In April 2016 Manchester eScholar was replaced by the University of Manchester’s new Research Information Management System, Pure. In the autumn the University’s research outputs will be available to search and browse via a new Research Portal. Until then the University’s full publication record can be accessed via a temporary portal and the old eScholar content is available to search and browse via this archive.

Studies Towards the Chemical Origins of Life

Islam, Saidul

[Thesis]. Manchester, UK: The University of Manchester; 2011.

Access to files

Abstract

The ‘RNA World’ hypothesis states that RNA was the first living system on the primitive Earth, where it carried out dual genotypic and phenotypic functions. Therefore, RNA must have self-assembled by purely chemical means from small prebiotic feedstock molecules. A plausible demonstration of the synthesis of RNA with the natural [5′→3′] phosphodiester linkage, and its self-replication has not been achieved so far. Some have speculated a ‘simpler’ informational polymer preceded it, and biology based on this polymer subsequently ‘invented’ RNA. The structurally simpler L-α-threofuranosyl nucleic acid (TNA) has been proposed as a primordial ancestor to RNA. A study into the potential self-assembly of TNA nucleotides was carried out. It is shown that as a direct result of TNA’s structural simplicity, its generational chemistry is more difficult than RNA. The tetrose aminooxazolines are unstable under the conditions of its formation. The tetrose anhydronucleosides efficiently incorporate phosphate to form activated tetrose cytidine-2′,3′-cyclic phosphates, but with the wrong stereochemistry.Strong support for the ‘RNA world’ hypothesis came from a report in 2009 of the prebiotic synthesis of activated pyridimine ribonucleoside-2′,3′-cyclic phosphates. Oligomerisation studies were carried out on these activated monomers with various catalysts, and NMR studies were carried out to determine the aspects of their reactivity. It was found that only short oligomers are formed. However, nucleoside-2′,3′-cyclic phosphates were found to selectively hydrolyse to a 2:1 mixture of 3′ and 2′-monophosphates, and this observation was considered as etiologically relevant. Nucleoside-2′ and 3′-monophosphates cyclise back to nucleoside-2′,3′-cyclic phosphates upon phosphate activation, and so cannot be considered as direct candidates for oligomerisation. A chemistry that selectively uses the nucleoside-3′-phosphate for the synthesis of RNA, and recycles the unwanted 2′-phosphate would be highly desirable. Thus, a regio- and chemoselective reaction that selectively acetylates monomer and oligomer nucleoside-3′-phosphates at the 2′-hydroxyl in water is presented. Nucleoside-2′-phosphates are shown to acetylate less efficiently, and show a greater propensity to recyclise back to nucleoside-2′,3′-cyclic phosphates. Purine nucleotides were also found to acetylate better than pyrimidines. This potentially primordial protecting group chemistry approach towards the prebiotic synthesis of RNA is conceptually novel, and has the potential to give a natural [5′→3′] phosphodiester linkage isomer. It is considered as a major step towards solving the long-standing problem of non-enzymatic self-replication of RNA.

Bibliographic metadata

Type of resource:
Content type:
Form of thesis:
Type of submission:
Degree type:
Doctor of Philosophy
Degree programme:
PhD Chemistry (42 month)
Publication date:
Location:
Manchester, UK
Total pages:
342
Abstract:
The ‘RNA World’ hypothesis states that RNA was the first living system on the primitive Earth, where it carried out dual genotypic and phenotypic functions. Therefore, RNA must have self-assembled by purely chemical means from small prebiotic feedstock molecules. A plausible demonstration of the synthesis of RNA with the natural [5′→3′] phosphodiester linkage, and its self-replication has not been achieved so far. Some have speculated a ‘simpler’ informational polymer preceded it, and biology based on this polymer subsequently ‘invented’ RNA. The structurally simpler L-α-threofuranosyl nucleic acid (TNA) has been proposed as a primordial ancestor to RNA. A study into the potential self-assembly of TNA nucleotides was carried out. It is shown that as a direct result of TNA’s structural simplicity, its generational chemistry is more difficult than RNA. The tetrose aminooxazolines are unstable under the conditions of its formation. The tetrose anhydronucleosides efficiently incorporate phosphate to form activated tetrose cytidine-2′,3′-cyclic phosphates, but with the wrong stereochemistry.Strong support for the ‘RNA world’ hypothesis came from a report in 2009 of the prebiotic synthesis of activated pyridimine ribonucleoside-2′,3′-cyclic phosphates. Oligomerisation studies were carried out on these activated monomers with various catalysts, and NMR studies were carried out to determine the aspects of their reactivity. It was found that only short oligomers are formed. However, nucleoside-2′,3′-cyclic phosphates were found to selectively hydrolyse to a 2:1 mixture of 3′ and 2′-monophosphates, and this observation was considered as etiologically relevant. Nucleoside-2′ and 3′-monophosphates cyclise back to nucleoside-2′,3′-cyclic phosphates upon phosphate activation, and so cannot be considered as direct candidates for oligomerisation. A chemistry that selectively uses the nucleoside-3′-phosphate for the synthesis of RNA, and recycles the unwanted 2′-phosphate would be highly desirable. Thus, a regio- and chemoselective reaction that selectively acetylates monomer and oligomer nucleoside-3′-phosphates at the 2′-hydroxyl in water is presented. Nucleoside-2′-phosphates are shown to acetylate less efficiently, and show a greater propensity to recyclise back to nucleoside-2′,3′-cyclic phosphates. Purine nucleotides were also found to acetylate better than pyrimidines. This potentially primordial protecting group chemistry approach towards the prebiotic synthesis of RNA is conceptually novel, and has the potential to give a natural [5′→3′] phosphodiester linkage isomer. It is considered as a major step towards solving the long-standing problem of non-enzymatic self-replication of RNA.
Thesis main supervisor(s):
Language:
en

Institutional metadata

University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:130330
Created by:
Islam, Saidul
Created:
12th September, 2011, 10:41:05
Last modified by:
Islam, Saidul
Last modified:
10th January, 2012, 13:42:47

Can we help?

The library chat service will be available from 11am-3pm Monday to Friday (excluding Bank Holidays). You can also email your enquiry to us.