bims-polyam 2025-01-26 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2025–01–26
nine papers selected by
Sebastian J. Hofer, University of Graz

The role of 1-Deoxysphingolipids and Polyamines in the pathogenesis of placental syndrome.
Hypusinated and unhypusinated isoforms of the translation factor eIF5A exert distinct effects in models of pancreas development and function.
Role of polyamines in intestinal mucosal barrier function.
Structural, functional, and regulatory evaluation of a cysteine post-translationally modified Gcn5-related N-acetyltransferase.
Lactobacillus reuteri ZJ617 attenuates metabolic syndrome via microbiota-derived spermidine.
Spermidine Recovers the Autophagy Defects Underlying the Pathophysiology of Cell Trafficking Disorders.
N-terminal domain swapping: A new paradigm for spermidine/spermine N-acetyltransferase (SSAT) protein structures?
Spermidine antagonizes the anti-cancer effect of cold atmospheric plasma and induces transit G0/G1 cell cycle arrest of triple negative breast cancers.
Spermine Enhances the Peroxidase Activities of Multimeric Antiparallel G-quadruplex DNAzymes.

BMC Pregnancy Childbirth. 2025 Jan 22. 25(1): 51

The role of 1-Deoxysphingolipids and Polyamines in the pathogenesis of placental syndrome.

Filiz Yarsilikal Guleroglu, Ali Cetin, Goknil Pelin Coskun, Meltem Caliskan, Fulya Karaduman, Can Bilginer, Resat Misirlioglu, Sinem Tekin, Merve Nur Al, Tugce Caklili, Yusuf Tutar.

   BACKGROUND: Placental syndrome, mainly composed of preeclampsia and fetal growth restriction, has an impact on the health of mother and baby dyads. While impaired placentation is central to their pathophysiology, the underlying molecular mechanisms remain incompletely understood. This study investigates the association between placental syndrome and metabolic alterations in 1-deoxysphingolipids (1-deoxySLs) and polyamines, along with their regulatory enzymes.
METHODS: This prospective case-control study involved 26 healthy pregnant women and 17 with placental syndrome. Blood samples were collected from maternal, uterine venous, and umbilical cord veins. Levels of 1-deoxySL, spermine, and spermidine, as well as related enzymes of polyamine metabolism such as ornithine decarboxylase (ODC), spermidine/spermine N1-acetyltransferase (SSAT), polyamine oxidase (PAO), and spermine oxidase (SMO), were measured using the techniques of LC-MS and ELISA, respectively.
RESULTS: Women with placental syndrome had significantly higher levels of 1-deoxySL, spermine, and spermidine in all blood samples compared to the healthy pregnancy group. Additionally, ODC and SSAT levels were reduced significantly in the placental syndrome group, while PAO and SMO levels showed no significant differences. Strong positive correlations were found between the studied enzymes and biomolecules in healthy pregnancies, which were notably weaker in the placental syndrome group.
CONCLUSION: This study demonstrates significantly altered levels of 1-deoxySL and polyamines, with corresponding enzyme activity changes, in placental syndrome compared to healthy pregnancies. The disrupted correlations between these biomolecules suggest alterations in their metabolic pathways and potential utility as biomarkers. Further mechanistic studies are warranted to elucidate their role in placental syndrome pathophysiology.

Keywords:  1-deoxysphingolipids; Fetal growth restriction; Placental syndrome; Polyamines; Preeclampsia

DOI:  https://doi.org/10.1186/s12884-025-07175-1
J Biol Chem. 2025 Jan 18. pii: S0021-9258(25)00056-0. [Epub ahead of print] 108209

Hypusinated and unhypusinated isoforms of the translation factor eIF5A exert distinct effects in models of pancreas development and function.

Cara M Anderson, Abhishek Kulkarni, Bernhard Maier, Fei Huang, Kayla Figatner, Advaita Chakraborty, Sarida Pratuangtham, Sarah C May, Sarah A Tersey, Ryan M Anderson, Raghavendra G Mirmira.

