bims-polyam 2024-10-06 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2024–10–06
nine papers selected by
Sebastian J. Hofer, University of Graz

Intestinal Lactobacillus murinus-derived small RNAs target porcine polyamine metabolism.
Effect of Spermidine on Endothelial Function in Systemic Lupus Erythematosus Mice.
"Enhancing polyamine enrichment from wheat germs: A study utilizing response surface methodology and liquid chromatography-mass spectrometry".
Diamine Fungal Inducers of Secondary Metabolism: 1,3-Diaminopropane and Spermidine Trigger Enzymes Involved in β-Alanine and Pantothenic Acid Biosynthesis, Precursors of Phosphopantetheine in the Activation of Multidomain Enzymes.
Spermidine Improves Freezing Tolerance by Regulating H2O2 in Brassica napus L.
A Fluorescence-Based Assay for Measuring Polyamine Biosynthesis Aminopropyl Transferase-Mediated Catalysis.
Polyamine Pathway Inhibitor DENSPM Suppresses Lipid Metabolism in Pheochromocytoma Cell Line.
Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons.
A Bis(Acridino)-Crown Ether for Recognizing Oligoamines in Spermine Biosynthesis.

Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2413241121

Intestinal Lactobacillus murinus-derived small RNAs target porcine polyamine metabolism.

Lijuan Fan, Bingnan Liu, Youxia Wang, Bin Tang, Tianqi Xu, Jian Fu, Chuanlong Wang, Yuan Liu, Liangpeng Ge, Hong Wei, Wenkai Ren.

  Gut microbiota plays a vital role in host metabolism; however, the influence of gut microbes on polyamine metabolism is unknown. Here, we found germ-free models possess elevated polyamine levels in the colon. Mechanistically, intestinal Lactobacillus murinus-derived small RNAs in extracellular vesicles down-regulate host polyamine metabolism by targeting the expression of enzymes in polyamine metabolism. In addition, Lactobacillus murinus delays recovery of dextran sodium sulfate-induced colitis by reducing polyamine levels in mice. Notably, a decline in the abundance of small RNAs was observed in the colon of mice with colorectal cancer (CRC) and human CRC specimens, accompanied by elevated polyamine levels. Collectively, our study identifies a specific underlying mechanism used by intestinal microbiota to modulate host polyamine metabolism, which provides potential intervention for the treatment of polyamine-associated diseases.

Keywords:  CRC; Lactobacillus murinus; colitis; polyamine metabolism; small RNAs

DOI:  https://doi.org/10.1073/pnas.2413241121
Int J Mol Sci. 2024 Sep 14. pii: 9920. [Epub ahead of print]25(18):

Effect of Spermidine on Endothelial Function in Systemic Lupus Erythematosus Mice.

Hyoseon Kim, Michael P Massett.

  Endothelial dysfunction is common in Systemic Lupus Erythematosus (SLE), even in the absence of cardiovascular disease. Evidence suggests that impaired mitophagy contributes to SLE. Mitochondrial dysfunction is also associated with impaired endothelial function. Spermidine, a natural polyamine, stimulates mitophagy by the PINK1-parkin pathway and counters age-associated endothelial dysfunction. However, the effect of spermidine on mitophagy and vascular function in SLE has not been explored. To address this gap, 9-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned to spermidine treatment (lpr_Spermidine and MpJ_Spermidine) for 8 weeks or as control (lpr_Control and MpJ_Control). lpr_Control mice exhibited impaired endothelial function (e.g., decreased relaxation to acetylcholine), increased markers of inflammation, and lower protein content of parkin, a mitophagy marker, in the thoracic aorta. Spermidine treatment prevented endothelial dysfunction in MRL-lpr mice. Furthermore, aortas from lpr_Spermidine mice had lower levels of inflammatory markers and higher levels of parkin. Lupus phenotypes were not affected by spermidine. Collectively, these results demonstrate the beneficial effects of spermidine treatment on endothelial function, inflammation, and mitophagy in SLE mice. These results support future studies of the beneficial effects of spermidine on endothelial dysfunction and cardiovascular disease risk in SLE.

