Quantifying Reductive Amination in Nonenzymatic Amino Acid Synthesis

• Published in: Angewandte Chemie International Edition Vol. 61; no. 48; pp. e202212237 - n/a
• Main Authors: Mayer, Robert J., Moran, Joseph
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 25.11.2022; Wiley-VCH Verlag; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Amination; Amines; Amino Acids; Amino Acids - chemistry; Ammonia; Ammonia - chemistry; Biosynthesis; Chemical Sciences; Glutamic Acid - metabolism; Hydride Transfer; Keto Acids; Ketoglutaric Acids - metabolism; Kinetics; Krebs cycle; Metabolism; Nucleophiles; Organic chemistry; Pyruvic acid; Reductive Amination; Tricarboxylic acid cycle; Kinetics; Hydride Transfer; Metabolism; Amino Acids; Reductive Amination
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202212237

Amino acid biosynthesis initiates with the reductive amination of α‐ketoglutarate with ammonia to produce glutamate. However, the other α‐keto acids derived from the glyoxylate and Krebs cycles are converted into amino acids by transamination, rather than by reductive amination. Why is only one amino acid synthesized by reductive amination and not the others? To explore this question, we quantified the inherent reactivities of keto acids in nonenzymatic reduction and reductive amination by using BH3CN− as a model nucleophile. Biological α‐keto acids were found to show pronounced nonenzymatic reactivity differences for the formation of amino acids (α‐ketoglutarate<oxaloacetate≈pyruvate≪glyoxylate). Accordingly, the flow of ammonia passes through the least reactive α‐keto acid of the Krebs cycle. One possible explanation for this choice is the position of the corresponding amino acid, glutamate, at the top of the thermodynamic landscape for subsequent transamination reactions. Why does biochemical amino acid synthesis proceed the way it does? Kinetic and mechanistic experiments with a model hydride donor were used to determine the intrinsic electrophilic reactivities of keto acids in reduction and reductive amination reactions. Comparing the nonenzymatic reactivity trends with those found in biology provides new insight into the structure of amino acid metabolism.