bims-polyam 2020-01-12 papers

on Polyamines

Issue of 2020–01–12
nine papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy.
Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function.
Thermospermine Synthase (ACL5) and Diamine Oxidase (DAO) Expression Is Needed for Zygotic Embryogenesis and Vascular Development in Scots Pine.
Metabolic adjustments during compatible interaction between barley genotypes and stripe rust pathogen.
Catabolism of biogenic amines in Pseudomonas species.
Spermidine Exhibits Protective Effects Against Traumatic Brain Injury.
The plasma-membrane polyamine transporter PUT3 is regulated by the Na+ /H+ antiporter SOS1 and protein kinase SOS2.
Analysis of interaction between intracellular spermine and transient receptor potential canonical 4 channel: multiple candidate sites of negatively charged amino acids for the inward rectification of transient receptor potential canonical 4.
Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria.

Nat Commun. 2020 Jan 07. 11(1): 52

Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy.

Hayley C Affronti, Aryn M Rowsam, Anthony J Pellerite, Spencer R Rosario, Mark D Long, Justine J Jacobi, Anna Bianchi-Smiraglia, Christoph S Boerlin, Bryan M Gillard, Ellen Karasik, Barbara A Foster, Michael Moser, John H Wilton, Kristopher Attwood, Mikhail A Nikiforov, Gissou Azabdaftari, Roberto Pili, James G Phillips, Robert A Casero, Dominic J Smiraglia.

Prostatic luminal epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen, sensitizing them to perturbations of connected metabolic pathways. Enhanced flux is driven by spermidine/spermine N1-acetyltransferase (SSAT) activity, which acetylates polyamines leading to their secretion and drives biosynthetic demand. The methionine salvage pathway recycles one-carbon units lost to polyamine biosynthesis to the methionine cycle to overcome stress. Prostate cancer (CaP) relies on methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme, to relieve strain. Here, we show that inhibition of MTAP alongside SSAT upregulation is synergistic in androgen sensitive and castration recurrent CaP models in vitro and in vivo. The combination treatment increases apoptosis in radical prostatectomy ex vivo explant samples. This unique high metabolic flux through polyamine biosynthesis and connected one carbon metabolism in CaP creates a metabolic dependency. Enhancing this flux while simultaneously targeting this dependency in prostate cancer results in an effective therapeutic approach potentially translatable to the clinic.

DOI: https://doi.org/10.1038/s41467-019-13950-4
Aging (Albany NY). 2020 Jan 06. 11

Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function.

Junying Wang, Shaoqi Li, Ju Wang, Feixiang Wu, Yuhan Chen, Hao Zhang, Yubo Guo, Yan Lin, Lingxu Li, Xue Yu, Ting Liu, Yajun Zhao.

  Polyamines have been shown to delay cellular and organismal aging and to provide cardiovascular protection in humans. Because age-related cardiovascular dysfunction is often accompanied by impaired mitochondrial biogenesis and function, we explored the ability of spermidine (SPD), a major mammalian polyamine, to attenuate cardiac aging through activation of mitochondrial biogenesis. Cardiac polyamine levels were reduced in aged (24-month-old) rats. Six-week SPD supplementation restored cardiac polyamine content, preserved myocardial ultrastructure, and inhibited mitochondrial dysfunction. Immunoblotting showed that ornithine decarboxylase (ODC) and SPD/spermine N1-acetyltransferase (SSAT) were downregulated and upregulated, respectively, in the myocardium of older rats. These changes were paralleled by age-dependent downregulation of components of the sirtuin-1/peroxisome proliferator-activated receptor gamma coactivator alpha (SIRT1/PGC-1α) signaling pathway, an important regulator of mitochondrial biogenesis. SPD administration increased SIRT1, PGC-1α, nuclear respiratory factors 1 and 2 (NRF1, NRF2), and mitochondrial transcription factor A (TFAM) expression; decreased ROS production; and improved OXPHOS performance in senescent (H2O2-treated) cardiomyocytes. Inhibition of polyamine biosynthesis or SIRT1 activity abolished these effects. PGC-1α knockdown experiments confirmed that SPD activated mitochondrial biogenesis through SIRT1-mediated deacetylation of PGC-1α. These data provide new insight into the antiaging effects of SPD, and suggest potential applicability to protect against deterioration of cardiac function with aging.

