Prebiotic Origin of Pre-RNA Building Blocks in a Urea “Warm Little Pond” Scenario

Article abstract of DOI:10.1002/cbic.202000510

Urea appears to be a key intermediate of important prebiotic synthetic pathways. Concentrated pools of urea likely existed on the surface of the early Earth, as urea is synthesized in significant quantities from hydrogen cyanide or cyanamide (widely accepted prebiotic molecules), it has extremely high water solubility, and it can concentrate to form eutectics from aqueous solutions. We propose a model for the origin of a variety of canonical and non-canonical nucleobases, including some known to form supramolecular assemblies that contain Watson-Crick-like base pairs.The dual nucleophilic-electrophilic character of urea makes it an ideal precursor for the formation of nitrogenous heterocycles. We propose a model for the origin of a variety of canonical and noncanonical nucleobases, including some known to form supramolecular assemblies that contain Watson-Crick-like base pairs. These reactions involve urea condensation with other prebiotic molecules (e. g., malonic acid) that could be driven by environmental cycles (e. g., freezing/thawing, drying/wetting). The resulting heterocycle assemblies are compatible with the formation of nucleosides and, possibly, the chemical evolution of molecular precursors to RNA. We show that urea eutectics at moderate temperature represent a robust prebiotic source of nitrogenous heterocycles. The simplicity of these pathways, and their independence from specific or rare geological events, support the idea of urea being of fundamental importance to the prebiotic chemistry that gave rise to life on Earth.

Full text of DOI:10.1002/cbic.202000510

Combining Chemistry and Biology
Accepted Article
Title: Prebiotic origin of pre-RNA building blocks in a urea “warm little
pond” scenario.
Authors: Cesar Menor-Salvan, Marcos Bouza, David M. Fialho,
Bradley T. Burcar, Facundo M. Fernández, and Nicholas V.
Hud
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemBioChem 10.1002/cbic.202000510
Link to VoR: https://doi.org/10.1002/cbic.202000510
01/2020

10.1002/cbic.202000510
ChemBioChem
COMMUNICATION
Prebiotic origin of pre-RNA building blocks in a urea “warm little
pond” scenario.
Cesar Menor-Salván*[a,c] Marcos Bouza[a,b], David M. Fialho[a,b], Bradley T. Burcar[a,b] , Facundo M.
Fernández[a,b], and Nicholas V. Hud[a,b]
[a]
Prof. C.Menor-Salvan, Prof. N. V. Hud, Dr. M. Bouza, Dr. D. Fialho, Dr. B. Burcar, Prof. F. Fernández.
NSF-NASA Center for Chemical Evolution
Georgia Institute of Technology
30302 Atlanta (USA)
E-mail: cesar.menor@chemistry.gatech.edu, Nick.hud@chemistry.gatech.edu
Prof. N. V. Hud, Dr. M. Bouza, Dr. D. Fialho, Dr. B. Burcar, Prof. F. Fernández
School of Chemistry and Biochemistry
Georgia Institute of Technology
30302 Atlanta (USA)
Prof. C. Menor-Salvan
[b]
[c]
Dep. de Biología de Sistemas/IQAR
Universidad de Alcalá
28806 Madrid (Spain)
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Urea appears to be a key intermediate of important
prebiotic synthetic pathways. Concentrated pools of urea likely
existed on the surface of the early Earth, as urea is synthesized in
significant quantities from hydrogen cyanide or cyanamide (widely
accepted prebiotic molecules), it has extremely high water solubility,
and it can concentrate to form eutectics from aqueous solutions. The
dual nucleophilic-electrophilic character of urea makes it an ideal
precursor for the formation of nitrogenous bases. We propose a
model for the origin of a variety of canonical and non-canonical
nucleobases, including some known to form supramolecular
assemblies that contain Watson-Crick-like base pairs. These
reactions involve urea condensation with other prebiotic molecules
(e.g., malonic acid) that could be driven by environmental cycles
(e.g., freezing/thawing, drying/wetting). The resulting heterocycle
assemblies are compatible with the formation of nucleosides and,
possibly, the chemical evolution of molecular precursors to RNA. We
show that urea eutectics at moderate temperature represent a robust
prebiotic source of nitrogenous heterocycles. The simplicity of these
pathways, and their independence from specific or rare geological
events, support the idea of urea being of fundamental importance to
the prebiotic chemistry that gave rise to life on Earth.
