bims-polyam 2022-01-23 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022‒01‒23
ten papers selected by
Sebastian J. Hofer
University of Graz

Biogenic Polyamines and Related Metabolites.
Unravelling the multi-faceted regulatory role of polyamines in plant biotechnology, transgenics and secondary metabolomics.
Polyamines: Α bioenergetic smart switch for plant protection and development.
Metabolism of Imidazole Dipeptides, Taurine, Branched-Chain Amino Acids, and Polyamines of the Breast Muscle Are Affected by Post-Hatch Development in Chickens.
Development of New Antimicrobial Oleanonic Acid Polyamine Conjugates.
New Analogs of Polyamine Toxins from Spiders and Wasps: Liquid Phase Fragment Synthesis and Evaluation of Antiproliferative Activity.
A Tear Metabolomic Profile Showing Increased Ornithine Decarboxylase Activity and Spermine Synthesis in Thyroid-Associated Orbitopathy.
In Silico Research of New Therapeutics Rotenoids Derivatives against Leishmania amazonensis Infection.
Irradiation Causes Alterations of Polyamine, Purine, and Sulfur Metabolism in Red Blood Cells and Multiple Organs.
Metabolic reprogramming in a slowly developing orthologous model of polycystic kidney disease.

Biomolecules. 2021 Dec 22. pii: 14. [Epub ahead of print]12(1):

Biogenic Polyamines and Related Metabolites.

Alexander V Ivanov, Alex R Khomutov.

The specific regulation of cell metabolism is one of cornerstones of biochemistry [...].

DOI: https://doi.org/10.3390/biom12010014
Appl Microbiol Biotechnol. 2022 Jan 18.

Unravelling the multi-faceted regulatory role of polyamines in plant biotechnology, transgenics and secondary metabolomics.

Samapika Nandy, Tuyelee Das, Champa Keeya Tudu, Tulika Mishra, Mimosa Ghorai, Vijaykumar Shivaji Gadekar, Uttpal Anand, Manoj Kumar, Tapan Behl, Nusrat K Shaikh, Niraj Kumar Jha, Mahipal S Shekhawat, Devendra Kumar Pandey, Padmanabh Dwivedi, Radha, Abhijit Dey.

  Polyamines (PAs) are ubiquitous low-molecular-weight, aliphatic compounds with wide as well as complex application in fundamental areas of plant growth and development. PAs are mediator of basic metabolism of organisms which include cell division and differentiation, biotic and abiotic stress tolerance, reversal of oxidative damage, stabilization of nucleic acids, and protein and phospholipid binding. In plants, it attributes in direct and indirect organogenesis, endogenous phytohormone regulation, cellular compartmentalization, fruit and flower development, senescence, and secondary metabolite production which are highly tuned as first line of defense response. There are several aspects of polyamine-directed mechanism that regulate overall plant growth in vitro and in vivo. In the present review, we have critically discussed the role played by polyamine on the enhanced production of bioactive natural products and how the same polyamines are functioning against different environmental stress conditions, i.e., salinity, drought, high CO2 content, herbivory, and physical wounding. The role of polyamines on elicitation process has been highlighted previously, but it is important to note that its activity as growth regulator under in vitro condition is correlated with an array of intertwined mechanism and physiological tuning. Medicinal plants under different developmental stages of micropropagation are characterized with different functional aspects and regulatory changes during embryogenesis and organogenesis. The effect of precursor molecules as well as additives and biosynthetic inhibitors of polyamines in rhizogenesis, callogenesis, tuberization, embryogenesis, callus formation, and metabolite production has been discussed thoroughly. The beneficial effect of exogenous application of PAs in elicitation of secondary metabolite production, plant growth and morphogenesis and overall stress tolerance are summarized in this present work. KEY POINTS: • Polyamines (PAs) play crucial roles in in vitro organogenesis. • PAs elicitate bioactive secondary metabolites (SMs). • Transgenic studies elucidate and optimize PA biosynthetic genes coding SMs.

Keywords:  Plant biotechnology; Polyamines; Putrescine; Secondary metabolomics; Transgenics

DOI:  https://doi.org/10.1007/s00253-021-11748-3
J Plant Physiol. 2022 Jan 13. pii: S0176-1617(22)00004-9. [Epub ahead of print]270 153618

Polyamines: Α bioenergetic smart switch for plant protection and development.

Eleni Navakoudis, Kiriakos Kotzabasis.

