How Small Heterocycles Make a Reaction Network of Amino Acids and Nucleotides Efficient in Water

Abstract

Organisms use enzymes to ensure af lowo f substrates through biosynthetic pathways. How the earliest form of life established biosynthetic networks and prevented hydrolysis of intermediates without enzymes is unclear. Organocatalysts may have played the role of enzymes. Quantitative analysis of reactions of adenosine 5-monophosphate and glycine that produce peptides,p yrophosphates,a nd RNAc hains reveals that organocapture by heterocycles gives hydrolytically stabilized intermediates with balanced reactivity. We determined rate constants for 20 reactions in aqueous solutions containing ac arbodiimide and measured product formation with cyanamide as ac ondensing agent. Organocapture favors reactions that are kinetically slow but productive,a nd networks,o vers ingle transformations.H eterocycles can increase the metabolic efficiency more than two-fold, with up to 0.6 useful bonds per fuel molecule spent, boosting the efficiency of life-like reaction systems in the absence of enzymes.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.

Synthesis of Peptido RNAs from Unprotected Peptides and Oligoribonucleotides via Coupling in Aqueous Solution

“…Further the solvent is non-toxic and inexpensive. Finally, extensive experience with the in situ activation of 5′-phosphates in recent years [37,9,10,12] helped to find conditions that lead to the necessary chemoselectivity.…”

“…[11] Peptido RNA formation can be induced by different condensation agents, [10] and the reactivity in the different reaction channels of the reaction system can be tuned by small organocatalysts, such as 1-ethylimidazole and 1-or 3methyladenine. [12] Scheme 1. Formation or synthesis of peptido RNA.…”

The Enzyme‐Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid

“…We measured the rate of hydrolysis in aqueous HEPES/1‐ethylimidazole buffer, pH 7.5, containing 0.08 m MgCl 2 via 31 P NMR. This combination of buffer components has previously been used successfully for the quantitative analysis of the formation of peptido RNAs [35, 36] . Figure 2 shows spectra and kinetics for the prolinyl phosphoramidate Pro‐A ( 5 ) at 37 °C.…”

“…A) Reaction scheme for the proline amidate Pro‐A ( 5 ). B) Overlay of 31 P NMR spectra with signals for Pro‐A, AMP, symmetrical pyrophosphate (PP), ethylimidazolium phosphate (EI‐AMP) and phosphodiesters (PD) labeled [36] . C) Comparison of the kinetics of hydrolysis for Pro‐A ( 5 ), Ala‐A ( 14 ) and Phe‐A ( 6 ); broken lines are monoexponential fits.…”

“…When the first screen, performed at 0 °C as in our earlier work on peptido RNAs, [34–36] gave unexpected differences in the rate of hydrolysis of amidates (entries 1–7), we decided to measure a larger data set at physiological temperature (37 °C). Again, the effect of the amino acid structure on the liberation of the nucleotide was strong.…”