  Hypusination of eukaryotic translation initiation factor 5A (eIF5A) is essential for its role in translation elongation and termination. Although the function of hypusinated eIF5A (eIF5AHyp) in cellular proliferation is well-characterized, the role of its unhypusinated form (eIF5ALys) remains unclear. We hypothesized that eIF5ALys exerts independent, negative effects on cellular replication and metabolism, distinct from the loss of eIF5AHyp. To test this hypothesis, we utilized zebrafish and mouse models with inducible knockdowns of deoxyhypusine synthase (DHPS) and eIF5A to investigate their roles in cellular growth. Gene expression analysis via RNA sequencing and morphometric measurements of pancreas and β-cell mass were performed to assess phenotypic changes and identify affected biological pathways. Loss of DHPS in zebrafish resulted in significant defects in pancreatic growth, accompanied by changes in gene expression related to mRNA translation, neurogenesis, and stress pathways. By contrast, knockdown of eIF5A had minimal impact on pancreas development, suggesting that the effects of DHPS loss are not solely due to the lack of eIF5AHyp. In mice, β cell-specific deletion of DHPS impaired β cell mass expansion and glucose tolerance, while eIF5A deletion had no statistically significant effects. These findings provide evidence for an independent role for eIF5ALys in regulating developmental and functional responses in pancreas health and disease.

Keywords:  eIF5A; hypusine; mouse; pancreas; polyamines; translation; zebrafish

DOI:  https://doi.org/10.1016/j.jbc.2025.108209
Semin Immunopathol. 2025 Jan 21. 47(1): 9

Role of polyamines in intestinal mucosal barrier function.

Atsuo Nakamura, Mitsuharu Matsumoto.

  The intestinal epithelium is a rapidly self-renewing tissue; the rapid turnover prevents the invasion of pathogens and harmful components from the intestinal lumen, preventing inflammation and infectious diseases. Intestinal epithelial barrier function depends on the epithelial cell proliferation and junctions, as well as the state of the immune system in the lamina propria. Polyamines, particularly putrescine, spermidine, and spermine, are essential for many cell functions and play a crucial role in mammalian cellular homeostasis, such as that of cell growth, proliferation, differentiation, and maintenance, through multiple biological processes, including translation, transcription, and autophagy. Although the vital role of polyamines in normal intestinal epithelial cell growth and barrier function has been known since the 1980s, recent studies have provided new insights into this topic at the molecular level, such as eukaryotic initiation factor-5A hypusination and autophagy, with rapid advances in polyamine biology in normal cells using biological technologies. This review summarizes recent advances in our understanding of the role of polyamines in regulating normal, non-cancerous, intestinal epithelial barrier function, with a particular focus on intestinal epithelial renewal, cell junctions, and immune cell differentiation in the lamina propria.

Keywords:  Cell proliferation; Inflammation; Intestinal microbiome; Intestinal mucosal barrier; Polyamines

DOI:  https://doi.org/10.1007/s00281-024-01035-4
Biochem Biophys Res Commun. 2025 Jan 11. pii: S0006-291X(25)00013-0. [Epub ahead of print]748 151299

Structural, functional, and regulatory evaluation of a cysteine post-translationally modified Gcn5-related N-acetyltransferase.

Patricia Uychoco, Karolina A Majorek, Ashley N Ives, Van Thi Bich Le, Pamela L Caro De Silva, Vanessa L Paurus, Isaac Kwame Attah, Mary S Lipton, Wladek Minor, Misty L Kuhn.

  Polyamines within the cell are tightly regulated by spermidine/spermine N-acetyltransferase (SSAT) enzymes. While several SSATs have been investigated in different bacterial species, there is still a significant gap in knowledge about which proteins are functional SSATs in many organisms. For example, while it is known that Pseudomonas aeruginosa synthesizes the polyamine spermidine, the SSAT that acetylates this molecule and its importance in regulating intracellular polyamines remains unknown. We previously identified a candidate Gcn5-related N-acetyltransferase (GNAT) protein from P. aeruginosa (PA2271) that could fulfill this role since it acetylates spermidine, but no further studies were conducted. Here, we explored the structure/function relationship of the PA2271 protein by determining its X-ray crystal structure and performing enzyme kinetics assays. We also identified active site residues that are essential for catalysis and substrate binding. As the study progressed, we encountered results that led us to explore the importance of four cysteine residues on enzyme activity and disulfide bond formation or modification of cysteine residues. We found these cysteine residues in PA2271 are important for protein solubility and activity, and there is an interrelationship between cysteine residues that contribute to these effects. Furthermore, we also found disulfide bonds could form between C121 and C165 and speculate that these residues may contribute to redox regulation of PA2271 protein activity.

Keywords:  Cysteine Post-Translational Modifications; Disulfide Bonds; Gcn5-related N-acetyltransferase (GNAT); Loss of enzyme activity with freeze/thaw cycles; Polyamine; Pseudomonas aeruginosa; Spermidine

DOI:  https://doi.org/10.1016/j.bbrc.2025.151299
Nat Commun. 2025 Jan 21. 16(1): 877

Lactobacillus reuteri ZJ617 attenuates metabolic syndrome via microbiota-derived spermidine.