  The present review highlights the bioenergetic role of polyamines in plant protection and development and proposes a universal model for describing polyamine-mediated stress responses. Any stress condition induces an excitation pressure on photosystem II by reforming the photosynthetic apparatus. To control this phenomenon, polyamines act directly on the molecular structure and function of the photosynthetic apparatus as well as on the components of the chemiosmotic proton-motive force (ΔpH/Δψ), thus regulating photochemical (qP) and non-photochemical quenching (NPQ) of energy. The review presents the mechanistic characteristics that underline the key role of polyamines in the structure, function, and bioenergetics of the photosynthetic apparatus upon light adaptation and/or under stress conditions. By following this mechanism, it is feasible to make stress-sensitive plants to be tolerant by simply altering their polyamine composition (especially the ratio of putrescine to spermine), either chemically or by light regulation.

Keywords:  Abiotic stress; Photoadaptation; Photodevelopment; Photosynthesis; Polyamines; Stress tolerance

DOI:  https://doi.org/10.1016/j.jplph.2022.153618
Metabolites. 2022 Jan 17. pii: 86. [Epub ahead of print]12(1):

Metabolism of Imidazole Dipeptides, Taurine, Branched-Chain Amino Acids, and Polyamines of the Breast Muscle Are Affected by Post-Hatch Development in Chickens.

Shozo Tomonaga, Takahiro Kawase, Takamitsu Tsukahara, Yoshiyuki Ohta, Jun-Ichi Shiraishi.

  To explore metabolic characteristics during the post-hatch developmental period, metabolomic analyses of breast muscle and plasma were performed in chickens. The most significant growth-related changes in metabolite levels were observed between seven and 28 days of age. Some of these metabolites are essential nutrients or reported as growth-promoting metabolites. In the muscle, two imidazole dipeptides-carnosine and its methylated metabolite, anserine-increased with the development. These dipeptide levels may be, in part, regulated transcriptionally because in the muscle mRNA levels of carnosine synthase and carnosine methylation enzyme increased. In contrast, taurine levels in the muscle decreased. This would be substrate availability-dependent because some upstream metabolites decreased in the muscle or plasma. In branched-chain amino acid metabolism, valine, leucine, and isoleucine decreased in the muscle, while some of their downstream metabolites decreased in the plasma. The polyamines, putrescine and spermidine, decreased in the muscle. Furthermore, mRNA levels associated with insulin/insulin-like growth factor 1 signaling, which play important roles in muscle growth, increased in the muscle. These results indicate that some metabolic pathways would be important to clarify metabolic characteristics and/or growth of breast muscle during the post-hatch developmental period in chickens.

Keywords:  carnosine; growth; insulin/IGF-1 signaling; metabolomics; plasma; skeletal muscle

DOI:  https://doi.org/10.3390/metabo12010086
Antibiotics (Basel). 2022 Jan 12. pii: 94. [Epub ahead of print]11(1):

Development of New Antimicrobial Oleanonic Acid Polyamine Conjugates.

Elmira F Khusnutdinova, Véronique Sinou, Denis A Babkov, Oxana Kazakova, Jean Michel Brunel.

  A series of oleanolic acid derivatives holding oxo- or 3-N-polyamino-3-deoxy-substituents at C3 as well as carboxamide function at C17 with different long chain polyamines have been synthesized and evaluated for antimicrobial activities. Almost all series presented good to moderate activity against Gram-positive S. aureus, S. faecalis and B. cereus bacteria with minimum inhibitory concentration (MIC) values from 3.125 to 200 µg/mL. Moreover, compounds possess important antimicrobial activities against Gram-negative E. coli, P. aeruginosa, S. enterica, and EA289 bacteria with MICs ranging from 6.25 to 200 µg/mL. The testing of ability to restore antibiotic activity of doxycycline and erythromycin at a 2 µg/mL concentration in a synergistic assay showed that oleanonic acid conjugate with spermine spacered through propargylamide led to a moderate improvement in terms of antimicrobial activities of the different selected combinations against both P. aeruginosa and E. coli. The study of mechanism of action of the lead conjugate 2i presenting a N-methyl norspermidine moiety showed the effect of disruption of the outer bacterial membrane of P. aeruginosa PA01 cells. Computational ADMET profiling renders this compound as a suitable starting point for pharmacokinetic optimization. These results give confidence to the successful outcome of bioconjugation of polyamines and oleanane-type triterpenoids in the development of antimicrobial agents.

Keywords:  antibiotic enhancers; antimicrobial activities; oleanolic acid; triterpenic polyamine conjugates

DOI:  https://doi.org/10.3390/antibiotics11010094
Molecules. 2022 Jan 10. pii: 447. [Epub ahead of print]27(2):

New Analogs of Polyamine Toxins from Spiders and Wasps: Liquid Phase Fragment Synthesis and Evaluation of Antiproliferative Activity.