expanded space of structures is compatible with the view that
the evolution of pre-biopolymers resulted in functionally superior
RNA and DNA[8]. We propose that concentrated solutions of
urea were essential for pre-RNA chemical evolution. This
proposal is based upon two primary observations: (1) urea is
produced in model prebiotic and astrochemical reactions from
one-carbon sources, such as cyanide, cyanamide, methane, or
carbon oxides[13–15], and (2) urea is relatively stable, allowing it to
accumulate over time on the surface of the early Earth. Urea
forms high-concentration viscous solutions[16] that favor its
accumulation in evaporating ponds. The abundance of urea in
the presence of other prebiotic components would allow for the
creation of large-scale stable eutectic as low-water
environments. In these environments, wet-dry cycles could have
easily concentrated and selected molecules, promoting
reactions potentially important for initiating life. The atmospheric
formation of reactive species over a concentrated solution of
urea (using methane or acetylene as precursors and UV
radiation or spark discharges as energy sources) subjected to
freeze-thaw cycles has been shown to result in the formation of
pyrimidines, triazines, and purines; significant yields being
observed of barbituric and cyanuric acid, together with their
corresponding aminopyrimidines and aminotriazines[17,18]. Hence,
the formation of eutectic urea solutions in
a prebiotic
environment could constitute a good scenario for the origination
of nucleobases; this property could be added to its previously
reported ability to promote phosphorylation of alcohols, including
nucleosides[16], and its physicochemical properties that are
The de novo prebiotic formation of RNA during the process
of life origination is challenging, due to the discussed availability
or plausibility of some reagents, and the complexity of the
numerous steps required for the synthesis of ribonucleotides
and their subsequent polymerization. In recent years, the
question of the formation of the canonical components of RNA
received intensive research[1–5]. The seeking of routes to RNA
from plausible abiotic precursors on early Earth is not exempt of
problems[6], and that have led many scientists to view the RNA
World as an intermediate stage in the origins of life, with simpler
polymers serving in catalytic and informational roles before the
emergence of RNA[7–10]. The possibility of pre-RNA structures
and precursors widely opens the evolutionary perspective of the
origin of life, as there exist alternative nucleobases that readily
form nucleosides with ribose and other sugars[11,12], and the
potentially useful for pre-enzyme nucleic acid evolution[19]
.
Heterocycle synthesis in urea solutions is of renewed interest
with the recent discovery of high-yielding model prebiotic
reactions
for
the
ribosylation
of
melamine,
2,4,6-
These
triaminopyrimidine (TAP) and barbituric acid[11,20]
.
nucleoside analogs are particularly interesting as they can form
supramolecular assemblies as monomers with complementary
heterocycles (e.g., TAP with cyanuric acid, melamine with
barbituric acid). The C-riboside formed by barbituric acid can be
regarded as a prebiotic analog of uridine and pseudouridine,
which opens the possibility of pre-RNA, informational carrying
structures with non-canonical nucleobases that are extremely
1
This article is protected by copyright. All rights reserved.

10.1002/cbic.202000510
ChemBioChem
COMMUNICATION
close to the extant nucleobases[20]. Taken together, these results
suggest an early important role of urea as a precursor to pre-
RNA and extant RNA building blocks[9]. We hypothesized that
urea enriched ponds could be a source of non-canonical
nucleosides, if malonic acid is present in the prebiotic chemical
space. In preliminary results[21] we showed that malonic acid,
which could be formed by hydrolysis of malononitrile[22,23], by
irradiation of urea[13], or by prebiotic proto-metabolic cycles, as
the malonate cycle[24], could condense efficiently with urea in a
“warm little pond” model to yield pyrimidines in prebiotic
conditions. In this communication we further explore the
formation of nucleobases and non-canonical nucleosides of
interest for chemical evolution[8], in a prebiotic urea-warm little
pond using malonic acid as precursor.
the dry phase, followed by rehydration and heating at 60ºC for
12 hours in the wet phase. After 3 days cycling, barbituric acid
crystals had grown. The solution was lyophilized, and the
viscous residue analyzed after formation of trimethylsilyl
derivatives (Fig S1 A). The analysis by gas chromatography-
mass spectrometry (GC-MS) showed the formation of barbituric
acid with a measured 42% yield with respect to initial malonic
acid. Also, 2-amino-4,6-dihydroxypyrimidine and 6-aminouracil
were found in low yields, as well as expected 5-carbamoylated
products[25]. The dry/wet cycling of the urea-malonic acid
solution did not reveal significant production of triazines.
