bims-polyam 2019-08-04 papers

on Polyamines

Issue of 2019–08–04
seven papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Lysine harvesting is an antioxidant strategy and triggers underground polyamine metabolism.
Polyamines - A New Metabolic Switch: Crosstalk With Networks Involving Senescence, Crop Improvement, and Mammalian Cancer Therapy.
Knockdown of SSATX, an alternative splicing variant of the SAT1 gene, promotes melanoma progression.
Microbial dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer.
Polyamines in Food.
Purification and Characterization of Ornithine Decarboxylase from Aspergillus terreus; Kinetics of Inhibition by Various Inhibitors.
Liquid Biopsy in Lung Cancer Screening: The Contribution of Metabolomics. Results of A Pilot Study.

Nature. 2019 Jul 31.

Lysine harvesting is an antioxidant strategy and triggers underground polyamine metabolism.

Viridiana Olin-Sandoval, Jason Shu Lim Yu, Leonor Miller-Fleming, Mohammad Tauqeer Alam, Stephan Kamrad, Clara Correia-Melo, Robert Haas, Joanna Segal, David Alejandro Peña Navarro, Lucia Herrera-Dominguez, Oscar Méndez-Lucio, Jakob Vowinckel, Michael Mülleder, Markus Ralser.

Both single and multicellular organisms depend on anti-stress mechanisms that enable them to deal with sudden changes in the environment, including exposure to heat and oxidants. Central to the stress response are dynamic changes in metabolism, such as the transition from the glycolysis to the pentose phosphate pathway-a conserved first-line response to oxidative insults1,2. Here we report a second metabolic adaptation that protects microbial cells in stress situations. The role of the yeast polyamine transporter Tpo1p3-5 in maintaining oxidant resistance is unknown6. However, a proteomic time-course experiment suggests a link to lysine metabolism. We reveal a connection between polyamine and lysine metabolism during stress situations, in the form of a promiscuous enzymatic reaction in which the first enzyme of the polyamine pathway, Spe1p, decarboxylates lysine and forms an alternative polyamine, cadaverine. The reaction proceeds in the presence of extracellular lysine, which is taken up by cells to reach concentrations up to one hundred times higher than those required for growth. Such extensive harvest is not observed for the other amino acids, is dependent on the polyamine pathway and triggers a reprogramming of redox metabolism. As a result, NADPH-which would otherwise be required for lysine biosynthesis-is channelled into glutathione metabolism, leading to a large increase in glutathione concentrations, lower levels of reactive oxygen species and increased oxidant tolerance. Our results show that nutrient uptake occurs not only to enable cell growth, but when the nutrient availability is favourable it also enables cells to reconfigure their metabolism to preventatively mount stress protection.

DOI: https://doi.org/10.1038/s41586-019-1442-6
Front Plant Sci. 2019 ;10 859

Polyamines - A New Metabolic Switch: Crosstalk With Networks Involving Senescence, Crop Improvement, and Mammalian Cancer Therapy.

Ewa Sobieszczuk-Nowicka, Ewelina Paluch-Lubawa, Autar K Mattoo, Magdalena Arasimowicz-Jelonek, Per L Gregersen, Andrzej Pacak.

  Polyamines (PAs) are low molecular weight organic cations comprising biogenic amines that play multiple roles in plant growth and senescence. PA metabolism was found to play a central role in metabolic and genetic reprogramming during dark-induced barley leaf senescence (DILS). Robust PA catabolism can impact the rate of senescence progression in plants. We opine that deciphering senescence-dependent polyamine-mediated multidirectional metabolic crosstalks is important to understand regulation and involvement of PAs in plant death and re-mobilization of nutrients during senescence. This will involve optimizing the use of PA biosynthesis inhibitors, robust transgenic approaches to modulate PA biosynthetic and catabolic genes, and developing novel germplasm enriched in pro- and anti-senescence traits to ensure sustained crop productivity. PA-mediated delay of senescence can extend the photosynthesis capacity, thereby increasing grain starch content in malting grains such as barley. On the other hand, accelerating the onset of senescence can lead to increases in mineral and nitrogen content in grains for animal feed. Unraveling the "polyamine metabolic switch" and delineating the roles of PAs in senescence should further our knowledge about autophagy mechanisms involved in plant senescence as well as mammalian systems. It is noteworthy that inhibitors of PA biosynthesis block cell viability in animal model systems (cell tumor lines) to control some cancers, in this instance, proliferative cancer cells were led toward cell death. Likewise, PA conjugates work as signal carriers for slow release of regulatory molecule nitric oxide in the targeted cells. Taken together, these and other outcomes provide examples for developing novel therapeutics for human health wellness as well as developing plant resistance/tolerance to stress stimuli.

