Harrison, Stuart A; (2022) Life as a guide to nucleotide synthesis and the origins of the genetic code. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A non-enzymatic protometabolic origins of life is gaining traction in origins of life research. This hypothesis, which uses life’s conserved chemistry as a guide to its own origins, has the capacity to explain the emergence of life in a way that resolves the “end-product problem”, places selection at the earliest stage of the emergence of life and can be used to determine ideal environments for such an emergence in an agnostic manner. There is experimental evidence for non-enzymatic reaction pathways which replicate the acetyl-CoA pathway, Krebs cycle, pentose-phosphate pathway, and glycolysis in a single, aqueous reaction system. The synthesis of nucleotides and their starting materials, ribose, aspartate, and glycine are not yet definitively proven and are separate investigations undertaken in this thesis. 1) I identified that whilst ribose stabilisation could be achieved in formose reaction conditions on addition of acetyl phosphate, this was due to alteration of the formose catalyst and termination of aldol chemistries rather than due to phosphorylation of sugar species. This points towards a potential, prebiotically relevant stabilisation of ribose on hydroxyapatite minerals. 2) I have identified from a limited investigation into the activity of pyridoxamine-5-phosphate-dependent transamination, that zinc dramatically improves transamination speed with only modest reduction in efficiency. Transamination is sufficiently fast to enable aspartate synthesis from oxaloacetate under non-optimal conditions. 3) I have identified that the formation of pyrimidine nucleobases is possible in a single, prebiotically plausible, one-pot reaction system. I have identified that the oxidation of dihydroorotate can take place with multiple oxidants, and copper (II) catalysis can enable production of both orotate and uracil. Investigating the environmental limitations of this reaction show that it can take place under a wide range of conditions, though optimal conditions appear to be most compatible with an alkaline hydrothermal vent hypothesis. Additionally, this thesis presents a hypothesis on the emergence of the genetic code in the context of this protometabolic network at the origins of life and uses conserved features of the genetic code as a guide to its own emergence.

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