Christos Vassileiou, Stefania Kalantzi, Eleanna Vachlioti, Constantinos M Athanassopoulos, Christos Koutsakis, Zoi Piperigkou, Nikos Karamanos, Theodora Stivarou, Peggy Lymberi, Konstantinos Avgoustakis, Dionissios Papaioannou.

  Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic carboxylic acids, which have been recently shown to present antiproliferative activity. Ten analogs of the spider PATs Agel 416, HO-416b, and JSTX-3 and the wasp PAT PhTX-433 were synthesized with changes in the lipophilic head group and/or the PA chain, and their antiproliferative activity was evaluated on MCF-7 and MDA-MB-231 breast cancer cells, using Agel 416 and HO-416b as reference compounds. All five analogs of PhTX-433 were of very low activity on both cell lines, whereas the two analogs of JSTX-3 were highly active only on the MCF-7 cell line with IC50 values of 2.63-2.81 μΜ. Of the remaining three Agel 416 or HO-416b analogs, only the one with the spermidine chain was highly active on both cells with IC50 values of 3.15-12.6 μM. The two most potent compounds in this series, Agel 416 and HO-416b, with IC50 values of 0.09-3.98 μΜ for both cell lines, were found to have a very weak cytotoxic effect on the MCF-12A normal breast cells. The present study points out that the structure of both the head group and the PA chain determine the strength of the antiproliferative activity of PATs and their selectivity towards different cells.

Keywords:  (indol-3-yl)acetic acid; 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid; antiproliferative activity; breast cancer cells; cytotoxicity; hydroxy amino acids; lipophilic head groups; polyamine toxins; polyamines; propargylglycine

DOI:  https://doi.org/10.3390/molecules27020447
J Clin Med. 2022 Jan 13. pii: 404. [Epub ahead of print]11(2):

A Tear Metabolomic Profile Showing Increased Ornithine Decarboxylase Activity and Spermine Synthesis in Thyroid-Associated Orbitopathy.

Benjamin Billiet, Juan Manuel Chao de la Barca, Marc Ferré, Jeanne Muller, Anaïs Vautier, Sophie Assad, Odile Blanchet, Lydie Tessier, Céline Wetterwald, Justine Faure, Geoffrey Urbanski, Gilles Simard, Delphine Mirebeau-Prunier, Patrice Rodien, Philippe Gohier, Pascal Reynier.

  About half of patients with Graves' disease develop an orbitopathy related to an inflammatory expansion of the periorbital adipose tissue and muscles. We used a targeted metabolomic approach measuring 188 metabolites by mass spectrometry to compare the metabolic composition of tears in patients with active (n = 21) versus inactive (n = 24) thyroid-associated orbitopathy. Among the 44 metabolites accurately measured, 8 showed a significant alteration of their concentrations between the two groups. Two short-chain acylcarnitines, propionylcarnitine and butyrylcarnitine, and spermine showed increased concentrations in the tears of patients with active orbitopathy, whereas ornithine, glycine, serine, citrulline and histidine showed decreased concentrations in this group. In addition, the ratio putrescine/ornithine, representing the activity of ornithine decarboxylase, was significantly increased in patients with active compared to inactive orbitopathy (p = 0.0011, fold change 3.75). The specificity of this candidate biomarker was maintained when compared to a control group with unclassified dry eye disease. Our results suggest that the stimulation of ornithine decarboxylase by TSH receptor autoantibodies in orbital fibroblasts could lead to increased synthesis of spermine, through the increased activity of ornithine decarboxylase, that may contribute to periorbital expansion in Graves' ophthalmopathy.

Keywords:  Graves’ ophthalmopathy; metabolomics; ornithine decarboxylase; spermine; thyroid-associated orbitopathy

DOI:  https://doi.org/10.3390/jcm11020404
Biology (Basel). 2022 Jan 14. pii: 133. [Epub ahead of print]11(1):

In Silico Research of New Therapeutics Rotenoids Derivatives against Leishmania amazonensis Infection.

Adrián Vicente-Barrueco, Ángel Carlos Román, Trinidad Ruiz-Téllez, Francisco Centeno.

