Magalhães, Álvaro Filipe Alves; (2023) Studies towards organocatalytic triose glycolysis and sulfide mediated peptide ligation at the origins of life. Doctoral thesis (Ph.D), UCL (University College London).

Text Magalhaes_Alvaro_PhD_Thesis_Corrections.pdf - Accepted Version Access restricted to UCL open access staff until 1 January 2025. Download (25MB)

Abstract

Metabolism sustains organisms through a complex set of catalytically regulated reactions that harness specific environmental inputs. In modern cells metabolism is made possible by genetically coded reaction-specific proteins, that in turn regulate reactions within the metabolic network. The first cells, like modern cells, must have been supported by their environment, but what were the first steps in establishing metabolic control over environmental inputs into life? Triose glycolysis is one of the most ancient metabolic pathways and is responsible for converting sugars into both pyruvate, the most interconnected node in metabolism, and phosphoenolpyruvate, biology’s highest energy phosphate. Our group has previously identified a protometabolic network that transforms the simplest sugar, glycolaldehyde, into phosphoenolpyruvate and pyruvate. Part of this thesis outlines a potential first step towards protein- catalysed triose glycolysis and highlights the potential importance of organocatalysis in bridging this gap. We specifically identify amino acid and peptide catalysts that accelerate a key step in this prebiotic pathway. Proline was specifically identified as an effective and prebiotically available co-catalyst. Through a rare aldol intermediate we shed light on the co-catalytic mechanism, and the enantioenrichement of D-glyceraldehyde-2-phosphate by L-proline. This work suggests that proline-containing peptides could play a role as an earlier version of complex proteins. Peptide synthesis is a key challenge for prebiotic chemistry. Prebiotic chemistry must identify high yielding peptide synthesis, within the limited substrate scope of the field, compatible with life’s other building blocks. Part of this thesis builds on previous reports of peptide ligation by chemoselective aminonitrile coupling, investigating peptidyl amidines as potential intermediates in prebiotic peptide synthesis. Peptidyl amidine synthesis is also investigated through thiol-catalysed peptide ligation within membraneless compartments; and in the presence of important metal ions found in co-factors. These discoveries present a step towards demonstrating interconnectivity of different prebiotic chemistries and showing how peptides can regulate metabolism.

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