Keywords:  PGC-1α; SIRT1; mitochondrial biogenesis; polyamine metabolism; spermidine

DOI:  https://doi.org/10.18632/aging.102647
Front Plant Sci. 2019 ;10 1600

Thermospermine Synthase (ACL5) and Diamine Oxidase (DAO) Expression Is Needed for Zygotic Embryogenesis and Vascular Development in Scots Pine.

Jaana Vuosku, Riina Muilu-Mäkelä, Komlan Avia, Marko Suokas, Johanna Kestilä, Esa Läärä, Hely Häggman, Outi Savolainen, Tytti Sarjala.

  Unlike in flowering plants, the detailed roles of the enzymes in the polyamine (PA) pathway in conifers are poorly known. We explored the sequence conservation of the PA biosynthetic genes and diamine oxidase (DAO) in conifers and flowering plants to reveal the potential functional diversification of the enzymes between the plant lineages. The expression of the genes showing different selective constraints was studied in Scots pine zygotic embryogenesis and early seedling development. We found that the arginine decarboxylase pathway is strongly preferred in putrescine production in the Scots pine as well as generally in conifers and that the reduced use of ornithine decarboxylase (ODC) has led to relaxed purifying selection in ODC genes. Thermospermine synthase (ACL5) genes evolve under strong purifying selection in conifers and the DAO gene is also highly conserved in pines. In developing Scots pine seeds, the expression of both ACL5 and DAO increased as embryogenesis proceeded. Strong ACL5 expression was present in the procambial cells of the embryo and in the megagametophyte cells destined to die via morphologically necrotic cell death. Thus, the high sequence conservation of ACL5 genes in conifers may indicate the necessity of ACL5 for both embryogenesis and vascular development. Moreover, the result suggests the involvement of ACL5 in morphologically necrotic cell death and supports the view of the genetic regulation of necrosis in Scots pine embryogenesis and in plant development. DAO transcripts were located close to the cell walls and between the walls of adjacent cells in Scots pine zygotic embryos and in the roots of young seedlings. We propose that DAO, in addition to the role in Put oxidation for providing H2O2 during the cell-wall structural processes, may also participate in cell-to-cell communication at the mRNA level. To conclude, our findings indicate that the PA pathway of Scots pines possesses several special functional characteristics which differ from those of flowering plants.

Keywords:  Scots pine; arginine decarboxylase; developmental regulation; diamine oxidase; enzyme pathway evolution; polyamine; thermospermine synthase; zygotic embryogenesis

DOI:  https://doi.org/10.3389/fpls.2019.01600
Plant Physiol Biochem. 2019 Dec 27. pii: S0981-9428(19)30546-7. [Epub ahead of print]147 295-302

Metabolic adjustments during compatible interaction between barley genotypes and stripe rust pathogen.

Prabhjot Singla, Rachana D Bhardwaj, Simarjit Kaur, Jaspal Kaur, Satvir K Grewal.

  Stripe rust is a fungal disease that has devastated the barley production for a long time. The present study focused on the role of β-glucan, PR proteins, diamine oxidase (DAO), polyamine oxidase (PAO), key enzymes and metabolites of phenol and proline metabolism in the stripe rust resistance of barley. RD2901 with resistant behavior against stripe rust showed increased levels of PR proteins, phenylalanine ammonia lyase (PAL), tyrosine ammonia lyase (TAL) along with the accumulation of β-glucan and lignin which strengthen the plant cell wall during plant-pathogen interaction. It also depicted the enhanced activities of glutamate dehydrogenase (GDH) and ornithine aminotransferase (OAT) coupled with the increased amounts of proline, glycine betaine and choline after infection with M-race of P. striiformis f. sp. hordei. On the contrary, the sensitive genotype Jyoti was unable to enhance the activities of most of these enzymes except PAL and OAT so that it showed an increase in lignin and choline contents only. Secondly, the increase in lignin content was less as compared to the tolerant genotype. Hence, it can be inferred that these key metabolites and enzymes of various metabolic pathways may contribute to the resistance of barley against stripe rust pathogen. This study suggested that these key enzymes and their metabolites could serve as markers for the characterization of plant defensive state that is essential for crop protection.