  Yearly, 1,500,000 cases of leishmaniasis are diagnosed, causing thousands of deaths. To advance in its therapy, we present an interdisciplinary protocol that unifies ethnobotanical knowledge of natural compounds and the latest bioinformatics advances to respond to an orphan disease such as leishmaniasis and specifically the one caused by Leishmania amazonensis. The use of ethnobotanical information serves as a basis for the development of new drugs, a field in which computer-aided drug design (CADD) has been a revolution. Taking this information from Amazonian communities, located in the area with a high prevalence of this disease, a protocol has been designed to verify new leads. Moreover, a method has been developed that allows the evaluation of lead molecules, and the improvement of their affinity and specificity against therapeutic targets. Through this approach, deguelin has been identified as a good lead to treat the infection due to its potential as an ornithine decarboxylase (ODC) inhibitor, a key enzyme in Leishmania development. Using an in silico-generated combinatorial library followed by docking approaches, we have found deguelin derivatives with better affinity and specificity against ODC than the original compound, suggesting that this approach could be adapted for developing new drugs against leishmaniasis.

Keywords:  CADD; Leishmania amazonensis; ODC; deguelin; docking; protein modeling

DOI:  https://doi.org/10.3390/biology11010133
J Proteome Res. 2022 Jan 19.

Irradiation Causes Alterations of Polyamine, Purine, and Sulfur Metabolism in Red Blood Cells and Multiple Organs.

Micaela Kalani Roy, Francesca La Carpia, Francesca Cendali, Sebastian Fernando, Chiara Moriconi, Boguslaw S Wojczyk, Lin Wang, Travis Nemkov, Eldad A Hod, Angelo D'Alessandro.

  Investigating the metabolic effects of radiation is critical to understand the impact of radiotherapy, space travel, and exposure to environmental radiation. In patients undergoing hemopoietic stem cell transplantation, iron overload is a common risk factor for poor outcomes. However, no studies have interrogated the multiorgan effects of these treatments concurrently. Herein, we use a model that recapitulates transfusional iron overload, a condition often observed in chronically transfused patients. We applied an omics approach to investigate the impact of both the iron load and irradiation on the host metabolome. The results revealed dose-dependent effects of irradiation in the red blood cells, plasma, spleen, and liver energy and redox metabolism. Increases in polyamines and purine salvage metabolites were observed in organs with high oxygen consumption including the heart, kidneys, and brain. Irradiation also impacted the metabolism of the duodenum, colon, and stool, suggesting a potential effect on the microbiome. Iron infusion affected the response to radiation in the organs and blood, especially in erythrocyte polyamines and spleen antioxidant metabolism, and affected glucose, methionine, and glutathione systems and tryptophan metabolism in the liver, stool, and the brain. Together, the results suggest that radiation impacts metabolism on a multiorgan level with a significant interaction of the host iron status.

Keywords:  iron; mass spectrometry; metabolism; methionine; organs; polyamine; radiation

DOI:  https://doi.org/10.1021/acs.jproteome.1c00912
Am J Physiol Renal Physiol. 2022 Jan 17.

Metabolic reprogramming in a slowly developing orthologous model of polycystic kidney disease.

Katharina Hopp, Emily K Kleczko, Berenice Y Gitomer, Michel Chonchol, Jost Klawitter, Uwe Christians, Jelena Klawitter.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. There is accumulating evidence suggesting that there are shared cellular mechanisms responsible for cystogenesis in human and murine PKD and that reprograming of metabolism is a key disease feature. In this study we utilized a targeted metabolomics approach in an orthologous mouse model of PKD (Pkd1RC/RC) to investigate the metabolic modifications a cystic kidney undergoes during disease progression. Using the KEGG pathway database, we identified several biologically relevant metabolic pathways which were altered early in this disease (in 3-month-old Pkd1RC/RC mice), the most highly represented being arginine biosynthesis and metabolism and tryptophan and phenylalanine metabolism. During the next 6 months of disease progression, multiple uremic solutes accumulated in the kidney of cystic mice including several established markers of oxidative stress and endothelial dysfunction (allantoin, asymmetric dimethylarginine (ADMA), homocysteine, malondialdehyde, methionine sulfoxide, and S-adenosylhomocysteine (SAH)). Levels of kynurenines and polyamines were also augmented in kidneys of Pkd1RC/RC versus wildtype mice, as were the levels of bacteria-produced indoles whose increase within PKD kidneys suggests microbial dysbiosis. In summary, we confirmed previously published and identified novel metabolic markers and pathways of PKD progression that may prove helpful for diagnosis and monitoring of cystic kidney disease in patients. Furthermore, they provide targets for novel therapeutic approaches that deserve further study and hint towards currently understudied pathomechanism.

Keywords:  ADPKD; Metabolomics; kidney-gut axis; tryptophan metabolism

DOI:  https://doi.org/10.1152/ajprenal.00262.2021