bims-polyam 2020-12-06 papers

on Polyamines

Issue of 2020–12–06
eight papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Podocyte healthy self-eating boosted by a spermidine meal?
Dietary Polyamines Intake and Risk of Colorectal Cancer: A Case-Control Study.
Polyamines Counteract Carbonate-Driven Proteasome Stalling in Alkaline Conditions.
Alternative pathways utilize or circumvent putrescine for biosynthesis of putrescine-containing rhizoferrin.
Untargeted Metabolomics and Polyamine Profiling in Serum before and after Surgery in Colorectal Cancer Patients.
Tailoring of silica-based nanoporous pod by spermidine multi-activity.
Chronic stress decreases ornithine decarboxylase expression and protects against 1,2-dimethylhydrazine-induced colon carcinogenesis.
Acylpolyamine Mygalin as a TLR4 Antagonist Based on Molecular Docking and In Vitro Analyses.

Kidney Int. 2020 Dec;pii: S0085-2538(20)30947-9. [Epub ahead of print]98(6): 1390-1392

Podocyte healthy self-eating boosted by a spermidine meal?

Olivia Lenoir, Pierre-Louis Tharaux.

The mechanisms sustaining a high level of autophagy in podocytes are not well delineated. Seminal studies had unraveled that the polyamine pathway is involved in the regulation of aging and autophagy. Polyamines (e.g., spermine, spermidine, and putrescine) are ubiquitous molecules essential for the physiological processes, including cell growth, development, and differentiation. Liang et al. examined the role of ornithine decarboxylase, and spermidine synthase, and demonstrated that endogenous spermidine is required to maintain intact podocyte autophagy.

DOI: https://doi.org/10.1016/j.kint.2020.07.032
Nutrients. 2020 Nov 22. pii: E3575. [Epub ahead of print]12(11):

Dietary Polyamines Intake and Risk of Colorectal Cancer: A Case-Control Study.

Chu-Yi Huang, Yu-Jing Fang, Alinuer Abulimiti, Xia Yang, Lei Li, Kai-Yan Liu, Xin Zhang, Xiao-Li Feng, Yu-Ming Chen, Cai-Xia Zhang.

  Polyamines (including putrescine, spermidine, and spermine) are small, cationic molecules that are necessary for cell proliferation and differentiation. Few studies have examined the association of dietary polyamines intake with colorectal cancer risk. The aim of this study was to evaluate total polyamines, putrescine, spermidine, and spermine intake in relation to colorectal cancer risk in China. In total, 2502 colorectal cancer cases and 2538 age-(5-year interval) and sex-matched controls were recruited from July 2010 to April 2019. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated by multivariable unconditional logistic regression after adjustment for various potential confounding factors. Higher intake of total polyamine, putrescine and spermidine was significantly associated with reduced risk of colorectal cancer. The adjusted ORs for the highest compared with the lowest quartile of intake were 0.60 (95% CI 0.50, 0.72; Ptrend < 0.001) for total polyamines, 0.35 (95% CI 0.29, 0.43; Ptrend < 0.001) for putrescine and 0.79 (95% CI 0.66, 0.95; Ptrend = 0.001) for spermidine, respectively. However, higher intake of spermine was associated with increased risk of colorectal cancer, with an adjusted OR of 1.58 (95% CI 1.29, 1.93; Ptrend < 0.001). This data indicate that higher intake of total polyamines, putrescine and spermidine, as well as lower intake of spermine, is associated with a decreased risk of colorectal cancer.

Keywords:  colorectal cancer; polyamine; putrescine; spermidine; spermine

DOI:  https://doi.org/10.3390/nu12113575
Biomolecules. 2020 Nov 24. pii: E1597. [Epub ahead of print]10(12):

Polyamines Counteract Carbonate-Driven Proteasome Stalling in Alkaline Conditions.

Anna A Kudriaeva, George A Saratov, Alena N Kaminskaya, Vasiliy I Vladimirov, Petro Yu Barzilovich, Alexey A Belogurov.

  Cancer cells tend to increase intracellular pH and, at the same time, are known to intensively produce and uptake polyamines such as spermine. Here, we show that various amines, including biogenic polyamines, boost the activity of proteasomes in a dose-dependent manner. Proteasome activity in the classical amine-containing buffers, such as 2-(N-morpholino)ethanesulfonic acid (MES), Tris, (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), glycylglycine, bis-Tris propane, and bicine, has a skewed distribution with a maximum at pH of 7.0-8.0. The activity of proteasomes in buffers containing imidazole and bis-Tris is maintained almost on the same level, in the pH range of 6.5-8.5. The third type of activation is observed in buffers based on the amino acids arginine and ornithine, as well as the natural polyamines spermine and spermidine. Proteasome activity in these buffers is dramatically increased at pH values greater than 7.5. Anionic buffers such as phosphate or carbonate, in contrast, inhibit proteasome activity during alkalization. Importantly, supplementation of a carbonate-phosphate buffer with spermine counteracts carbonate-driven proteasome stalling in alkaline conditions, predicting an additional physiological role of polyamines in maintaining the metabolism and survival of cancer cells.