If urea is replaced by biuret in the same conditions,
cyanuric acid is formed (Fig. S1 B). These results are consistent
with our previous results on the formation of s-triazines in an ice
matrix[18], in which we postulated that the s-triazine synthesis
proceeded through the formation of
biuret with spark discharges through
the ice matrix containing brines of
dry-heat
for 12 h
A
highly
concentrated
urea.
This
5-10x
reaction is equivalent to the classic
cyanuric acid synthesis from urea at
high temperature[26], suggesting that s-
Rehydration
triazines
could
be
formed
in
dehydrating urea solutions through the
formation of biuret.
It is unlikely that eutectic or
B
concentrated urea solutions in
a
prebiotic setting were formed by pure
urea. Cyanide in a dry/wet scenario in
the presence of ammonia in oxidative
environments could be an efficient
prebiotic source of urea[14]; however,
the irradiation of an ammonium
cyanide solution would lead to
a
C
D
mixture of urea and guanidine, and it
is possible to verify the formation of a
viscous solution in the heating/dry-wet
experiments (Fig. S2). Guanidine
could represent a prebiotic precursor
of 2,4,6-triaminopyrimidine (TAP), a
non-canonical nucleobase that readily
forms N-glycosides and C-glycosides
*
(1%)
(4%)
(8%)
**
*
2 TMS
(45%)
(11%)
(55%)
***
3 TMS
4 TMS
**
(1.5%)
(3%)
***
with ribose and other aldoses[12]
.
*
*
Although TAP was not previously
reported in prebiotic model reactions,
Retention time (min)
Retention time (min)
the condensation of guanidine and malononitrile to yield TAP
(and melamine, from self-condensation of guanidine) was
observed to happen at high yield in dry conditions at T100 ºC,
as a mixture of TAP and melamine (Fig. S3). Moreover, in the
more prebiotically relevant conditions of dry-wet cycles at 85 ºC,
a mixture of urea and guanidine to which malononitrile has been
added yielded TAP, melamine, and related amino-
hydroxypyrimidines (Fig. S4); given that malononitrile could be a
Figure 1. (A) Synthesis of 2,4,6-functionalized pyrimidines by condensation of
urea/guanidine and malonic acid during environmental cycles under prebiotic
conditions; (B) Cocrystals of barbituric acid and 2-aminopyrimidine-4,6-diol
formed during dry/wet cycles experiment at 65ºC; (C) GC-MS chromatogram
showing the trimethylsilyl derivatives of the products of condensation of
malonic acid in an equimolar urea/guanidine solution subjected to cycles of
drying and momentary rewetting. Product yield indicated at each structure; (D)
GC-MS chromatogram showing the trimethylsilyl derivatives of the products
resulting from the condensation of malonic acid and urea in a solution
subjected to dry/wet cycles at 65ºC.
prebiotic precursor produced from cyanoacetylene[22]
, and
malonic acid produced by irradiation of urea solutions[13,21], could
malonic acid be a precursor of pyrimidines in the warm little
pond prebiotic scenario? Considering that guanidine is a likely
prebiotic product along with urea, a solution containing 2 mmol
of urea and 1 mmol each of guanidine and malonic acid were
subjected to dry-wet cycle under the same conditions previously
detailed with urea or biuret alone (Fig S1). After 5 days of
To explore whether the malonic acid-urea condensation
could be a prebiotic reaction for the origin of the barbituric acid
family of pyrimidines, we subjected a solution of 2 mmol urea
and 0.5 mmol malonic acid to dry-wet cycles: 85ºC for 6 hours in
2
This article is protected by copyright. All rights reserved.

10.1002/cbic.202000510
ChemBioChem
COMMUNICATION
wet/dry cycles at 65 ºC, a mixture containing pyrimidines was
formed (Fig. 1) along with the formation of co-crystals (melting
point 240-260 ºC), whose analysis by GC-MS shows are formed
by barbituric acid and 2-amino-4,6-dihydroxypyrimidine,
consistently with the melting point (Fig. 1B).
incorporated by other processes. One significant aspect is the
formation of the 2,4,5-triaminopyrimidine (Fig.1), identified
through electron impact mass fragmentation signatures in GC-
MS (Fig. S8) and consistent retention times with reference
samples; this constitutes a possible prebiotic synthesis of this
pyrimidine, which has also been proposed as possible building
block of pre-RNA[27]
Urea and guanidine are essential in these reactions (Scheme 3),
and the two possible urea alteration pathways in solution involve
its decomposition into ammonia and carbon dioxide, and its
isomerization to ammonium cyanate. The released NH3 could
lead to the formation of monoamidomalonic acid (observed in
the experiments with malonic acid, Fig.1), and malonodiamide.
