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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.
JACS Au
|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.
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.
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