Keywords:  CRISPR/Cas9; autophagy; cancer therapy; cell death; crop improvement; polyamines-nitric oxide conjugates; senescence; transcriptome profiling

DOI:  https://doi.org/10.3389/fpls.2019.00859
Gene. 2019 Jul 25. pii: S0378-1119(19)30669-9. [Epub ahead of print] 144010

Knockdown of SSATX, an alternative splicing variant of the SAT1 gene, promotes melanoma progression.

Qiong Yang, Youhui Deng, Yuanyuan Xu, Nan Ding, Chen Wang, Xuetong Zhao, Xiaomin Lou, Yongjun Li, Hua Zhao, Xiangdong Fang.

  Alternative splicing can generate multiple protein messages from a single gene and has emerged as an important mechanism to regulate cancer pathways. The human SAT1 gene produces two transcript variants: one translates spermidine/spermine N-1 acetyltransferase (SSAT1), the rate-limiting enzyme in the catabolism of polyamines, and the other generates SSATX, which has largely unknown biological functions. Here, we used experimental data and analyses of several melanoma transcriptome datasets to reveal that SSATX is weakly expressed in melanoma cells. SSATX knockdown promoted the proliferation, migration, and invasion of human melanoma cells via the activation of the Wnt signaling pathway in a manner that was independent of SSAT1 expression. Based on our data, we propose that SSATX functions as a long non-coding RNA prior to its degradation in melanoma cells. Overall, our findings indicate that SSATX acts as a tumor suppressor, which may aid the future diagnosis and treatment of melanoma.

Keywords:  Alternative splicing; Melanoma; SSATX; Tumor suppressor; Wnt signaling pathway

DOI:  https://doi.org/10.1016/j.gene.2019.144010
Carcinogenesis. 2019 Aug 01. pii: bgz116. [Epub ahead of print]

Microbial dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer.

Roberto Mendez, Kousik Kesh, Nivedita Arora, Leá Di Martino, Florencia McAllister, Nipun Merchant, Sulagna Banerjee, Santanu Banerjee.

The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated with the abysmal survival rates in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. We used a combination of 16s rRNA pyrosequencing and whole-genome sequencing of gut fecal microbiota in a genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUMAnN2 pipeline. Serum polyamine levels were measured from murine and patient samples using chromogenic assay. Our results showed a Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentrations. Therefore, at the early stages of tumorigenesis, there is a strong correlation between microbial changes and release of metabolites that foster host tumorigenesis, thereby fulfilling the 'vicious cycle hypothesis' of the role of microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which may result in improved outcomes.

DOI: https://doi.org/10.1093/carcin/bgz116
Front Nutr. 2019 ;6 108

Polyamines in Food.

Nelly C Muñoz-Esparza, M Luz Latorre-Moratalla, Oriol Comas-Basté, Natalia Toro-Funes, M Teresa Veciana-Nogués, M Carmen Vidal-Carou.

  The polyamines spermine, spermidine, and putrescine are involved in various biological processes, notably in cell proliferation and differentiation, and also have antioxidant properties. Dietary polyamines have important implications in human health, mainly in the intestinal maturation and in the differentiation and development of immune system. The antioxidant and anti-inflammatory effect of polyamine can also play an important role in the prevention of chronic diseases such as cardiovascular diseases. In addition to endogenous synthesis, food is an important source of polyamines. Although there are no recommendations for polyamine daily intake, it is known that in stages of rapid cell growth (i.e., in the neonatal period), polyamine requirements are high. Additionally, de novo synthesis of polyamines tends to decrease with age, which is why their dietary sources acquire a greater importance in an aging population. Polyamine daily intake differs among to the available estimations, probably due to different dietary patterns and methodologies of data collection. Polyamines can be found in all types of foods in a wide range of concentrations. Spermidine and spermine are naturally present in food whereas putrescine could also have a microbial origin. The main polyamine in plant-based products is spermidine, whereas spermine content is generally higher in animal-derived foods. This article reviews the main implications of polyamines for human health, as well as their content in food and breast milk and infant formula. In addition, the estimated levels of polyamines intake in different populations are provided.

Keywords:  breast milk; food; human health; polyamines; putrescine; spermidine; spermine

DOI:  https://doi.org/10.3389/fnut.2019.00108
Molecules. 2019 Jul 29. pii: E2756. [Epub ahead of print]24(15):

Purification and Characterization of Ornithine Decarboxylase from Aspergillus terreus; Kinetics of Inhibition by Various Inhibitors.

