bims-polyam 2019-09-29 papers

on Polyamines

Issue of 2019–09–29
ten papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Link between spermine oxidase and apoptosis antagonizing transcription factor: A new pathway in neuroblastoma.
DFMD: Fast and Effective DelPhiForce Steered Molecular Dynamics Approach to Model Ligand Approach Toward a Receptor: Application to Spermine Synthase Enzyme.
Elevation of cellular Mg2+ levels by the Mg2+ transporter, Alr1, supports growth of polyamine-deficient Saccharomyces cerevisiae cells.
Polyamines (spermidine and putrescine) mitigate the adverse effects of manganese induced toxicity through improved antioxidant system and photosynthetic attributes in Brassica juncea.
Polyamine Catabolism in Acute Kidney Injury.
Polyamine Synthesis Effects Capsule Expression by Reduction of Precursors in Streptococcus pneumoniae.
Involvement of Spermidine in the Reduced Lifespan of Caenorhabditis elegans During Vitamin B12 Deficiency.
Spermine application alleviates salinity induced growth and photosynthetic inhibition in Solanum lycopersicum by modulating osmolyte and secondary metabolite accumulation and differentially regulating antioxidant metabolism.
Discovery of Gut Bacteria Specific to Alzheimer's Associated Diseases is a Clue to Understanding Disease Etiology: Meta-Analysis of Population-Based Data on Human Gut Metagenomics and Metabolomics.
Comparative psychopharmacology of autism and psychotic-affective disorders suggests new targets for treatment.

Int J Oncol. 2019 Sep 13.

Link between spermine oxidase and apoptosis antagonizing transcription factor: A new pathway in neuroblastoma.

Emiliano Fratini, Manuela Cervelli, Paolo Mariottini, Yuta Kanamori, Roberto Amendola, Enzo Agostinelli.

Neuroblastoma (NB) is a heterogeneous extra‑cranial childhood type of cancer, responsible for approximately 15% of all paediatric cancer‑related deaths. Although several critical genetic aberrations have been related to NB, only a few established molecular markers have been associated with prognosis [V‑myc avian myelocytomatosis viral oncogene (MYCN) locus amplification, deletions of part of chromosome 1p, 11q23 and gain of 17q]. Regrettably, direct evidence of NB‑related tumour suppressors or oncogenes has not been currently identified at these chromosomal regions. MYCN locus amplification is present in approximately 20‑30% of cases and is associated with a poor clinical outcome, representing the most important genetic prognostic marker. The functional guidelines for the prognosis of NB identify high‑risk patients (<40% survival probabilities), but fail to identify patients at low and intermediate stages of the disease, which remains an issue to be resolved in NB. It has been shown that in NB cell lines and in a total‑spermine oxidase (SMOX) transgenic mouse model, SMOX overexpression induces cellular stress via reactive oxygen species (ROS) imbalance. In this study, we demonstrated that the high expression level of the cytoprotective gene, apoptosis-antagonizing transcription factor (AATF), was driven by SMOX gene overexpression in both NB cells and Total‑SMOX mice. The anti‑apoptotic effect of AATF was supported by analysing the inhibition of the expression of the pro‑apoptotic genes, BAX, BAK and PUMA, which were decreased, in both the in vitro and in vivo SMOX overexpressing model systems investigated. On the whole, this study supports the hypothesis that the SMOX gene can be considered as a novel anti‑apoptotic marker in NB.

DOI: https://doi.org/10.3892/ijo.2019.4878
Front Mol Biosci. 2019 ;6 74

DFMD: Fast and Effective DelPhiForce Steered Molecular Dynamics Approach to Model Ligand Approach Toward a Receptor: Application to Spermine Synthase Enzyme.

Yunhui Peng, Ye Yang, Lin Li, Zhe Jia, Weiguo Cao, Emil Alexov.

  Here we report a novel approach, the DelPhiForce Molecular Dynamics (DFMD) method, for steered molecular dynamics simulations to model receptor-ligand association involving charged species. The main purpose of developing DFMD is to simulate ligand's trajectory toward the receptor and thus to predict the "entrance" of the binding pocket and conformational changes associated with the binding. We demonstrate that the DFMD is superior compared with molecular dynamics simulations applying standard cut-offs, provides correct binding forces, allows for modeling the ligand approach at long distances and thus guides the ligand toward the correct binding spot, and it is very fast (frequently the binding is completed in <1 ns). The DFMD is applied to model the binding of two ligands to a receptor (spermine synthase) and it is demonstrated that it guides the ligands toward the corresponding pockets despite of the initial ligand's position with respect to the receptor. Predicted conformational changes and the order of ligand binding are experimentally verified.

