bims-polyam 2025-02-16 papers

Issue of 2025–02–16
three papers selected by
Sebastian J. Hofer, University of Graz

Gut Microbes. 2025 Dec;17(1): 2464225

Uncovering de novo polyamine biosynthesis in the gut microbiome and its alteration in inflammatory bowel disease.

Xinwei Li, Xia Xiao, Shengnan Wang, Biyu Wu, Yixuan Zhou, Pan Deng.

Polyamines are important gut microbial metabolites known to affect host physiology, yet the mechanisms behind their microbial production remain incompletely understood. In this study, we developed a stable isotope-resolved metabolomic (SIRM) approach to track polyamine biosynthesis in the gut microbiome. Viable microbial cells were extracted from fresh human and mouse feces and incubated anaerobically with [U-13C]-labeled inulin (tracer). Liquid chromatography-high resolution mass spectrometry analysis revealed distinct 13C enrichment profiles for spermidine (SPD) and putrescine (PUT), indicating that the arginine-agmatine-SPD pathway contributes to SPD biosynthesis in addition to the well-known spermidine synthase pathway (PUT aminopropylation). Species differences were observed in the 13C enrichments of polyamines and related metabolites between the human and mouse microbiome. By analyzing the fecal metabolomics and metatranscriptomic data from an inflammatory bowel disease (IBD) cohort, we found significantly higher polyamine levels in IBD patients compared to healthy controls. Further investigations using single-strain SIRM and in silico analyses identified Bacteroides spp. as key contributors to polyamine biosynthesis, harboring essential genes for this process and potentially driving the upregulation of polyamines in IBD. Taken together, this study expands our understanding of polyamine biosynthesis in the gut microbiome and will facilitate the development of precision therapies to target polyamine-associated diseases.

Keywords: Polyamine; gut microbiome; inflammatory bowel disease; metabolomics; stable isotope

DOI: https://doi.org/10.1080/19490976.2025.2464225

PLoS One. 2025 ;20(2): e0308049

Development of a reliable, sensitive, and convenient assay for the discovery of new eIF5A hypusination inhibitors.

Oumayma Benaceur, Paula Ferreira Montenegro, Michel Kahi, Fabien Fontaine-Vive, Nathalie M Mazure, Mohamed Mehiri, Frederic Bost, Pascal Peraldi.

eIF5A is a translation factor dysregulated in several pathologies such as cancer and diabetes. eIF5A activity depends upon its hypusination, a unique post-translational modification catalyzed by two enzymes: DHPS and DOHH. Only a few molecules able to inhibit hypusination have been described, and none are used for the treatment of patients. The scarcity of new inhibitors is probably due to the challenge of measuring DHPS and DOHH activities. Here, we describe the Hyp'Assay, a convenient cell-free assay to monitor eIF5A hypusination. Hypusination is performed in 96-well plates using recombinant human eIF5A, DHPS, and DOHH and is revealed by an antibody against hypusinated eIF5A. Pharmacological values obtained with the Hyp'Assay, such as the EC50 of DHPS for spermidine or the IC50 of GC7 for DHPS, were similar to published data, supporting the reliability of the Hyp'Assay. As a proof of concept, we synthesized four new GC7 analogs and showed, using the Hyp'Assay, that these derivatives inhibit hypusination. In summary, we present the Hyp'Assay; a reliable and sensitive assay for new hypusination inhibitors. This assay could be of interest to researchers wanting an easier way to study hypusination, and also a valuable tool for large-scale screening of chemical libraries for new hypusination inhibitors.

DOI: https://doi.org/10.1371/journal.pone.0308049

Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01474-8. [Epub ahead of print]44(1): 115123

Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.

Veronica Ruggieri, Silvia Scaricamazza, Andrea Bracaglia, Chiara D'Ercole, Cristina Parisi, Paolo D'Angelo, Daisy Proietti, Chiara Cappelletti, Alberto Macone, Biliana Lozanoska-Ochser, Marina Bouchè, Lucia Latella, Cristiana Valle, Alberto Ferri, Lorenzo Giordani, Luca Madaro.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1G93A mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1G93A mice, opening new perspectives for the treatment of ALS.

Keywords: CP: Metabolism; CP: Neuroscience; amyotrophic lateral sclerosis; muscular atrophy; neuromuscular junction; polyamines; skeletal muscle; spatial transcriptomics

DOI: https://doi.org/10.1016/j.celrep.2024.115123