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Progress toward a Nonenzymatic Gluconeogenesis: One-Pot Reactions and Model Systems.

Joris Zimmermann¹, Quentin Dherbassy¹, Noemí Nogal²

¹Institut de Science et d'Ingénierie Supramoléculaires (ISIS), CNRS UMR 7006, Université de Strasbourg, 8 Allée Gaspard Monge, 67000 Strasbourg, France.

|May 29, 2026

Summary

Early life may have used nonenzymatic gluconeogenesis. This study explored conditions like metals and pH for nonenzymatic sugar synthesis, suggesting early life needed simultaneous acid-base catalysis beyond simple solutions.

Keywords:

catalysis gluconeogenesis nonenzymatic thioesterification and reduction prebiotic chemistry

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Area of Science:

Biochemistry
Origin of Life Studies
Metabolic Pathway Research

Background:

Phylogenetic reconstructions suggest early cells synthesized sugars via gluconeogenesis from ketoacids.
Metabolic theories propose that early metabolic pathways originated from nonenzymatic processes.
The specific conditions enabling nonenzymatic gluconeogenesis remain largely unknown.

Purpose of the Study:

To investigate the influence of metals and pH on nonenzymatic gluconeogenesis reactions.
To establish conditions for key nonenzymatic conversions within gluconeogenesis.
To explore the catalytic requirements for early nonenzymatic metabolic pathways.

Main Methods:

Developed one-pot reaction conditions for nonenzymatic phosphoenolpyruvate to 3-phosphoglycerate conversion.
Established conditions for nonenzymatic fructose-1,6-bisphosphate to glucose-6-phosphate conversion.
Demonstrated proof-of-concept for nonenzymatic acyl phosphate to thioester and aldehyde formation using model compounds.

Main Results:

Successfully achieved nonenzymatic conversions central to gluconeogenesis under specific conditions.
Identified the necessity of simultaneous acid and base catalysis for these reactions.
Model compound reactions mimicked key steps in the nonenzymatic conversion of 1,3-bisphosphoglycerate to glyceraldehyde-3-phosphate.

Conclusions:

Nonenzymatic gluconeogenesis is plausible under specific environmental conditions.
The origin of life likely involved simultaneous acid-base catalysis, possibly in localized environments.
Findings suggest early metabolic processes may have originated in environments beyond simple bulk solutions.