Keywords:  Glutamate dehydrogenase; Ornithine transaminase; Osmolytes; PR proteins; Polyamines; Secondary metabolites

DOI:  https://doi.org/10.1016/j.plaphy.2019.12.030
Environ Microbiol. 2020 Jan 08.

Catabolism of biogenic amines in Pseudomonas species.

José M Luengo, Elías R Olivera.

Biogenic amines (2-phenylethylamine, tyramine, dopamine, epinephrine, norepinephrine, octopamine, histamine, tryptamine, serotonin, agmatine, cadaverine, putrescine, spermidine, spermine and certain aliphatic amines) are widely distributed organic molecules that play basic physiological functions in animals, plants and microorganisms. Pseudomonas species can grow in media containing different biogenic amines (BA) as carbon and energy sources, a reason why these bacteria are excellent models for studying such catabolic pathways. In this review, we analyse most of the routes used by different species of Pseudomonas (P. putida, P. aeruginosa, P. entomophila and P. fluorescens) to degrade BA. Analysis of these pathways has led to the identification of a huge number of genes, catabolic enzymes, transport systems and regulators, as well as to understanding of their hierarchy and functional evolution. Knowledge of these pathways has allowed the design and collection of genetically manipulated microbes useful for eliminating BA from different sources, highlighting the biotechnological applications of these studies. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1111/1462-2920.14912
Cell Mol Neurobiol. 2020 Jan 08.

Spermidine Exhibits Protective Effects Against Traumatic Brain Injury.

Jianxing Huang, Heping Zhang, Jinning Zhang, Huiping Yu, Zhizhong Lin, Yonghui Cai.

  Traumatic brain injury (TBI) causes permanent neurological and cognitive impairments. Effective pharmacological interventions remain elusive. Spermidine is a polyamine compound found in our body that may play a role in brain development and congenital function. In this study, we aimed to investigate the therapeutic potential of spermidine for TBI. We employed experimental closed head injury (CHI) model to evaluate the protective function of spermidine on brain injury. We assessed the neurobehavioral function recovery using Neurologic Severity Score (NSS) and Morris water maze test. At histological level, we evaluated the improvement on brain edema, brain-blood barrier integrity, and cell apoptosis. We also measured inflammatory cytokines and brain injury biomarkers to monitor the treatment outcomes. Last, we correlated the level of spermidine with CHI animal model and TBI patients with different levels of severity. Spermidine administration post-CHI was found effectively to accelerate NSS improvement and shorten latency in maze test. We observed consistent improvements in brain edema, BBB function, and cell death in spermidine-treated group. Inflammatory cytokines and TBI biomarkers, e.g., S100B, MBP and CFAP were reduced significantly in treatment group. Interestingly, inhibiting spermidine synthesis influenced the neurobehavioral recovery in CHI mice. ODC1, a rate-limiting enzyme for spermidine synthesis, was found lower in CHI mice. Serum level of spermidine was significantly lower in TBI patients with severe pathological scores. Spermidine pathway may carry an endogenous role in pathophysiological process of CHI. For the first time, we demonstrated that administrating spermidine may provide a new treatment for TBI.

Keywords:  Closed head injury; ODC1; Spermidine; Traumatic head injury

DOI:  https://doi.org/10.1007/s10571-019-00783-4
New Phytol. 2020 Jan 04.

The plasma-membrane polyamine transporter PUT3 is regulated by the Na+ /H+ antiporter SOS1 and protein kinase SOS2.