Yanfei Ma, Yifan Zhong, Wenjie Tang, Teresa G Valencak, Jingliang Liu, Zhaoxi Deng, Jiangdi Mao, Daren Liu, Shanshan Wang, Yuhao Wang, Haifeng Wang.

Metabolic syndrome (MetS) is a difficult-to-manage disease that poses a significant risk to human health. Here, we show that the supplementation of Lactobacillus reuteri ZJ617 ameliorates symptoms of MetS in mice induced by the high-fat diet. L. reuteri ZJ617 modulates host metabolism by interacting with the microbiome, resulting in the production of spermidine synthesized by the microbiota. L. reuteri ZJ617 serves as a source of substrates for the microbiota to synthesize spermidine, hence preventing the decline of bacteria responsible for spermidine production. Spermidine treatment mimics the metabolic effects of L. reuteri ZJ617, whereas pharmacological inhibition of spermidine biosynthesis in mice abolishes these benefits. Our findings reveal the mechanism by which L. reuteri ZJ617 alleviates MetS symptoms and provide support for its potential use as a probiotic for promoting metabolic health.

DOI: https://doi.org/10.1038/s41467-025-56105-4
J Inherit Metab Dis. 2025 Jan;48(1): e12841

Spermidine Recovers the Autophagy Defects Underlying the Pathophysiology of Cell Trafficking Disorders.

Yaiza Díaz-Osorio, Helena Gimeno-Agud, Rosanna Mari-Vico, Sofía Illescas, Jose Miguel Ramos, Alejandra Darling, Àngels García-Cazorla, Alfonso Oyarzábal.

  Cell trafficking alterations are a growing group of disorders and one of the largest categories of Inherited Metabolic Diseases. They have complex and variable clinical presentation. Regarding neurological manifestations they can present a wide repertoire of symptoms ranging from neurodevelopmental to neurodegnerative disorders. The study of monogenic cell trafficking diseases draws an scenario to understanding this complex group of disorders and to find new therapeutic avenues. Within their pathophysiology, alterations in autophagy outstand as a targetable mechanism of disease, ammended to be modulated through different strategies. In this work we have studied the pathophysiology of two cell trafficking disorders due to mutations in SYNJ1 and NBAS genes. Specifically, we have assesed the autophagic flux in primary fibroblast cultures of the patients and gender/age-matched controls and whether it could be address with a therapeutic purpose. The results have shaped autophagy as one of the hallmarks of the disease. Moreover, we tested in vitro the effect of spermidine, a natural polyamine that acts as an autopagy inductor. Due to the positive results, its efficacy was evaluated later on the patients as well, in a series of n-of-1 clinical trials, achieving improvement in some clinical aspects related to motricity and cognition. Defining autophagy alterations as a common feature in the pathophysiology of cell trafficking disorders is a great step towards their treatment, as it represents a potential actionable target for the personalized treatement of these disorders.

Keywords:  NBAS; SYNJ1; autophagy; cell trafficking; neurodevelopmental diseases; spermidine

DOI:  https://doi.org/10.1002/jimd.12841
Biochem Biophys Res Commun. 2025 Jan 10. pii: S0006-291X(25)00016-6. [Epub ahead of print]748 151302

N-terminal domain swapping: A new paradigm for spermidine/spermine N-acetyltransferase (SSAT) protein structures?

Claudia E Mayer-Harnisch, Daniel Figueroa Paniagua, Natalia Maltseva, Youngchang Kim, Van Thi Bich Le, Andrzej Joachimiak, Misty L Kuhn.

  Enterococcus faecalis is a multi-drug-resistant human pathogen that is found in a variety of environments and is challenging to treat. Under stress conditions, some bacteria regulate intracellular polyamine concentrations via polyamine acetyltransferases to reduce their toxicity. The E. faecalis genome encodes two polyamine acetyltransferases: PmvE and BltD. Both of these proteins belong to the Gcn5-related N-acetyltransferase (GNAT) superfamily. It is unclear why there are two enzymes with similar substrate specificities in this organism. To better understand the structure/function relationship of the E. faecalis BltD enzyme, we determined its crystal structure and performed additional assays to explore its oligomeric state and enzymatic activity. The goal was to determine whether there were structural or catalytic differences between this enzyme and other polyamine acetyltransferases that could explain this redundancy and be exploited for future development of targeted inhibitors for this important human pathogen. We found the BltD enzyme was structurally unique due to its N-terminal domain swapped dimer. However, this enzyme adopts a catalytically active monomer rather than dimer in solution. This indicates the crystal structure we obtained may represent a state that forms at high protein and salt concentrations and at low pH used during crystallization. The BltD dimer found in the crystal may represent a unique view of how an inhibitory peptide or molecule could be designed to occupy its active site. Additionally, this structure shows the extensive flexibility of the N-terminal portion of the E. faecalis BltD enzyme.

