Chemists Synthesize Carboxypolyamines and Design Inhibitors of Bacterial Polyamine Enzyme

Biogenic polyamines such as spermidine and spermine are small organic polycations that are vitally important across all domains of life. Recent studies have shown that polyamine biosynthesis has undergone convergent evolution, and that some bacteria rely on biosynthetic routes in which aspartate, rather than decarboxylated S-adenosylmethionine, supplies the three-carbon moiety needed to build these molecules. Carboxypolyamines are key intermediates in these aspartate-dependent pathways, and at the final step a specific PLP-dependent enzyme, carboxyspermidine decarboxylase (CASDC), converts carboxypolyamines into the corresponding polyamines.

A new open-access study published in the journal Amino Acids addresses a practical obstacle that has slowed progress in this field: investigating aspartate beta-semialdehyde-dependent pathways requires substrates that are not commercially available, along with potent enzyme inhibitors. The authors, including Arthur Salikhov, Alex Khomutov, Inna Karpenko, Yaroslav Tkachev, Anthony Michael and Maxim Khomutov, report a convenient chemical synthesis of three such substrates: carboxyspermidine, carboxyspermine, and carboxythermospermine. Having these compounds available in the laboratory makes it possible to study these poorly understood bacterial pathways directly.

The study also describes a mechanism-based inhibitor strategy. The researchers designed isosteric hydroxylamine-containing analogs of carboxypolyamines, molecules in which a hydroxylamine group replaces part of the natural scaffold, and report that the use of these analogs will lead to selective and effective inhibition of CASDC. The synthesis of these O-substituted hydroxylamines is described in the paper. Because CASDC catalyzes the final decarboxylation step of the pathway, inhibitors modeled on its natural substrates offer a targeted way to block the route in experimental systems.

The work is published as an Original Article and was released on 29 August 2026 as an open-access, peer-reviewed accepted manuscript that is citable under a permanent DOI, with a final Version of Record to follow. Within the scope defined by the authors, the reported syntheses of carboxypolyamine substrates and hydroxylamine-containing analogs provide chemical tools for probing an alternative bacterial polyamine biosynthetic route and for designing selective inhibitors of its terminal decarboxylase, an approach the authors position as a foundation for further investigation of these pathways in bacteria.

Subject of Research: Chemical synthesis of carboxypolyamines and mechanism-based inhibitors of carboxyspermidine decarboxylase in bacterial aspartate-dependent polyamine biosynthesis

Article Title: Aspartate-dependent polyamine biosynthesis in bacteria: chemical synthesis of carboxypolyamines and mechanism-based design of hydroxylamine-containing inhibitors of carboxyspermidine decarboxylase

Article References: Salikhov, A., Khomutov, A., Karpenko, I., Tkachev, Y., Michael, A., & Khomutov, M. (2026). Aspartate-dependent polyamine biosynthesis in bacteria: chemical synthesis of carboxypolyamines and mechanism-based design of hydroxylamine-containing inhibitors of carboxyspermidine decarboxylase. Amino Acids. https://doi.org/10.1007/s00726-026-03550-0

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DOI: 10.1007/s00726-026-03550-0

Keywords: polyamines, bacteria, biosynthesis, carboxypolyamines, carboxyspermidine decarboxylase, enzyme inhibitors, hydroxylamine analogs, aspartate pathway, chemical synthesis, PLP-dependent enzyme, Amino Acids journal, convergent evolution