Ashraf S A El-Sayed, Nelly M George, Marwa A Yassin, Bothaina A Alaidaroos, Ahmed A Bolbol, Marwa S Mohamed, Amgad M Rady, Safa W Aziz, Rawia A Zayed, Mahmoud Z Sitohy.

  l-Ornithine decarboxylase (ODC) is the rate-limiting enzyme of de novo polyamine synthesis in humans and fungi. Elevated levels of polyamine by over-induction of ODC activity in response to tumor-promoting factors has been frequently reported. Since ODC from fungi and human have the same molecular properties and regulatory mechanisms, thus, fungal ODC has been used as model enzyme in the preliminary studies. Thus, the aim of this work was to purify ODC from fungi, and assess its kinetics of inhibition towards various compounds. Forty fungal isolates were screened for ODC production, twenty fungal isolates have the higher potency to grow on L-ornithine as sole nitrogen source. Aspergillus terreus was the most potent ODC producer (2.1 µmol/mg/min), followed by Penicillium crustosum and Fusarium fujikuori. These isolates were molecularly identified based on their ITS sequences, which have been deposited in the NCBI database under accession numbers MH156195, MH155304 and MH152411, respectively. ODC was purified and characterized from A. terreus using SDS-PAGE, showing a whole molecule mass of ~110 kDa and a 50 kDa subunit structure revealing its homodimeric identity. The enzyme had a maximum activity at 37 °C, pH 7.4-7.8 and thermal stability for 20 h at 37 °C, and 90 days storage stability at 4 °C. A. terreus ODC had a maximum affinity (Km) for l-ornithine, l-lysine and l-arginine (0.95, 1.34 and 1.4 mM) and catalytic efficiency (kcat/Km) (4.6, 2.83, 2.46 × 10-5 mM-1·s-1). The enzyme activity was strongly inhibited by DFMO (0.02 µg/mL), curcumin (IC50 0.04 µg/mL), propargylglycine (20.9 µg/mL) and hydroxylamine (32.9 µg/mL). These results emphasize the strong inhibitory effect of curcumin on ODC activity and subsequent polyamine synthesis. Further molecular dynamic studies to elucidate the mechanistics of ODC inhibition by curcumin are ongoing.

Keywords:  Aspergillus terreus; curcumin; inhibition; kinetics; ornithine decarboxylase

DOI:  https://doi.org/10.3390/molecules24152756
Cancers (Basel). 2019 Jul 29. pii: E1069. [Epub ahead of print]11(8):

Liquid Biopsy in Lung Cancer Screening: The Contribution of Metabolomics. Results of A Pilot Study.

Sandeep Singhal, Christian Rolfo, Andrew W Maksymiuk, Paramjit S Tappia, Daniel S Sitar, Alessandro Russo, Parveen S Akhtar, Nazrina Khatun, Parveen Rahnuma, Ahmed Rashiduzzaman, Rashid Ahmed Bux, Guoyu Huang, Bram Ramjiawan.

  Background: Lung cancer is the most common cause of cancer-related deaths worldwide. Early diagnosis is crucial to increase the curability chance of the patients. Low dose CT screening can reduce lung cancer mortality, but it is associated with several limitations. Metabolomics is a promising technique for cancer diagnosis due to its ability to provide chemical phenotyping data. The intent of our study was to explore metabolomic effects and profiles of lung cancer patients to determine if metabolic perturbations in the SSAT-1/polyamine pathway can distinguish between healthy participants and lung cancer patients as a diagnostic and treatment monitoring tool. Patients and Methods: Plasma samples were collected as part of the SSAT1 Amantadine Cancer Study. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify and quantify metabolite concentrations in lung cancer patient and control samples. Standard statistical analyses were performed to determine whether metabolite concentrations could differentiate between healthy subjects and lung cancer patients, as well as risk prediction modeling applied to determine whether metabolic profiles could provide an indication of cancer progression in later stage patients. Results: A panel consisting of 14 metabolites, which included 6 metabolites in the polyamine pathway, was identified that correctly discriminated lung cancer patients from controls with an area under the curve of 0.97 (95% CI: 0.875-1.0). Conclusion: When used in conjunction with the SSAT-1/polyamine pathway, these metabolites may provide the specificity required for diagnosing lung cancer from other cancer types and could be used as a diagnostic and treatment monitoring tool.

Keywords:  NSCLC; SSAT-1; lung cancer; metabolomic fingerprint; metabolomics; polyamine

DOI:  https://doi.org/10.3390/cancers11081069