Non-enzymatic Analogues of Amino Acid Biosynthesis to Understand the Origin of Life
Final Report Abstract
Biochemical amino acid synthesis starting from α-keto acids takes a rather unusual detour: nitrogen, in the form of ammonia, is used to synthesize glutamate from α-ketoglutarate via reductive amination. The amino group of all other natural amino acids or their synthetic precursors is subsequently introduced by transamination reactions with glutamate. The aim of my research project was to investigate whether this detour is related to underlying reactivity trends that were already relevant within prebiotic chemistry. First, nonenzymatic transamination was investigated. Systematic screening allowed the identification of several metal ions (Cu2+, Ni2+, Co2+, V5+), which catalyze the transamination reactions of various keto with amino acids. In a detailed mechanistic study, the mechanism of this reaction and the specific way in which metal ions act as catalysts was elucidated. Building on these results, it was furthermore demonstrated that nonenzymatic transamination reactions are promoted even more effectively by co-catalysis of metal ions (Al3+, Fe3+) with the biological coenzyme pyridoxal. The identified nonenzymatic transamination reactions without and with the coenzyme pyridoxal occur under very mild conditions and are thus potentially relevant for the emergence of metabolism. Second, reduction reactions were studied. On the one hand, the nucleophilic reactivity of the biochemically relevant hydride donors NADH and NADPH was characterized using benzhydrylium ions and compared with the reducing agent BH3CN– commonly used in organic synthesis. It was found that the BH3CN– ion exhibited similar nucleophilic reactivity compared to the biological hydride donors. Using BH3CN– as a model nucleophile, a systematic kinetic study of reduction and reductive amination was performed. This showed that α-ketoglutarate, which is the only substrate that is biochemically converted to the amino acid glutamate by reductive amination, is the least reactive of the investigated keto acids. However, glutamate was found in the first phase of the project to be the thermochemically best amine donor in transamination reactions. Thus, the importance of the reductive amination of α-ketoglutarate in biology can be rationalized by the role of glutamate as a “high-energy” amine species within amino acid metabolism, from which all other amino acids can be conveniently obtained by thermochemically feasible transamination reactions. Finally, the role of metal ions in the direct reduction of keto acids with NADH was investigated. It was shown that some metal ions acting as Lewis acids increase the reactivity of keto acids by more than five orders of magnitude and thereby enable their reduction with NADH.
Publications
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Mechanistic Insight into Metal Ion-Catalyzed Transamination. Journal of the American Chemical Society, 143(45), 19099-19111.
Mayer, Robert J.; Kaur, Harpreet; Rauscher, Sophia A. & Moran, Joseph
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Quantifying Reductive Amination in Nonenzymatic Amino Acid Synthesis. Angewandte Chemie International Edition, 61(48).
Mayer, Robert J. & Moran, Joseph
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Mechanism and catalysis of nonenzymatic analogs of amino acid biosynthesis. Advances in Physical Organic Chemistry, 1-39. Elsevier.
Mayer, Robert J. & Moran, Joseph
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Metal-Pyridoxal Cooperativity in Nonenzymatic Transamination. Journal of the American Chemical Society, 145(24), 13357-13370.
Dherbassy, Quentin; Mayer, Robert J.; Muchowska, Kamila B. & Moran, Joseph
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Quantification of the hydride donor abilities of NADH, NADPH, and BH3CN−in water. Organic & Biomolecular Chemistry, 21(1), 85-88.
Mayer, Robert J. & Moran, Joseph
