and protein folding. Our work uncovers functions of the hypusine modification by considering the substrate requirement of the post-translational modification, highlights the unique challenges of translating the N termini of proteins, and reveals an oxygen-sensing mechanism in eukaryotic cells.

Keywords:  CP: Metabolism; CP: Molecular biology; deoxyhypusine hydroxylase; hypusine; oxidative phosphorylation; oxygen sensing; translation

DOI:  https://doi.org/10.1016/j.celrep.2022.110855
Antioxidants (Basel). 2022 Apr 30. pii: 897. [Epub ahead of print]11(5):

Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.

Rubén Rodríguez-Agudo, Naroa Goikoetxea-Usandizaga, Marina Serrano-Maciá, Pablo Fernández-Tussy, David Fernández-Ramos, Sofía Lachiondo-Ortega, Irene González-Recio, Clàudia Gil-Pitarch, María Mercado-Gómez, Laura Morán, Maider Bizkarguenaga, Fernando Lopitz-Otsoa, Petar Petrov, Miren Bravo, Sebastiaan Martijn Van Liempd, Juan Manuel Falcon-Perez, Amaia Zabala-Letona, Arkaitz Carracedo, Jose Vicente Castell, Ramiro Jover, Luis Alfonso Martínez-Cruz, Teresa Cardoso Delgado, Francisco Javier Cubero, María Isabel Lucena, Raúl Jesús Andrade, Jon Mabe, Jorge Simón, María Luz Martínez-Chantar.

  Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.

Keywords:  acetaminophen (APAP); ammonia; drug-induced liver injury (DILI); methionine cycle; miR-873-5p; mitochondria; polyamines; therapy

DOI:  https://doi.org/10.3390/antiox11050897
Front Plant Sci. 2022 ;13 881032

Role of Promising Secondary Metabolites to Confer Resistance Against Environmental Stresses in Crop Plants: Current Scenario and Future Perspectives.

Delai Chen, Bismillah Mubeen, Ammarah Hasnain, Muhammad Rizwan, Muhammad Adrees, Syed Atif Hasan Naqvi, Shehzad Iqbal, Muhammad Kamran, Ahmed M El-Sabrout, Hosam O Elansary, Eman A Mahmoud, Abdullah Alaklabi, Manda Sathish, Ghulam Muhae Ud Din.

  Plants often face incompatible growing environments like drought, salinity, cold, frost, and elevated temperatures that affect plant growth and development leading to low yield and, in worse circumstances, plant death. The arsenal of versatile compounds for plant consumption and structure is called metabolites, which allows them to develop strategies to stop enemies, fight pathogens, replace their competitors and go beyond environmental restraints. These elements are formed under particular abiotic stresses like flooding, heat, drought, cold, etc., and biotic stress such as a pathogenic attack, thus associated with survival strategy of plants. Stress responses of plants are vigorous and include multifaceted crosstalk between different levels of regulation, including regulation of metabolism and expression of genes for morphological and physiological adaptation. To date, many of these compounds and their biosynthetic pathways have been found in the plant kingdom. Metabolites like amino acids, phenolics, hormones, polyamines, compatible solutes, antioxidants, pathogen related proteins (PR proteins), etc. are crucial for growth, stress tolerance, and plant defense. This review focuses on promising metabolites involved in stress tolerance under severe conditions and events signaling the mediation of stress-induced metabolic changes are presented.

Keywords:  PR proteins; antioxidants; compatible solutes; polyamines; stresses

DOI:  https://doi.org/10.3389/fpls.2022.881032