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Origins of Sugars in the Prebiotic World • One theory: the formose reaction (discovered by Butterow in 1861) O Mineral catalysis H H mixture of sugars, including a small amount of ribose eg Ca(OH)2 formaldehyde H Mechanism? H HOH O H HO H O O O O H O O OH paraformaldehyde H H2O slow, very unfavorable O OH O O * O O H OH H O O O OH n * OH Con’t O O O OH depolymerise H OH O glycolaldehyde: simplest sugar & a catalyst for further rxns H Ca(OH)2 O HO HO H OH O -O H glyceraldehyde H H ene-diloate (enol) pentoses, hexoses via ene-diolate OH O H OH -OH H OH OH O -O O OH OH OH dihydroxyacetone via ene-diolate H O OH HO OH erythrose/threose H O OH -OH 2x OH HO OH erythrose/threose retro-aldol O H glycolaldehyde: cycle back for catalysis • Today, similar reactions are catalyzed by thiazolium, e.g., Vitamin B1 (TPP), another cofactor: • Cf Exp. 7: Benzoin (PP) HO S condensation H • e.g. N+ Py H OH + H O O HO OP glycolaldehyde OH O G3P OH HO OP D-xylulose-5-P Mechanism? Uses thiazolium O HO R -OH S S H - H N+ N+ Py Py OH R OH S carbanion: zwitterionic; stablized by +/- charge interaction N+ :B H OH Py N+ acidifies H O OP OH R S OH N+ thiazolium anion catalyst regenerated R Py HO OH OP S N+ Py HO + O HO OH OP xylulose-5-P HO H R S N Py OH OH enamine • We have seen how the intermediacy of the resonancestablized oxonium ion accounts for facile substitution at the anomeric centre of a sugar • What about nitrogen nucleophiles? CO2 H Many examples: CO2 H RO O + CO2 H N quinolinate N NADH CO2 H OH RO O RO O OH + OPP OH OH OH OH R = H or P NH3 RO O + NH2 nucleosides OH OH Could this process have occurred in the prebiotic world? • Reaction of an oxonium ion with a nitrogenous base: NUCLEOSIDES! HO OH O Mn+ Mineral days? OH O Hydrothermal vents? OH NH N H &/or apatite HO (mineral phosphate) O O NH HO + O O N O O OH HO O P OH O O OH OH OH OH Thymidine (a nuclesoside) OH Activated leaving group: CATALYSIS • Nucleosides are quite stable: 1) 2) Weaker anomeric effect: N< O < Cl (low electronegativity of N) N lone pair in aromatic ring hard to protonate O 1) O NH NH HO O HO O N + OH O N O - Charge separation:unfavorable, since -ve charge is on N, a less electronegative group OH OH OH Anomeric effect: Cl > O > N (remember the glycosyl chloride prefers Cl axial O 2) O NH NH HO O N O H+ + HO O X OH O N H OH OH lone pair part of aromatic sextet OH aromaticity destroyed (i.e., pyridine & pyrrole) • These effects stabilize the nucleoside making its formation possible in the pre-biotic soup • Thermodynamics are reasonably balanced • However, the reaction is reversible – e.g. deamination of DNA occurs ~ 10,000x/day/cell in vivo – Deamination is due to spontaneous hydrolysis & by damage of DNA by environmental factors – Principle of microscopic reversibility: spontaneous reaction occurs via the oxonium ion Ribonucleosides & Deoxyribonucleosides Ribonucleosides • Contain ribose & found in RNA: Cytosine Uracil Adenine Guanine + + + + Ribose Ribose Ribose Ribose Cytidine (C) Uridine (U) Adenosine (A) Guanosine (G) Deoxyribonucleosides • Contain 2-deoxyribose, found in DNA Cytosine Thymine Adenine Guanine + + + + 2-dR 2-dR 2-dR 2-dR 2’-deoxycytidine (dC) 2’-deoxythymidine (dT) 2’-deoxyadenosine (dA) 2’-deoxyguanosine (dG) Ribonucleosides O NH2 N N HO O OH O N HO O OH OH NH2 H N O N HO OH OH uridine (U) cytidine (C) O O N N N N HO OH O OH N N N NH2 OH guanosine (G) adenosine (A) Deoxyribonucleosides O NH2 N N HO O N O OH 2'-deoxycytidine (dC) HO O N NH2 H N O OH 2'-deoxythymidine (dT) HO O N O N N N OH 2'-deoxyadenosine (dA) HO O N N N OH 2'-deoxyguanosine (dG) NH2 Important things to Note: • Numbering system: – The base is numbered first (1,2, etc), then the sugar (1’, 2’, etc) • Thymine (5-methyl uracil) replaces uracil in DNA • Confusing letter codes: – A represents adenine, the base – A also represents adenosine, the nucleoside – A also represents deoxyadenosine (i.e., in DNA sequencing, where “d” is often omitted) – A can also represent alanine, the amino acid • Nucleoside + phoshphate nucleotide • In the modern world, enzymes (kinases) attach phosphate groups O HO O A -O P OH OH P O O O HO A OH P O O O O OH OH Adenosine-5'monophosphate (AMP) OH Adenosine-5'diphosphate (ADP) O HO A O O OH P P O O O P O O O Adenosine-5'triphosphate (ATP) Energy source for cell Central to metabolism In the pre-RNA world, how might this happen? P O O A O OH OH Observation: O NH HO 5' clay O N 4' 5' phosphate + 3' phosphate + higher phosphates (30 % + 50%) O (apatite) 1' NUCLEOTIDES! 2' 3' OH OH • Surprisingly easy to attach phosphate without needing an enzyme – One hypothesis: cyclo-triphosphate (explains preference for triphosphate O O O P P O O O O O P ATP O HO O T Primary OH? sterics? OH OH release of some ring strain in cylcotriphosphate drives reaction? • If correct, this indicates a central role for triphosphates of nucleosides (NTPs) in early evolution of RNA (i.e., development of the RNA world) • NTPs central to modern cellular biology