Keywords:  electrostatic forces; electrostatic funnel; electrostatic interaction; protein-ligand binding; spermine synthase; steered molecular dynamics simulation

DOI:  https://doi.org/10.3389/fmolb.2019.00074
J Biol Chem. 2019 Sep 22. pii: jbc.RA119.009705. [Epub ahead of print]

Elevation of cellular Mg2+ levels by the Mg2+ transporter, Alr1, supports growth of polyamine-deficient Saccharomyces cerevisiae cells.

Ashleigh S Hanner, Matthew Dunworth, Robert A Casero, Colin W MacDiarmid, Myung Hee Park.

  The polyamines, putrescine, spermidine, and spermine, are required for normal eukaryotic cellular functions. However, the minimum requirement for polyamines varies widely, ranging from very high concentrations (mM) in mammalian cells to extremely low in the yeast Saccharomyces cerevisiae. Yeast strains deficient in polyamine biosynthesis (spe1∆, lacking ornithine decarboxylase, and spe2∆, lacking S-adenosylmethionine decarboxylase) require externally supplied polyamines, but supplementation with as little as 10-8 M spermidine restores their growth. Here, we report that culturing a spe1∆ mutant or a spe2∆ mutant in standard polyamine-free minimal medium (SDC) leads to marked increases cellular Mg2+ content. To determine which yeast Mg2+ transporter mediated this increase, we generated mutant strains with a deletion of SPE1 or SPE2 combined with a deletion of one of the three Mg2+ transporter genes, ALR1, ALR2, and MNR2, known to maintain cytosolic Mg2+ concentration. Neither Alr2 nor Mnr2 was required for increased Mg2+ accumulation, as all four double mutants (spe1∆ alr2∆, spe2∆ alr2∆, spe1∆ mnr2∆, and spe2∆ mnr2∆) exhibited significant Mg2+ accumulation upon polyamine depletion. In contrast, a spe2∆ alr1∆ double mutant cultured in SDC medium exhibited little increase in Mg2+ content and displayed severe growth defects compared with single mutants, alr1∆ and spe2∆, under polyamine-deficient conditions. These findings indicate that Alr1 is required for the upregulation of the Mg2+ content in polyamine-depleted cells and suggest that elevated Mg2+ can support growth of polyamine-deficient S. cerevisiae mutants. Upregulation of cellular polyamine content in a Mg2+-deficient alr1∆ mutant provided further evidence for a crosstalk between Mg2+ and polyamine metabolism.

Keywords:  cell growth; gene knockout; magnesium transport; polyamine; yeast genetics; yeast metabolism

DOI:  https://doi.org/10.1074/jbc.RA119.009705
Chemosphere. 2019 Sep 12. pii: S0045-6535(19)32069-7. [Epub ahead of print]236 124830

Polyamines (spermidine and putrescine) mitigate the adverse effects of manganese induced toxicity through improved antioxidant system and photosynthetic attributes in Brassica juncea.

Anjuman Hussain, Faroza Nazir, Qazi Fariduddin.

  Polyamines (PAs) are recognized as plant growth regulators that are involved in the stress management in various crops. In the current study, mitigative roles of spermidine (Spd) and putrescine (Put) were assessed in manganese (Mn) stressed Brassica juncea plants. Spd or Put (1.0 mM) were applied to the foliage of Brassica juncea at 35 days after sowing (DAS) grown in the presence of Mn (30 or 150 mg kg-1 soil). The higher level of Mn (150 mg kg-1) diminished photosynthetic attributes and growth, enhanced the production of reactive oxygen species (ROS) like hydrogen peroxide (H2O2) and superoxide anion ( [Formula: see text] ) content, affected stomatal movement and increased the Mn concentration in roots and shoots of the plant at 45 DAS, whereas it enhanced the activities of various antioxidant enzymes and proline content in the foliage of Brassica juncea plants. On the other hand, treatment of PAs (Spd or Put) to Mn stressed as well as non-stressed plants resulted in a remarkable improvement in the stomatal behaviour, photosynthetic attributes, growth and biochemical traits, decreased the production of ROS (H2O2 and [Formula: see text] ) and concentration of Mn in different parts of plant. It is concluded that out of the two polyamines (Spd or Put), Spd proved more efficient and enhanced growth, photosynthesis, and metabolic state of the plants which bestowed tolerance and helped the plants to cope efficiently under Mn stress.