The carbamoylation of monoamidomalonic acid by urea-derived
isocyanate, followed by cyclization through intramolecular
nucleophilic attack of the amino group, could explain the
synthesis of the 4-amino-2,6-dihydroxypyrimidine. Finally, the
condensation of malonodiamide (derived from malonic acid or
malononitrile) with urea or guanidine, lead to the formation 2-
hydroxy-4,6-diaminopyrimidine and TAP (scheme 3).
This reaction reached a maximum yield of 55% 2-amino-4,6-
dihydroxypyrimidine, calculated from chromatographic peak
areas and expressed as molar percentage of total malonic acid
introduced in the experiment; as accompanying products,
significant formation of 2,4,5-triaminopyrimidine, melamine, and
a small amount of TAP were observed (Fig 1C). The reaction
proceeds optimally in the range 65-85 ºC, losing efficiency at
higher temperatures due to the increase of malonic acid
decarboxylation to acetic acid and CO2. In parallel, an
experiment performed in the same conditions with urea alone in
absence of guanidine, shows barbituric acid as main product,
with an increased yield of 6-aminouracil respect to the
experiment with guanidine (Fig. 1D); note the absence of
cyanuric acid, which seems to be formed only when the
carbamoylurea (biuret) is present in the experiment (Fig. S1)
Figure 3. (A) Reaction tube showing
A
B
C
formation of a pyrimidines precipitate after
dilution with water of the product of wet-
170.0199
170.0560
dry cycles at 85ºC of a urea/guanidine
solution to which malonic acid was added;
168.0401
(B) Positive ion mode electrospray mass
171.023
spectrum obtained after dissolution of
127.0139
127.0736
precipitates in an ammoniacal water-
methanol solution. (C) Mass spectrum
(negative ion mode) of the precipitate
dissolved in ammoniacal water-methanol,
showing the exact masses of identified
compounds. D: Dry-wet reaction model.
Dehydration of the urea rich solution led to
the condensation of urea and malonic acid,
169.0720
157.083
152.096
172.0351
152.993
D
forming
pyrimidines.
Furthermore,
decomposition of urea into isocyanic acid
could be the key step in the formation of 5-
carbamoylpyrimidines and the triazines. In
the next phase of rehydration and dilution,
previously formed pyrimidines could form
supramolecular aggregates by base
pairing (blue hexagons) that precipitate.
An increase of concentration of urea, by
evaporation or input of urea by hydrolysis
of hydrogen cyanide or cyanamide, could
dissolve the aggregates totally or partially.
Hence, base pairing and dry-wet cycles
could be a selection and concentration
mechanism of nucleobases formed
E
+
-
C9H14N3O6
BARCC9H11N2O7
m/z 260.08750(-0.80 ppm)
m/z 259.05727(0.20 ppm)
+
-
+
C6H13N2O5
m/z 193.08190(0.20 ppm)
Acetyl C11H13N2O8
Acetyl
C11H16N3O7
m/z 302.09852(0.79 ppm)
m/z 301.06757(-0.67ppm)
-
C
12H14N3O9
Malonyl
m/z 344.07341(-0.39ppm)
+
C
14H22N3O10
N-ribosyl
previously
in
urea
solutions;
(E)
m/z 392.12986(-0.28ppm)
Experimental m/z, mass error and
possible structures to relevant products
found in the reaction between ribose and
nucleobase aggregates.
+
C8H15N6O4
m/z 259.11495(0.08 ppm)
+
Acetyl C10H17N6O5
-
C13H16N3O8
m/z 301.12530(-0.67ppm)
+
m/z 302.06280 (-0.62ppm)
C
13H23N6O8
Ribosyl
m/z 391.15780(1.55 ppm)
Hence, the experiment suggests that condensation of malonic
acid in the urea/guanidine mixture, subjected to environmental
cycles at moderate temperature, could generate trisubstituted
pyrimidines in plausible prebiotic conditions. This milieu and
environment would be favorable for the capture of sugars
The weaker electrophilicity of an amide carbonyl compared with
malonic acid is consistent with the observed yields, and with the
preference for 2-amino-4,6-dihydroxypyrimidine in presence of
guanidine (Fig.1). In support of this proposed reaction pathway,
3
This article is protected by copyright. All rights reserved.