Keywords:  MRL/MpJ-Faslpr/J; PINK1–parkin; autoantibodies; mitophagy; thoracic aorta; vascular; vascular cell adhesion molecule 1 (Vcam1)

DOI:  https://doi.org/10.3390/ijms25189920
Food Chem. 2024 Sep 23. pii: S0308-8146(24)03058-9. [Epub ahead of print]463(Pt 3): 141408

"Enhancing polyamine enrichment from wheat germs: A study utilizing response surface methodology and liquid chromatography-mass spectrometry".

Maryam Mohajeri, Shaya Mokhtari, Maryam Khandan, Seyed Abdulmajid Ayatollahi, Farzad Kobarfard, Anita Hudaverdi.

  Wheat germ is one of the richest natural sources of polyamines, especially spermidine. Cell proliferation property of polyamines has given them inductive effects in the reduction of a variety of chronic diseases and fertility enhancement. Preparing a polyamine-rich extract powder from wheat germ for use in supplements is the aim of the present study. For the first time, the effects of three independent variables of clean-up replicate (A), extraction time (B), and solid-to-liquid ratio (C) on the response of total spermidine content (Y) were investigated using a central composite design optimizing polyamine enrichment. The optimal extraction conditions were 7 h, 3 clean-up replicates, and 1:4 solid to liquid ratio. This is the first production report of spermidine-enriched powder for encapsulation purposes. To obtain an acceptable rheological property, the polyamine-enriched extract was spray dried together with a selected group of excipients, among which glucose was evidenced as the best choice based on encapsulation properties.

Keywords:  Extraction optimization; LC-MS/MS; Oral supplement; Polyamine extraction; RSM; Wheat germ

DOI:  https://doi.org/10.1016/j.foodchem.2024.141408
Antibiotics (Basel). 2024 Sep 01. pii: 826. [Epub ahead of print]13(9):

Diamine Fungal Inducers of Secondary Metabolism: 1,3-Diaminopropane and Spermidine Trigger Enzymes Involved in β-Alanine and Pantothenic Acid Biosynthesis, Precursors of Phosphopantetheine in the Activation of Multidomain Enzymes.

Juan Francisco Martín, Paloma Liras.

  The biosynthesis of antibiotics and other secondary metabolites (also named special metabolites) is regulated by multiple regulatory networks and cascades that act by binding transcriptional factors to the promoter regions of different biosynthetic gene clusters. The binding affinity of transcriptional factors is frequently modulated by their interaction with specific ligand molecules. In the last decades, it was found that the biosynthesis of penicillin is induced by two different molecules, 1,3-diaminopropane and spermidine, but not by putrescine (1,4-diaminobutane) or spermine. 1,3-diaminopropane and spermidine induce the expression of penicillin biosynthetic genes in Penicillium chrysogenum. Proteomic studies clearly identified two different proteins that respond to the addition to cultures of these inducers and are involved in β-alanine and pantothenic acid biosynthesis. These compounds are intermediates in the biosynthesis of phosphopantetheine that is required for the activation of non-ribosomal peptide synthetases, polyketide synthases, and fatty acid synthases. These large-size multidomain enzymes are inactive in the "apo" form and are activated by covalent addition of the phosphopantetheine prosthetic group by phosphopantetheinyl transferases. Both 1,3-diaminopropane and spermidine have a similar effect on the biosynthesis of cephalosporin by Acremonium chrysogenum and lovastatin by Aspergillus terreus, suggesting that this is a common regulatory mechanism in the biosynthesis of bioactive secondary metabolites/natural products.

Keywords:  1,3-diaminopropane; filamentous fungi; modular synthetases; pantothenic acid; phosphopantetheinyl modification; polyamines; putrescine; secondary metabolites; spermidine; spermine; β-alanine

DOI:  https://doi.org/10.3390/antibiotics13090826
Antioxidants (Basel). 2024 Aug 26. pii: 1032. [Epub ahead of print]13(9):

Spermidine Improves Freezing Tolerance by Regulating H2O2 in Brassica napus L.

Shun Li, Yan Liu, Yu Kang, Wei Liu, Weiping Wang, Zhonghua Wang, Xiaoyan Xia, Xiaoyu Chen, Chen Wang, Xin He.