Keywords:  Domain-swapped dimer; Gcn5-related N-Acetyltransferase (GNAT); N-terminal Domain Swapping; Polyamine Acetylation; Polyamine Acetyltransferase; Spermidine/Spermine N-Acetyltransferase (SSAT)

DOI:  https://doi.org/10.1016/j.bbrc.2025.151302
Free Radic Biol Med. 2025 Jan 15. pii: S0891-5849(25)00024-3. [Epub ahead of print]229 30-38

Spermidine antagonizes the anti-cancer effect of cold atmospheric plasma and induces transit G0/G1 cell cycle arrest of triple negative breast cancers.

Li Shen, Xinyu Lv, Yixin Li, Xiaofeng Dai.

  Cancer remains as a global health threat, with the incidence of breast cancers keep increasing. Dis-regulated redox homeostasis has been considered with essential roles for tumor initiation and progression. Using triple negative breast cancers, the most malignant subtype of breast cancers, as the tumor model, we explored the roles of the anti-oxidant spermidine, the pro-oxidative tool cold atmospheric plasma (CAP), and their combined use in cancer growth, anti-oxidative ability and cell cycle. We also characterized the important roles of FTO in driving the redox modulatory functionalities of spermidine and CAP-activated medium (PAM) as well as their demonstrated synergy on breast cancer cells. We found that spermidine reversed the anti-cancer effect of PAM and stimulated outrageous progression of transformed cells to the level exceeding that treated with spermidine alone, and combined launch of spermidine and PAM enabled cancer cells with elevated anti-oxidant ability and enhanced survival in response to instant redox perturbation via transient stalk at the G0/G1 stage. We, in addition, identified the vital role of FTO in mediating the observed effect of spermidine, PAM and their synergy, on triple negative breast cancer cells. Our results reported the antagonism between PAM and anti-oxidants as represented by spermidine for cancer treatment, and implicated the differential responses of healthy and diseased individuals to anti-oxidants for improved design on redox-based anti-cancer regimen.

Keywords:  Cell cycle arrest; Cold atmospheric plasma; Spermidine; Triple negative breast cancer

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.024
Biosensors (Basel). 2025 Jan 02. pii: 12. [Epub ahead of print]15(1):

Spermine Enhances the Peroxidase Activities of Multimeric Antiparallel G-quadruplex DNAzymes.

Raphael I Adeoye, Theresia K Ralebitso-Senior, Amanda Boddis, Amanda J Reid, Francesca Giuntini, Amos A Fatokun, Andrew K Powell, Adaoha Ihekwaba-Ndibe, Sylvia O Malomo, Femi J Olorunniji.

  G-quadruplex (G4) DNAzymes with peroxidase activities hold potential for applications in biosensing. While these nanozymes are easy to assemble, they are not as efficient as natural peroxidase enzymes. Several approaches are being used to better understand the structural basis of their reaction mechanisms, with a view to designing constructs with improved catalytic activities. Spermine alters the structures and enhances the activities of some G4 DNAzymes. The reported effect of spermine in shifting the conformation of some G4 DNAzymes from antiparallel to parallel has not been tested on multimeric G4 DNAzymes. In this study, we examined the effects of spermine on the catalytic activities of multivalent constructs of Bcl2, c-MYC, PS2.M, and PS5.M. Our findings show that spermine significantly improved the peroxidase activity of PS2.M, an antiparallel G4 DNAzyme, while there was no significant effect on c-MYC, which already exists in a parallel conformation. The addition of spermine led to a substantial increase in the initial velocity of PS2.M and its multimeric form, enhancing it by approximately twofold. Therefore, spermine enhancement offers promise in expanding the range of DNAzymes available for use as biosensing tools.

Keywords:  DNAzymes; G-quadruplex; biosensing; multivalent G-quartets; nanozymes; spermine

DOI:  https://doi.org/10.3390/bios15010012