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<p>One of the crucial questions about the origin of life is how the first metabolic networks emerged. Cofactors such as nicotinamide adenine dinucleotide (NAD⁺/NADH) are essential in modern metabolism, and their prebiotic analogues may have played a key role in the non-enzymatic coupling of protometabolic reactions. In this study we explore the potential of prebiotically plausible pyridinium/1,4-dihydropyridine pairs as reversible redox cofactors capable of linking catabolic and anabolic transformations. Using pyruvate as a model substrate, we demonstrate that one such pair can simultaneously mediate oxidative decarboxylation and reductive amination without enzymes. This redox activity extends to other α-ketoacids, producing key metabolites and amino acids such as succinate, acetate, formate, glutamate, alanine, and glycine. Structure-activity relationships highlight the importance of a carbamoyl group at the 3-position and suitable <i>N</i>-substitution for redox efficiency and stability, offering a physicochemical rationale for the natural selection of the nicotinamide ring. Electrochemical analyses and density functional theory (DFT) calculations provide mechanistic insights into the redox behaviour and reaction pathways of these cofactors. Our results suggest that simple redox-active molecules could have enabled early protometabolic coupling, helping bridge the gap between prebiotic chemistry and biological evolution.</p>

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Non-enzymatic coupling of protometabolic reactions with a prebiotic redox cofactor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月6日

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  • David González-Martínez,
  • Noemí Nogal,
  • Iván de la Infanta,
  • Pilar Ocón,
  • Fernando Aguilar-Galindo,
  • Javier Luis-Barrera,
  • Andrés de la Escosura

摘要

One of the crucial questions about the origin of life is how the first metabolic networks emerged. Cofactors such as nicotinamide adenine dinucleotide (NAD⁺/NADH) are essential in modern metabolism, and their prebiotic analogues may have played a key role in the non-enzymatic coupling of protometabolic reactions. In this study we explore the potential of prebiotically plausible pyridinium/1,4-dihydropyridine pairs as reversible redox cofactors capable of linking catabolic and anabolic transformations. Using pyruvate as a model substrate, we demonstrate that one such pair can simultaneously mediate oxidative decarboxylation and reductive amination without enzymes. This redox activity extends to other α-ketoacids, producing key metabolites and amino acids such as succinate, acetate, formate, glutamate, alanine, and glycine. Structure-activity relationships highlight the importance of a carbamoyl group at the 3-position and suitable N-substitution for redox efficiency and stability, offering a physicochemical rationale for the natural selection of the nicotinamide ring. Electrochemical analyses and density functional theory (DFT) calculations provide mechanistic insights into the redox behaviour and reaction pathways of these cofactors. Our results suggest that simple redox-active molecules could have enabled early protometabolic coupling, helping bridge the gap between prebiotic chemistry and biological evolution.