Haoxi Chai, Jianfei Guo, Yingli Zhong, Chuan-Chih Hsu, Changsong Zou, Pengcheng Wang, Jian-Kang Zhu, Huazhong Shi.

  In Arabidopsis, the plasma membrane transporter PUT3 is important to maintain the cellular homeostasis of polyamines and plays a role in stabilizing mRNAs of some heat-inducible genes. The plasma membrane Na+ /H+ transporter SOS1 and the protein kinase SOS2 are two salt-tolerance determinants crucial for maintaining the intracellular Na+ and K+ homeostasis. Here, we report that PUT3 genetically and physically interacts with SOS1 and SOS2, and these interactions modulate PUT3 transport activity. Overexpression of PUT3 (PUT3OE) results in hypersensitivity of the transgenic plants to polyamine and paraquat. The hypersensitivity of PUT3OE is inhibited by the sos1 and sos2 mutations, which indicates that SOS1 and SOS2 are required for PUT3 transport activity. Protein interaction assay revealed that PUT3 physically interacts with SOS1 and SOS2 in yeast and plant cells. SOS2 phosphorylates PUT3 both in vitro and in vivo. SOS1 and SOS2 synergistically activate the polyamine transport activity of PUT3, and PUT3 also modulates SOS1 activity by activating SOS2 in yeast cells. Overall, our findings suggest that both plasma-membrane proteins PUT3 and SOS1 could form a complex with the protein kinase SOS2 in response to stress conditions and modulate the transport activity of each other through protein interactions and phosphorylation.

Keywords:  Membrane transporter; PUT3; Phosphorylation; Polyamine; SOS1; SOS2; Salt tolerance

DOI:  https://doi.org/10.1111/nph.16407
Korean J Physiol Pharmacol. 2020 Jan;24(1): 101-110

Analysis of interaction between intracellular spermine and transient receptor potential canonical 4 channel: multiple candidate sites of negatively charged amino acids for the inward rectification of transient receptor potential canonical 4.

Jinsung Kim, Sang Hui Moon, Taewook Kim, Juyeon Ko, Young Keul Jeon, Young-Cheul Shin, Ju-Hong Jeon, Insuk So.

  Transient receptor potential canonical 4 (TRPC4) channel is a nonselective calcium-permeable cation channels. In intestinal smooth muscle cells, TRPC4 currents contribute more than 80% to muscarinic cationic current (mIcat). With its inward-rectifying current-voltage relationship and high calcium permeability, TRPC4 channels permit calcium influx once the channel is opened by muscarinic receptor stimulation. Polyamines are known to inhibit nonselective cation channels that mediate the generation of mIcat. Moreover, it is reported that TRPC4 channels are blocked by the intracellular spermine through electrostatic interaction with glutamate residues (E728, E729). Here, we investigated the correlation between the magnitude of channel inactivation by spermine and the magnitude of channel conductance. We also found additional spermine binding sites in TRPC4. We evaluated channel activity with electrophysiological recordings and revalidated structural significance based on Cryo-EM structure, which was resolved recently. We found that there is no correlation between magnitude of inhibitory action of spermine and magnitude of maximum current of the channel. In intracellular region, TRPC4 attracts spermine at channel periphery by reducing access resistance, and acidic residues contribute to blocking action of intracellular spermine; channel periphery, E649; cytosolic space, D629, D649, and E687.

Keywords:  Polyamines; Spermine; Transient receptor potential channels

DOI:  https://doi.org/10.4196/kjpp.2020.24.1.101
Cells. 2019 Dec 28. pii: E82. [Epub ahead of print]9(1):

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria.

Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, María Mittelbrunn.

  Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. In fact, both mitochondrial dysfunction or autophagy decline compromise cellular homeostasis and induce inflammation. Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseases.

Keywords:  aging; autophagy; calorie restriction; inflammation; metabolism; mitochondria

DOI:  https://doi.org/10.3390/cells9010082