Keywords:  activation; carbonate; inhibition; intracellular alkalization; polyamine; proteasome; spermine

DOI:  https://doi.org/10.3390/biom10121597
J Biol Chem. 2020 Dec 04. pii: jbc.RA120.016738. [Epub ahead of print]

Alternative pathways utilize or circumvent putrescine for biosynthesis of putrescine-containing rhizoferrin.

Bin Li, Xiaoyi Deng, Sok Ho Kim, Leann Buhrow, Diana R Tomchick, Margaret A Phillips, Anthony J Michael.

  The siderophore rhizoferrin (N 1,N 4-dicitrylputrescine) is produced in fungi and bacteria to scavenge iron. Putrescine-producing bacterium Ralstonia pickettii synthesizes rhizoferrin and encodes a single nonribosomal peptide synthetase-independent siderophore (NIS) synthetase. From biosynthetic logic, we hypothesized that this single enzyme is sufficient for rhizoferrin biosynthesis. We confirmed this by expression of R. pickettii NIS synthetase in E. coli, resulting in rhizoferrin production. This was further confirmed in vitro using the recombinant NIS synthetase, synthesizing rhizoferrin from putrescine and citrate. Heterologous expression of homologous lbtA from Legionella pneumophila, required for rhizoferrin biosynthesis in that species, produced siderophore activity in E. coli Rhizoferrin is also synthesized by Francisella tularensis and F. novicida, but unlike R. pickettii or L. pneumophila, Francisella species lack putrescine biosynthetic pathways due to genomic decay. Francisella encodes a NIS synthetase FslA/FigA and an ornithine decarboxylase (ODC) homologue FslC/FigC, required for rhizoferrin biosynthesis. ODC produces putrescine from ornithine but we show here in vitro that FigA synthesizes N-citrylornithine, and FigC is an N-citrylornithine decarboxylase that together synthesize rhizoferrin without using putrescine. We co-expressed F. novicida figA and figC in E. coli, and produced rhizoferrin. A 2.1Å X-ray crystal structure of the FigC N-citrylornithine decarboxylase reveals how the larger substrate is accommodated and how active site residues have changed to recognize N-citrylornithine. FigC belongs to a new subfamily of alanine racemase-fold PLP-dependent decarboxylases that are not involved in polyamine biosynthesis. These data reveal a natural product biosynthetic workaround that evolved to bypass a missing precursor and re-establish it in the final structure.

Keywords:  Francisella; citrate; decarboxylase; enzyme structure; ornithine; polyamine; putrescine; rhizoferrin; secondary metabolism; siderophore

DOI:  https://doi.org/10.1074/jbc.RA120.016738
Metabolites. 2020 Nov 27. pii: E487. [Epub ahead of print]10(12):

Untargeted Metabolomics and Polyamine Profiling in Serum before and after Surgery in Colorectal Cancer Patients.

Yu Ra Lee, Ki-Yong An, Justin Jeon, Nam Kyu Kim, Ji Won Lee, Jongki Hong, Bong Chul Chung.

  Colorectal cancer is one of the most prevalent cancers in Korea and globally. In this study, we aimed to characterize the differential serum metabolomic profiles between pre-operative and post-operative patients with colorectal cancer. To investigate the significant metabolites and metabolic pathways associated with colorectal cancer, we analyzed serum samples from 68 patients (aged 20-71, mean 57.57 years). Untargeted and targeted metabolomics profiling in patients with colorectal cancer were performed using liquid chromatography-mass spectrometry. Untargeted analysis identified differences in sphingolipid metabolism, steroid biosynthesis, and arginine and proline metabolism in pre- and post-operative patients with colorectal cancer. We then performed quantitative target profiling of polyamines, synthesized from arginine and proline metabolism, to identify potential polyamines that may serve as effective biomarkers for colorectal cancer. Results indicate a significantly reduced serum concentration of putrescine in post-operative patients compared to pre-operative patients. Our metabolomics approach provided insights into the physiological alterations in patients with colorectal cancer after surgery.

Keywords:  biomarker; colorectal cancer; liquid chromatography-mass spectrometry; metabolomics; polyamine; tumorectomy

DOI:  https://doi.org/10.3390/metabo10120487
Sci Rep. 2020 Dec 03. 10(1): 21142

Tailoring of silica-based nanoporous pod by spermidine multi-activity.

Giulia Della Rosa, Riccardo Di Corato, Sara Carpi, Beatrice Polini, Antonietta Taurino, Lorena Tedeschi, Paola Nieri, Rosaria Rinaldi, Alessandra Aloisi.