10.1002/cbic.202000510
ChemBioChem
COMMUNICATION
a guanidine solution with malondiamide added showed TAP
production by mass spectrometry after 3 days of dry/wet cycles
at 85ºC (Fig. S5).
could be more easily explained by the increase of formation of
melamine, whose insoluble aggregate with barbituric acid
derivatives precipitates even at very low concentrations. Hence,
These results show that the synthesis of 2,4,6-trisubstituted
pyrimidines is possible in mild, prebiotically plausible conditions,
by the condensation of malonic acid with urea or guanidine in a
simple evaporative setting; this dry-wet warm little pond model,
leads to a scenario favorable for the prebiotic local concentration
of relevant pyrimidines through precipitation/crystallization.
Dilution of the reaction mixture with water after 2 days of cycles
results in the formation of a flocculent precipitate, which is
observed to dissolve in a concentrated urea solution, re-
precipitating by dilution. The separation of the precipitate and its
the urea solution in
a
wet-dry scenario at moderate
temperatures provides a single environment for the synthesis
and selection and concentration of nucleobases through the
formation of supramolecular aggregates by base-pairing (case of
barbituric acid/melamine, Fig. 3), coprecipitation with aggregates,
by trapping in the flocculent precipitates, or formation of other
low solubility structures (case of barbituric acid-TAP precipitate,
for which it has not been demonstrated the formation of
hexameric rosettes).
Scheme 1. The versatility of
malononitrile. Formation of the
barbituric acid family of pyrimidines
by urea/guanidine and malonic acid
condensation,
driven
by
the
decomposition/isomerization of urea
in ammonia and isocyanic acid; the
condensation of resulting mono and
diamides of malonic acid with
guanidine
or
urea
lead
the
corresponding
pyrimidines.
One
possible origin of malonic acid is the
hydrolysis of malononitrile, which, in
turn, could condense directly with
urea/guanidine to yield the 4,6-
diaminopyrimidines, or, in presence
of atmospheric NO, form 4,5,6-
triaminopyrimidines, as observed by
Becker et al.[28]
The pyrimidines of the
barbituric acid family could
have played
a key role in
chemical evolution through the
spontaneous
formation
of
supramolecular
aggregates
and C-glycosides by reaction
with aldoses, preferential at the C5 ring position, even in the
presence of amino groups (in the instance of TAP). Considering
an input of sugars from external sources, the presence of
pyrimidine bases could harvest the reactive aldoses, resulting in
the concentration of these nucleosides through the formation of
insoluble supramolecular aggregates. The synthesis of sugars or
nucleosides in the urea-rich scenario is unlikely, due to the
reactivity of urea with aldehyde precursors (impairing formose
reaction) or glyoxylic acid (inhibiting the glyoxylate scenario) and
forming the corresponding urea derivatives. If aldose-reactive
nucleobases were accumulated as aggregates as a form of
prebiotic organic mineral, further input of ribose could lead to the
formation of nucleosides and gradually concentrated it,
preserved in the form of aggregates. To test this concept, we
collected by centrifugation the precipitates formed by
condensation of malonic acid in a viscous urea/guanidine
mixture and heated the precipitates with ribose in solution at
70ºC for 6 hours. In a similar experiment, after wet/dry cycles of
a urea/guanidine and malonic acid solution, ribose was added
during the last wet/dry cycle, with no previous separation of
precipitates. The products of both of these reactions were
analysis by Orbitrap mass spectrometry, after dissolution in a
methanol-water-ammonia solution, revealed the formation of
barbituric acid, melamine, and the acetyl and carbamoyl
derivatives of these bases. The fragmentation of m/z 170.0560
in positive mode (Fig. S6a) suggests it corresponds to the
acetylated pyrimidine at C5 (expected due to stabilization by its
aromatic ring) rather than the acetyl ester. The temperature is an
important factor in the process, as the formation of the
precipitate and the acetyl and carbamoyl derivatives is favored
at of 85 ºC, whereas at 65 ºC the crystallization of bases is
preferred (Fig. 2B).
