bims-hypusi 2026-08-30 papers

Issue of 2026–08–30
two papers selected by
Sebastian J. Hofer, Max Delbrück Center

J Biol Chem. 2026 Aug 28. pii: S0021-9258(26)02382-3. [Epub ahead of print] 113510

Mutually exclusive pathways for biosynthesis of polyamine homospermidine dependent on putrescine or agmatine.

Bin Li, Hamid R Baniasadi, Jue Liang, Margaret A Phillips, Anthony J Michael.

Homospermidine is a structural analog of spermidine, a polyamine that is essential for growth and cell proliferation in eukaryotes. The eukaryotic enzyme deoxyhypusine synthase (DHS) can synthesize homospermidine directly from spermidine and putrescine. Nonhomologous bacterial homospermidine synthase (HSS) synthesizes homospermidine directly from two molecules of putrescine. SpeY is a homolog of DHS in bacteria that is essential for homospermidine biosynthesis in a cyanobacterium. Recently, it was shown in the bacterial hyperthermophile Thermus thermophilus, that SpeY couples two molecules of agmatine produced by arginine decarboxylase to form N1,N9-bis(guanidino)homospermidine (G44G), which is then converted to homospermidine by a ureohydrolase. We sought to determine whether synthesis of G44G was a common feature of phylogenetically diverse SpeY homologs. Herein, we demonstrate that SpeY homologs from diverse bacterial phyla, and from species encoding arginine decarboxylases from three different protein folds, with either agmatinase or agmatine iminohydrolase partners, all form G44G. Diverse agmatine, N1-aminopropylagmatine and presumed G44G ureohydrolases convert G44G to homospermidine but SpeY-associated G44G ureohydrolases do not act on agmatine. Similarly, diverse agmatine, N1-aminopropylagmatine and presumed G44G iminohydrolases convert G44G to N1,N9-bis(carbamoyl)homospermidine but SpeY-associated G44G iminohydrolases do not act on agmatine. We identified ornithine decarboxylases in both the SpeY and HSS pathways that have become neofunctionalized to arginine decarboxylases, and in the HSS pathway are associated with an agmatinase. Bacterial homospermidine biosynthetic pathways are therefore dependent either on agmatine/SpeY or putrescine/HSS. Our study highlights a new role for agmatine in bacterial polyamine biosynthesis, which also includes the N1-aminopropylagmatine and carboxyaminopropylagmatine pathways for spermidine production.

DOI: https://doi.org/10.1016/j.jbc.2026.113510

Neuropharmacol Ther. 2026 ;3 49-62

Polyamine Metabolism in Brain Health and Disease.

Xianzun Tao, Tracey Nassuna, R Grace Zhai.

Polyamines, primarily spermidine and spermine, are small polycationic molecules essential for cell growth, signaling, and survival. Through electrostatic interactions with nucleic acids, lipids, and proteins, they regulate gene expression, organelle function, and adaptive responses to environmental cues. Polyamine metabolism also intersects with a myriad of other cellular pathways, including methionine, acetyl-CoA, and oxidative stress pathways, and is therefore involved in epigenetic control, cellular metabolism, and stress-response regulation. In the brain, beyond these general cellular functions, polyamines act as dynamic modulators of neurodevelopment, neural maintenance, and synaptic plasticity by influencing local proteostasis, transmitter release, and ion channel activity in both neurons and glia. Emerging evidence indicates that disruption of polyamine homeostasis contributes to neurological disorders as diverse as rare inborn errors of metabolism and common neurodegenerative diseases. Mutations in polyamine metabolic or transport genes lead to syndromes characterized by intellectual disability, hypotonia, movement disorders, and neurodegeneration; therefore, polyamine balance is critical for brain development and maintenance. In conditions such as Alzheimer's and Parkinson's diseases, dysregulated polyamine synthesis, catabolism, or lysosomal transport perturbs autophagic flux and proteostasis, thereby promoting Tau and α-synuclein aggregation, oxidative stress, and neuronal loss. Multi-omics analyses have further revealed that polyamine metabolism shapes glial inflammatory responses. Therapeutically, modulation of polyamine metabolism offers multiple intervention points. Spermidine supplementation or administration of polyamine analogues has been found to enhance autophagy and improve cognitive performance in models of aging and Alzheimer's disease. Additional strategies to reestablish metabolic equilibrium and support neuronal resilience include targeted manipulation of key enzymes, such as ornithine decarboxylase 1 (ODC1), spermidine/spermine acetyltransferase 1 (SAT1), spermine oxidase (SMOX), and spermine synthase (SMS), or restoration of lysosomal polyamine export via ATP13A2. This review synthesizes current understanding of polyamine metabolism in brain health and disease, by integrating molecular, cellular, and systems-level perspectives, and further highlights emerging therapeutic directions aimed at harnessing this pathway to mitigate neurological pathology.

Keywords: autophagy; mitochondria; neurological disorders; neuroprotection; polyamine

DOI: https://doi.org/10.15212/npt-2025-0028