Keywords:  Antioxidant enzymes; Manganese toxicity; Photosynthesis; Polyamines; Reactive oxygen species; Stomata

DOI:  https://doi.org/10.1016/j.chemosphere.2019.124830
Int J Mol Sci. 2019 Sep 26. pii: E4790. [Epub ahead of print]20(19):

Polyamine Catabolism in Acute Kidney Injury.

Kamyar Zahedi, Sharon Barone, Manoocher Soleimani.

  Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care patients. Mortality from acute kidney injury remains high, particularly in critically ill patients, where it can be more than 50%. The primary causes of AKI include ischemia/reperfusion (I/R), sepsis, or nephrotoxicity; however, AKI patients may present with a complicated etiology where many of the aforementioned conditions co-exist. Multiple bio-markers associated with renal damage, as well as metabolic and signal transduction pathways that are involved in the mediation of renal dysfunction have been identified as a result of the examination of models, patient samples, and clinical data of AKI of disparate etiologies. These discoveries have enhanced our ability to diagnose AKIs and to begin to elucidate the mechanisms involved in their pathogenesis. Studies in our laboratory revealed that the expression and activity of spermine/spermidine N1-acetyltransferase (SAT1), the rate-limiting enzyme in polyamine back conversion, were enhanced in kidneys of rats after I/R injury. Additional studies revealed that the expression of spermine oxidase (SMOX), another critical enzyme in polyamine catabolism, is also elevated in the kidney and other organs subjected to I/R, septic, toxic, and traumatic injuries. The maladaptive role of polyamine catabolism in the mediation of AKI and other injuries has been clearly demonstrated. This review will examine the biochemical and mechanistic basis of tissue damage brought about by enhanced polyamine degradation and discuss the potential of therapeutic interventions that target polyamine catabolic enzymes or their byproducts for the treatment of AKI.

Keywords:  3-aminopropanal; H2O2; MDL72527; acute kidney injury; catalase; cell cycle; diminazene aceturate; endoplasmic reticulum stress/unfolded protein response; innate immune response; lysosome; mitochondria; phenelzine; polyamine; polyamine catabolism; spermidine; spermine; spermine oxidase; spermine/spermidine N1-acetyltransferase

DOI:  https://doi.org/10.3390/ijms20194790
Front Microbiol. 2019 ;10 1996

Polyamine Synthesis Effects Capsule Expression by Reduction of Precursors in Streptococcus pneumoniae.

Moses B Ayoola, Leslie A Shack, Mary F Nakamya, Justin A Thornton, Edwin Swiatlo, Bindu Nanduri.

  Streptococcus pneumoniae (pneumococcus, Spn) colonizes the human nasopharynx asymptomatically but can cause infections such as otitis media, and invasive pneumococcal disease such as community-acquired pneumonia, meningitis, and sepsis. Although the success of Spn as a pathogen can be attributed to its ability to synthesize and regulate capsular polysaccharide (CPS) for survival in the host, the mechanisms of CPS regulation are not well-described. Recent studies from our lab demonstrate that deletion of a putative polyamine biosynthesis gene (ΔcadA) in Spn TIGR4 results in the loss of the capsule. In this study, we characterized the transcriptome and metabolome of ΔcadA and identified specific mechanisms that could explain the regulatory role of polyamines in pneumococcal CPS biosynthesis. Our data indicate that impaired polyamine synthesis impacts galactose to glucose interconversion via the Leloir pathway which limits the availability of UDP-galactose, a precursor of serotype 4 CPS, and UDP-N-acetylglucosamine (UDP-GlcNAc), a nucleotide sugar precursor that is at the intersection of CPS and peptidoglycan repeat unit biosynthesis. Reduced carbon flux through glycolysis, coupled with altered fate of glycolytic intermediates further supports impaired synthesis of UDP-GlcNAc. A significant increase in the expression of transketolases indicates a potential shift in carbon flow toward the pentose phosphate pathway (PPP). Higher PPP activity could constitute oxidative stress responses in ΔcadA which warrants further investigation. The results from this study clearly demonstrate the potential of polyamine synthesis, targeted for cancer therapy in human medicine, for the development of novel prophylactic and therapeutic strategies for treating bacterial infections.