Overal, the resulting composition in the range 65-85ºC is
similar, but increased temperature favors both the
decarboxylation of malonic acid to acetic acid and the formation
of isocyanic acid from urea. As a result, the experiments
performed at 85ºC shows an increase in acetylated and
carbamoylated pyrimidines, as well as in melamine. The
formation of 2-amino-4,6-dihydroxy-5-acetyl pyrimidine is
preferred compared to the formation of acetyl esters by
resonance stabilization. It is interesting to note that the
precipitation of supramolecular aggregates is favored when
acetyl and carbamoyl derivatives are present; nevertheless, it
4
This article is protected by copyright. All rights reserved.

10.1002/cbic.202000510
ChemBioChem
COMMUNICATION
[6]
[7]
H.-J. Kim, S. A. Benner, Proc. Natl. Acad. Sci. 2017, 201710778.
A. E. Engelhart, N. V. Hud, Cold Spring Harb. Perspect. Biol. 2010,
2, 1–21.
N. V. Hud, B. J. Cafferty, R. Krishnamurthy, L. D. Williams, Chem.
Biol. 2013, 20, 466–474.
analyzed by mass spectrometry, showing the exacts masses
corresponding to BARC (confirmed by fragmentation and exact
mass, after a control experiment showed in Fig. S7), 5-ribosyl-2-
[8]
aminopyrimidine-4,6-diol,
C-nucleoside
of
2,4,6-
[9]
[10]
B. J. Cafferty, N. V. Hud, Curr. Opin. Chem. Biol. 2014, 22, 146–157.
N. V. Hud, Synlett 2017, 28, 36–55.
triaminopyrimidine (TARC), and N-riboside of melamine (Fig. 3).
It is interesting to note that the formation of monoacetyl-
nucleosides is common, as confirmed by observation of the
exact m/z of monoacetyl derivatives of all identified nucleosides
(Table S1). Regarding the formation of malonic acid esters, we
only identified the malonyl ester of 5-ribosyl-2-aminopyrimidine-
4,6-diol. The formation of dicarboxylic acid esters of nucleosides
could be an alternative pathway to the formation of nucleoside
oligomers but, in this case, malonic acid is too prone to
decarboxylation, leading to the observed acetyl esters. The
formation of C-nucleoside of 2-aminopyrimidine-4,6-diol and
TARC are demonstrated by the identification of the exact m/z of
the corresponding di-ribosides. All characterized species formed
are listed in Supplementary Table 1. The resulting qualitative
composition in both experiments is similar. As expected, the
addition of ribose to the urea-rich pond in one-pot without
previous separation of precipitates, lead to ribosyl-urea (Fig.3E)
and unidentified species. Hence, the separation and stabilization
of non-canonical nucleobases in a small pond, which gradually
concentrated and accumulated nucleobases and nucleosides by
a simple selection mechanism, could have been a pathway to
the collection of reactive sugars from different sources and the
selection of nucleosides as building blocks for a potential pre-
RNA molecule.
In summary, we showed that the condensation of malonic
acid and urea or urea/guanidine in a prebiotic scenario,
consisting in evaporating warm ponds at moderate temperatures,
lead to a mixture of pyrimidines and triazines; furthermore, it
leads to the spontaneous selection and concentration of
nucleobases or nucleosides, if a suitable sugar is present. This
process is mediated by the spontaneous glycosylation and
formation of supramolecular assemblages by base pairing and
base coprecipitates. A little warm pond enriched in urea could
lead to a prebiotic mechanism of formation, concentration and
selection of pre-RNA building blocks, powered by cycles of
synthesis, precipitation, and redissolution, associated to
environmental dry/wet cycles in the surface of early Earth.
[11]
B. J. Cafferty, D. M. Fialho, J. Khanam, R. Krishnamurthy, N. V. Hud,
Nat. Commun. 2016, 7, 1–8.
D. M. Fialho, K. C. Clarke, M. K. Moore, G. B. Schuster, R.
Krishnamurthy, N. V. Hud, Org. Biomol. Chem. 2018, 16, 1263–
1271.
[12]
[13]
R. Navarro-González, A. Negrón-mendoza, E. Chacón, Orig. Life
Evol. Biosph. 1989, 19, 109–118.