  Low temperature is a common abiotic stress that causes significant damage to crop production. Polyamines (PAs) are a class of aliphatic amine compounds that serve as regulatory molecules involved in plant growth, development, and response to abiotic and biotic stresses. In this study, we found that the exogenous application of two concentrations of spermidine (Spd) significantly enhanced the freezing tolerance of three differently matured rapeseed (Brassica napus L.) varieties, as manifested by higher survival rates, lower freezing injury indexes, and reduced H2O2 content. RNA-seq and qRT-PCR analyses showed that Spd enhanced the freezing tolerance of rapeseed by regulating genes related to the PA metabolic pathway and antioxidant mechanism, and generally inhibited the expression of genes related to the JA signaling pathway. This study provides a reference basis for understanding the functionality and molecular mechanisms of polyamines in the response of rapeseed to freezing stress.

Keywords:  Brassica napus L.; H2O2; freezing stress; polyamines

DOI:  https://doi.org/10.3390/antiox13091032
J Biol Chem. 2024 Sep 27. pii: S0021-9258(24)02334-2. [Epub ahead of print] 107832

A Fluorescence-Based Assay for Measuring Polyamine Biosynthesis Aminopropyl Transferase-Mediated Catalysis.

Pallavi Singh, Jae-Yeon Choi, Weiwei Wang, Tukiet Lam, Philip Lechner, Christopher D Vanderwal, Sovitj Pou, Aaron Nilsen, Choukri Ben Mamoun.

  Polyamines are polycationic molecules that are crucial in a wide array of cellular functions. Their biosynthesis is mediated by aminopropyl transferases (APTs), which are promising targets for antimicrobial, antineoplastic and antineurodegenerative therapies. A major limitation in studying APT enzymes, however, is the lack of high-throughput assays to measure their activity. We have developed the first fluorescence-based assay, DAB-APT, for the measurement of APT activity using 1,2-diacetyl benzene (DAB), which forms fluorescent conjugates with putrescine, spermidine, and spermine, with fluorescence intensity increasing with the carbon chain length. The assay has been validated using APT enzymes from Saccharomyces cerevisiae and Plasmodium falciparum, and the data further validated by mass spectrometry and thin-layer chromatography. Using mass spectrometry analysis, the structures of the fluorescent putrescine, spermidine and spermine 1,2-DAB adducts were determined to be substituted 1,3-dimethyl isoindoles. The DAB-APT assay is optimized for high-throughput screening, facilitating the evaluation of large chemical libraries. Given the critical roles of APTs in infectious diseases, oncology, and neurobiology, the DAB-APT assay offers a powerful tool with broad applicability, poised to drive advancements in research and drug discovery.

Keywords:  1,2-diacetyl benzene; Babesia; Plasmodium; Putrescine; aminopropyl transferases; drug discovery; enzyme activity; fluorescence assay; inhibition; isoindole; kinetics; polyamines; spermidine; spermine; yeast

DOI:  https://doi.org/10.1016/j.jbc.2024.107832
Int J Mol Sci. 2024 Sep 18. pii: 10029. [Epub ahead of print]25(18):

Polyamine Pathway Inhibitor DENSPM Suppresses Lipid Metabolism in Pheochromocytoma Cell Line.

Hans K Ghayee, Kaylie A Costa, Yiling Xu, Heather M Hatch, Mateo Rodriguez, Shelby C Straight, Marian Bustamante, Fahong Yu, Fatima Smagulova, John A Bowden, Sergei G Tevosian.