Keywords:  Leloir pathway; Streptococcus pneumoniae; capsule; glycolysis; pentose phosphate pathway; peptidoglycan; polyamines

DOI:  https://doi.org/10.3389/fmicb.2019.01996
Metabolites. 2019 Sep 19. pii: E192. [Epub ahead of print]9(9):

Involvement of Spermidine in the Reduced Lifespan of Caenorhabditis elegans During Vitamin B12 Deficiency.

Tomohiro Bito, Naho Okamoto, Kenji Otsuka, Yukinori Yabuta, Jiro Arima, Tsuyoshi Kawano, Fumio Watanabe.

  Vitamin B12 deficiency leads to various symptoms such as neuropathy, growth retardation, and infertility. Vitamin B12 functions as a coenzyme for two enzymes involved in amino acid metabolisms. However, there is limited information available on whether amino acid disorders caused by vitamin B12 deficiency induce such symptoms. First, free amino acid levels were determined in vitamin B12-deficient Caenorhabditis elegans to clarify the mechanisms underlying the symptoms caused by vitamin B12 deficiency. Various amino acids (valine, leucine, isoleucine, methionine, and cystathionine, among others) metabolized by vitamin B12-dependent enzymes were found to be significantly changed during conditions of B12 deficiency, which indirectly affected certain amino acids metabolized by vitamin B12-independent enzymes. For example, ornithine was significantly increased during vitamin B12 deficiency, which also significantly increased arginase activity. The accumulation of ornithine during vitamin B12 deficiency constitutes the first report. In addition, the biosynthesis of spermidine from ornithine was significantly decreased during vitamin B12 deficiency, likely due to the reduction of S-adenosylmethionine as a substrate for S-adenosylmethionine decarboxylase, which catalyzes the formation of spermidine. Moreover, vitamin B12 deficiency also demonstrated a significant reduction in worm lifespan, which was partially recovered by the addition of spermidine. Collectively, our findings suggest that decreased spermidine is one factor responsible for reduced lifespan in vitamin B12-deficient worms.

Keywords:  Caenorhabditis elegans; arginase; ornithine; spermidine; vitamin B12

DOI:  https://doi.org/10.3390/metabo9090192
Plant Physiol Biochem. 2019 Sep 16. pii: S0981-9428(19)30365-1. [Epub ahead of print]144 1-13

Spermine application alleviates salinity induced growth and photosynthetic inhibition in Solanum lycopersicum by modulating osmolyte and secondary metabolite accumulation and differentially regulating antioxidant metabolism.

Mohammad Abass Ahanger, Cheng Qin, Qi Maodong, Xu Xue Dong, Parvaiz Ahmad, Elsayed Fathi Abd Allah, Lixin Zhang.

  Influence of exogenously applied spermine (Spm) on growth and salinity stress tolerance in tomato was investigated. Salinity reduced growth, chlorophyll synthesis and mineral uptake leading to significant reduction in photosynthesis, however Spm application proved beneficial in alleviating the decline to considerable extent. Applied Spm improved nitrate reductase activity, δ-amino levulinic acid content and gas exchange parameters more apparently at 100 μM than 50 μM concentrations. Spm application enhanced the accumulation of compatible osmolytes including proline, glycine betaine and sugars leading to greater tissue water content and photosynthesis. Salinity stress induced oxidative effects were mitigated by Spm treatment reflected interms of reduced accumulation of reactive oxygen species and the activities of protease and lipoxygenase, hence leading to membrane strengthening and protection of their function. Differential influence of exogenous Spm was evident on the functioning of antioxidant system with SOD, GR and APX activities much higher in Spm treated seedlings than CAT and DHAR. Increased synthesis of GSH, AsA and tocopherol in Spm treated seedlings was obvious thereby helping in maintaining the redox homeostasis and the enzymatic antioxidant functioning. Interestingly Spm application maintained the nitric oxide levels higher than control under normal condition while as lowered its concentrations in salinity stressed seedlings depicting existence of probable interaction. Activities of polyamine metabolizing enzymes was up-regulated and the accumulation of secondary metabolites including phenols and flavonoids also increased due to Spm application. Further studies are required to understand the mechanisms clearly.