[14]
[15]
[16]
R. Lohrmann, J. Mol. Evol. 1972, 1, 263–269.
L. Stanley Miller, Science (80-. ). 1953, 117, 528–529.
B. Burcar, M. Pasek, M. Gull, B. J. B. J. Cafferty, F. Velasco, N. V.
N. V. Hud, C. Menor-Salván, Angew. Chemie - Int. Ed. 2016, 55,
13249–13253.
[17]
[18]
C. Menor-Salván, M. R. Marín-Yaseli, Chem. - A Eur. J. 2013, 19,
6488–6497.
C. Menor-Salván, D. M. Ruiz-Bermejo, M. I. Guzmán, S. Osuna-
Esteban, S. Veintemillas-Verdaguer, Chem. - A Eur. J. 2009, 15,
4411–4418.
C. He, I. Gállego, B. Laughlin, M. A. Grover, N. V. Hud, Nat. Chem.
2017, 9, 318–324.
M. C. Chen, B. J. Cafferty, I. Mamajanov, I. Gállego, J. Khanam, R.
Krishnamurthy, N. V. Hud, J. Am. Chem. Soc. 2014, 136, 5640–
5646.
C. Menor-Salván, in Prebiotic Chem. Chem. Evol. Nucleic Acids
(Ed.: C. Menor-Salván), Springer International Publishing, Basel,
2018, pp. 85–142.
S. Becker, J. Feldmann, S. Wiedemann, H. Okamura, C. Schneider,
K. Iwan, A. Crisp, M. Rossa, T. Amatov, T. Carell, Science (80-. ).
2019, 366, 76–82.
U. P. Trinks, Zur Chemie Der Aminopyrimidine, Eidgenössischen
Technichen Hochschule, 1987.
G. Springsteen, J. R. Yerabolu, J. Nelson, C. J. Rhea, R.
Krishnamurthy, Nat. Commun. 2018, 9, 91.
J. C. Ambelang, T. B. Johnson, J. Am. Chem. Soc. 1941, 63, 1289–
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
1291.
E. Smolin, L. Rapoport, The Chemistry of Heterocyclic Compounds.
S-Triazines and Derivatives., Interscience Publishers Inc., New York,
1959.
M. Hernández-Rodríguez, J. Xie, Y. M. Osornio, R. Krishnamurthy,
Chem. - An Asian J. 2011, 6, 1252–1262.
[27]
[28]
S. Becker, C. Schneider, H. Okamura, A. Crisp, T. Amatov, M.
Dejmek, T. Carell, Nat. Commun. 2018, 9, 1–9.
Acknowledgements
This work was supported by NSF and the NASA Astrobiology
Program under the NSF Center for Chemical Evolution (CHE-
1504217). We thank Prof. Charles L. Liotta for his support
facilitating the GC-MS analyses and fruitful discussions.
Keywords: Prebiotic Chemistry • Urea • Origins of Life •
pyrimidines • nucleosides
[1]
M. W. Powner, J. D. Sutherland, Philos. Trans. R. Soc. B Biol. Sci.
2011, 366, 2870–2877.
[2]
[3]
J. D. Sutherland, Angew. Chemie - Int. Ed. 2016, 55, 104–121.
M. W. Powner, B. Gerland, J. D. Sutherland, Nature 2009, 459,
239–242.
[4]
[5]
H. Okamura, S. Becker, N. Tiede, S. Wiedemann, J. Feldmann, T.
Carell, Chem. Commun. 2019, DOI 10.1039/C8CC09435G.
S. Becker, I. Thoma, A. Deutsch, T. Gehrke, P. Mayer, H. Zipse, T.
Carell, Science (80-. ). 2016, 352, 833–836.
5
This article is protected by copyright. All rights reserved.

10.1002/cbic.202000510
ChemBioChem
COMMUNICATION
Entry for the Table of Contents
Insert graphic for Table of Contents here. ((Please ensure your graphic is in one of following formats))
Concentrated pools of water enriched with urea would have been an efficient source for the formation of non-canonical pyrimidines.
In the presence of ribose, or other aldose sugars, the bases derived from these urea-rich pools could react with these sugars through
spontaneous glycosylation, ultimately concentrating these de novo nucleosides through aggregation. We demonstrate how a setting
rich in urea and guanidine could lead to the synthesis and concentration of non-canonical nucleosides on a prebiotic Earth.
Institute and/or researcher Twitter usernames: ((optional))
6
This article is protected by copyright. All rights reserved.