Ubiquitous in nature, polyamines (PAs) are a class of low-molecular aliphatic amines critically involved in cell growth, survival and differentiation. The polycation behavior is validated as a successful strategy in delivery systems to enhance oligonucleotide loading and cellular uptake. In this study, the chemical features and the functional roles of the PA spermidine are synergistically exploited in the synthesis and bioactive functionalization of SiO2-based structures. Inspired by biosilicification, the role of spermidine is assessed both as catalyst and template in a biomimetic one-pot synthesis of dense silica-based particles (SPs) and as a competitive agent in an interfacial reassembly strategy, to empty out SPs and generate spermidine-decorated hollow silica nanoporous pods (spd-SNPs). Spermidine bioactivity is then employed for targeting tumor cell over-expressed polyamine transport system (PTS) and for effective delivery of functional miRNA into melanoma cells. Spermidine decoration promotes spd-SNP cell internalization mediated by PTS and along with hollow structure enhances oligonucleotide loading. Accordingly, the functional delivery of the tumor suppressor miR-34a 3p resulted in intracellular accumulation of histone-complexed DNA fragments associated with apoptosis. Overall, the results highlight the potential of spd-SNP as a multi-agent anticancer therapy.

DOI: https://doi.org/10.1038/s41598-020-77957-4
Mol Biol Rep. 2020 Dec 01.

Chronic stress decreases ornithine decarboxylase expression and protects against 1,2-dimethylhydrazine-induced colon carcinogenesis.

Edgar Oswaldo Zamora-González, Patricia Castro-Félix, María Del Rosario Huizar-López, Josefina Casas-Solís, María de la Luz Blanca Isabel Marques-González, Martha Fabiola Martin Del Campo-Solís, Anne Santerre.

  Biological response to stress depends on the type, timing, and severity of the stressor. Acute stressful environments may positively activate molecular and cellular mechanisms to favor adaptation; however, chronic stress is often associated with detrimental health effects. Colon cancer (CC) is one of the leading causes of death associated with cancer and has been mentioned as a stress-related disease. In the present work, the effect of chronic stress on the initial phase of CC was evaluated, and special emphasis was placed on ornithine decarboxylase (ODC) expression and polyamines for their role in hyperproliferative diseases. BALB/c mice (n = 5/group) were administered the pro-carcinogen 1,2-dimethylhydrazine (DMH) for 8 weeks (20 mg/kg body weight/week) to induce colon carcinogenesis, and then exposed for 4 weeks to two physical stressors: restraint and forced-swimming. Distal colon inflammatory lesions and histomorphological changes were evaluated by hematoxylin-eosin staining; plasma corticosterone levels, colon ODC expression, and urinary polyamines were determined by competitive ELISA, RT-qPCR, Western Blot, and HPLC, respectively. The short-term exposure to DMH triggered colon inflammation, initiated colon carcinogenesis and increased ODC expression; meanwhile, the exposure to chronic stress activated the hypothalamic-pituitary-adrenal (HPA) axis, elicited the production of plasmatic corticosterone, and decreased ODC expression. The exposure of DMH-treated mice to chronic stress counteracted the inflammatory effect of DMH and maintained ODC homeostasis. In early phase of carcinogenesis, the exposure of DMH-treated mice to chronic stress had a positive effect against colon inflammation and maintained ODC homeostasis. The cross-talk between corticosterone, ODC expression, and inflammation in a tumor environment is discussed.

Keywords:  1,2-Dimethylhydrazine; Chronic stress; Colon carcinogenesis; Corticosterone; Ornithine decarboxylase

DOI:  https://doi.org/10.1007/s11033-020-06022-0
Biomolecules. 2020 Dec 01. pii: E1624. [Epub ahead of print]10(12):

Acylpolyamine Mygalin as a TLR4 Antagonist Based on Molecular Docking and In Vitro Analyses.

Abraham Espinoza-Culupú, Ricardo Vázquez-Ramírez, Mariella Farfán-López, Elizabeth Mendes, Maria Notomi Sato, Pedro Ismael da Silva Junior, Monamaris Marques Borges.

  Toll-like receptors (TLRs) are transmembrane proteins that are key regulators of innate and adaptive immune responses, particularly TLR4, and they have been identified as potential drug targets for the treatment of disease. Several low-molecular-weight compounds are being considered as new drug targets for various applications, including as immune modulators. Mygalin, a 417 Da synthetic bis-acylpolyamine, is an analog of spermidine that has microbicidal activity. In this study, we investigated the effect of mygalin on the innate immune response based on a virtual screening (VS) and molecular docking analysis. Bone marrow-derived macrophages and the cell lines J774A.1 and RAW 264.7 stimulated with lipopolysaccharide (LPS) were used to confirm the data obtained in silico. Virtual screening and molecular docking suggested that mygalin binds to TLR4 via the protein myeloid differentiation factor 2 (MD-2) and LPS. Macrophages stimulated by mygalin plus LPS showed suppressed gene expression of tumor necrosis factor (TNF-α), interleukine 6 (IL-6), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as inhibition of signaling protein p65 of the nuclear factor κB (NF-κB), resulting in decreased production of nitric oxide (NO) and TNF-α. These results indicate that mygalin has anti-inflammatory potential, being an attractive option to be explored. In addition, we reinforce the importance of virtual screening analysis to assist in the discovery of new drugs.

Keywords:  TLR4; drug discovery; inflammation; molecular docking; mygalin; virtual screening

DOI:  https://doi.org/10.3390/biom10121624