Keywords:  Antioxidant system; Lipoxygenase; Oxidative stress; Protease; Secondary metabolites; Solanum lycopersicum; Spermine

DOI:  https://doi.org/10.1016/j.plaphy.2019.09.021
J Alzheimers Dis. 2019 Sep 24.

Discovery of Gut Bacteria Specific to Alzheimer's Associated Diseases is a Clue to Understanding Disease Etiology: Meta-Analysis of Population-Based Data on Human Gut Metagenomics and Metabolomics.

Elena L Paley.

  Alzheimer's disease (AD)-associated sequence (ADAS) of cultured fecal bacteria was discovered in human gut targeted screening. This study provides important information to expand our current understanding of the structure/activity relationship of ADAS and putative inhibitors/activators that are potentially involved in ADAS appearance/disappearance. The NCBI database analysis revealed that ADAS presents at a large proportion in American Indian Oklahoman (C&A) with a high prevalence of obesity/diabetes and in colorectal cancer (CRC) patients from the US and China. An Oklahoman non-native group (NNI) showed no ADAS. Comparison of two large US populations reveals that ADAS is more frequent in individuals aged ≥66 and in females. Prevalence and levels of fecal metabolites are altered in the C&A and CRC groups versus controls. Biogenic amines (histamine, tryptamine, tyramine, phenylethylamine, cadaverine, putrescine, agmatine, spermidine) that present in food and are produced by gut microbiota are significantly higher in C&A (e.g., histamine/histidine 95-fold) versus NNI (histamine/histidine 16-fold). The majority of these bio-amines are cytotoxic at concentrations found in food. Inositol phosphate signaling implicated in AD is altered in C&A and CRC. Tryptamine stimulated accumulation of inositol phosphate. The seizure-eliciting tryptamine induced cytoplasmic vacuolization and vesiculation with cell fragmentation. Present additions of ADAS-carriers at different ages including infants led to an ADAS-comprising human sample size of 2,830 from 27 studies from four continents (North America, Australia, Asia, Europe). Levels of food-derived monoamine oxidase inhibitors and anti-bacterial compounds, the potential modulators of ADAS-bacteria growth and biogenic amine production, were altered in C&A versus NNI. ADAS is attributable to potentially modifiable risk factors of AD associated diseases.

Keywords:  Alzheimer’s human gut metagenome; angiogenesis; biogenic amines; food; gut metabolomics; protein biosynthesis

DOI:  https://doi.org/10.3233/JAD-190873
Evol Med Public Health. 2019 ;2019(1): 149-168

Comparative psychopharmacology of autism and psychotic-affective disorders suggests new targets for treatment.

Bernard J Crespi.

  The first treatments showing effectiveness for some psychiatric disorders, such as lithium for bipolar disorder and chlorpromazine for schizophrenia, were discovered by accident. Currently, psychiatric drug design is seen as a scientific enterprise, limited though it remains by the complexity of brain development and function. Relatively few novel and effective drugs have, however, been developed for many years. The purpose of this article is to demonstrate how evolutionary biology can provide a useful framework for psychiatric drug development. The framework is based on a diametrical nature of autism, compared with psychotic-affective disorders (mainly schizophrenia, bipolar disorder and depression). This paradigm follows from two inferences: (i) risks and phenotypes of human psychiatric disorders derive from phenotypes that have evolved along the human lineage and (ii) biological variation is bidirectional (e.g. higher vs lower, faster vs slower, etc.), such that dysregulation of psychological traits varies in two opposite ways. In this context, the author review the evidence salient to the hypothesis that autism and psychotic-affective disorders represent diametrical disorders in terms of current, proposed and potential psychopharmacological treatments. Studies of brain-derived neurotrophic factor, the PI3K pathway, the NMDA receptor, kynurenic acid metabolism, agmatine metabolism, levels of the endocannabinoid anandamide, antidepressants, anticonvulsants, antipsychotics, and other treatments, demonstrate evidence of diametric effects in autism spectrum disorders and phenotypes compared with psychotic-affective disorders and phenotypes. These findings yield insights into treatment mechanisms and the development of new pharmacological therapies, as well as providing an explanation for the longstanding puzzle of antagonism between epilepsy and psychosis. Lay Summary: Consideration of autism and schizophrenia as caused by opposite alterations to brain development and function leads to novel suggestions for pharmacological treatments.

Keywords:  autism; evolution; psychopharmacology; psychosis; schizophrenia

DOI:  https://doi.org/10.1093/emph/eoz022