  Pheochromocytomas (PCCs) are tumors arising from chromaffin cells in the adrenal medulla, and paragangliomas (PGLs) are tumors derived from extra-adrenal sympathetic or parasympathetic paraganglia; these tumors are collectively referred to as PPGL cancer. Treatment for PPGL primarily involves surgical removal of the tumor, and only limited options are available for treatment of the disease once it becomes metastatic. Human carriers of the heterozygous mutations in the succinate dehydrogenase subunit B (SDHB) gene are susceptible to the development of PPGL. A physiologically relevant PCC patient-derived cell line hPheo1 was developed, and SDHB_KD cells carrying a stable short hairpin knockdown of SDHB were derived from it. An untargeted metabolomic approach uncovered an overactive polyamine pathway in the SDHB_KD cells that was subsequently fully validated in a large set of human SDHB-mutant PPGL tumor samples. We previously reported that treatment with the polyamine metabolism inhibitor N1,N11-diethylnorspermine (DENSPM) drastically inhibited growth of these PCC-derived cells in culture as well as in xenograft mouse models. Here we explored the mechanisms underlying DENSPM action in hPheo1 and SDHB_KD cells. Specifically, by performing an RNAseq analysis, we have identified gene expression changes associated with DENSPM treatment that broadly interfere with all aspects of lipid metabolism, including fatty acid (FA) synthesis, desaturation, and import/uptake. Furthermore, by performing an untargeted lipidomic liquid chromatography-mass spectrometry (LC/MS)-based analysis we uncovered specific groups of lipids that are dramatically reduced as a result of DENSPM treatment. Specifically, the bulk of plasmanyl ether lipid species that have been recently reported as the major determinants of cancer cell fate are notably decreased. In summary, this work suggests an intersection between active polyamine and lipid pathways in PCC cells.

Keywords:  DENSPM; SDHB; paraganglioma; pheochromocytoma; plasmanyl

DOI:  https://doi.org/10.3390/ijms251810029
Mol Brain. 2024 Sep 27. 17(1): 68

Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons.

Elham Shojaeinia, Teresa L Mastracci, Remon Soliman, Orrin Devinsky, Camila V Esguerra, Alexander D Crawford.

  DHPS deficiency syndrome is an ultra-rare neurodevelopmental disorder (NDD) which results from biallelic mutations in the gene encoding the enzyme deoxyhypusine synthase (DHPS). DHPS is essential to synthesize hypusine, a rare amino acid formed by post-translational modification of a conserved lysine in eukaryotic initiation factor 5 A (eIF5A). DHPS deficiency syndrome causes epilepsy, cognitive and motor impairments, and mild facial dysmorphology. In mice, a brain-specific genetic deletion of Dhps at birth impairs eIF5AHYP-dependent mRNA translation. This alters expression of proteins required for neuronal development and function, and phenotypically models features of human DHPS deficiency. We studied the role of DHPS in early brain development using a zebrafish loss-of-function model generated by knockdown of dhps expression with an antisense morpholino oligomer (MO) targeting the exon 2/intron 2 (E2I2) splice site of the dhps pre-mRNA. dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature. In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons. Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of dhps model features of DHPS deficiency syndrome.

Keywords:  Deoxyhypusine synthase; Epilepsy; Hypusine; Neurodevelopmental disorder; Zebrafish

DOI:  https://doi.org/10.1186/s13041-024-01139-w
Molecules. 2024 Sep 15. pii: 4390. [Epub ahead of print]29(18):

A Bis(Acridino)-Crown Ether for Recognizing Oligoamines in Spermine Biosynthesis.

Péter Kisfaludi, Sára Spátay, Marcell Krekó, Panna Vezse, Tünde Tóth, Péter Huszthy, Ádám Golcs.

  Oligoamines in cellular metabolism carry extremely diverse biological functions (i.e., regulating Ca2+-influx, neuronal nitric oxide synthase, membrane potential, Na+, K+-ATPase activity in synaptosomes, etc.). Furthermore, they also act as longevity agents and have a determinative role in autophagy, cell growth, proliferation, and death, while oligoamines dysregulation is a key in a variety of cancers. However, many of their mechanisms of actions have just begun to be understood. In addition to the numerous biosensing methods, only a very few simple small molecule-based tests are available for their selective but reversible tracking or fluorescent labeling. Motivated by this, we present herein a new fluorescent bis(acridino)-crown ether as a sensor molecule for biogenic oligoamines. The sensor molecule can selectively distinguish oligoamines from aliphatic mono- and diamino-analogues, while showing a reversible 1:2 (host:guest) complexation with a stepwise binding process accompanied by a turn-on fluorescence response. Both computational simulations on molecular docking and regression methods on titration experiments were carried out to reveal the oligoamine-recognition properties of the sensor molecule. The new fluorescent chemosensor molecule has a high potential for molecular-level functional studies on the oligoamine systems in cell processes (cellular uptake, transport, progression in cancers, etc.).

Keywords:  biogenic oligoamines; chemosensor; crown ether; fluorescence; spermidine; spermine

DOI:  https://doi.org/10.3390/molecules29184390