Darwin's Warm Little Pond: A One-Pot Reaction for Prebiotic Phosphorylation and the Mobilization of Phosphate from Minerals in a Urea-Based Solvent

Article abstract of DOI:10.1002/anie.201606239

The poor reactivity of insoluble phosphates, such as apatite-group minerals, has been a long-appreciated obstacle for proposed models of prebiotic organophosphate formation. This obstacle presents a significant challenge to the nascent development of an RNA world and other models for the origins of life on Earth. Herein, we demonstrate that a scenario based on the formation of a urea/ammonium formate/water (UAFW) eutectic solution leads to an increase in phosphorylation when compared to urea alone for phosphate sources of varying solubility. In addition, under evaporative conditions and in the presence of MgSO₄, the UAFW eutectic mobilizes the phosphate sequestered in water-insoluble hydroxyapatite, giving rise to a marked increase in phosphorylation. These results suggest that the prebiotic concentrations of urea in a geologically plausible evaporitic environment could solve the problem of organic phosphorylation on a prebiotic Earth.

Full text of DOI:10.1002/anie.201606239

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201606239
German Edition: DOI: 10.1002/ange.201606239
Origins of Life
Darwinꢀs Warm Little Pond: A One-Pot Reaction for Prebiotic
Phosphorylation and the Mobilization of Phosphate from Minerals in
a Urea-based Solvent
Bradley Burcar, Matthew Pasek, Maheen Gull, Brian J. Cafferty, Francisco Velasco,
Nicholas V. Hud,* and Cꢀsar Menor-Salvꢁn*
[
4]
Abstract: The poor reactivity of insoluble phosphates, such as
apatite-group minerals, has been a long-appreciated obstacle
for proposed models of prebiotic organophosphate formation.
This obstacle presents a significant challenge to the nascent
development of an RNA world and other models for the origins
of life on Earth. Herein, we demonstrate that a scenario based
on the formation of a urea/ammonium formate/water (UAFW)
eutectic solution leads to an increase in phosphorylation when
compared to urea alone for phosphate sources of varying
solubility. In addition, under evaporative conditions and in the
phosphate in nucleic acids. If organophosphates can be
readily formed in “warm little ponds” then these compounds
could have been abundant on the prebiotic Earth and played
important roles leading to the origins of life. However, owing
to the strong affinity of phosphate towards divalent cations, it
is assumed that most phosphate would have been sequestered
in low-solubility minerals on a prebiotic Earth, rendering it
unavailable for use in prebiotic chemical reactions and
[5]
leading to the phosphate problem for the origin of RNA.
Additionally, the most plausible routes to phosphorylation of
organic molecules are through condensation reactions, reac-
tions that are thermodynamically unfavored in aqueous
solutions. Consequently, a fundamental question raised by
the phosphate problem is what are the appropriate geo-
chemical settings and mineral assemblages that could lead to
the origin of the first organophosphates of prebiotic rele-
vance?
presence of MgSO , the UAFW eutectic mobilizes the phos-
4
phate sequestered in water-insoluble hydroxyapatite, giving
rise to a marked increase in phosphorylation. These results
suggest that the prebiotic concentrations of urea in a geo-
logically plausible evaporitic environment could solve the
problem of organic phosphorylation on a prebiotic Earth.
T
he synthesis of the first organophosphates has been a major
To address the problems associated with the initial entry
of phosphate into biochemistry, model prebiotic phosphor-
ylation reactions have been investigated using condensation
question in origin of life studies at least as far back as 1871
when Charles Darwin mused about a “warm little pond, with
all sorts of ammonia and phosphoric salts,…that a protein
compound was chemically formed ready to undergo still more
[
6]
agents, under dry and elevated temperature conditions
[
7]
[8]
(ꢀ 858C), in water-free solvent systems, and with reduced
[1]
[9]
complex changes.” This question captivates prebiotic chem-
ists owing to the indispensable role of phosphate in modern
biochemistry; a role it attains by ensuring the aqueous
solubility of biomolecules, such as DNA and RNA, and by
also forming kinetically stable phosphate ester and phospho-
diester bonds. These properties can be lost when phosphate
is replaced with similar, alternate molecules, indicating
a strong evolutionary pressure for the early incorporation of
phosphorus species. Notably, the dry and organic solvent-
based reactions have demonstrated significant phosphoryla-
tion when soluble phosphate salts are used, or when insoluble
[
7e]
apatite is used in the presence of oxalate chelators. Results
from these studies have been invaluable for characterizing
abiotic phosphorylation reaction pathways, such as the role of
reduced pH environments, or the importance of urea as
[2]
[
3]
[
6,7f,10]
a catalyst for phosphorylation (Scheme 1),
which gen-
erates a reaction intermediate similar to the intermediate of
[
11]
carbodiimide crosslinking chemistry. However, these reac-
tions do not fully address the question of the origin of
phosphate in biochemistry as they are problematic in their use
of potentially rare phosphorus species, elevated temperatures,
compounds that are insoluble in the presence of divalent
cations, and/or solvent systems that are unlikely to have been
common under realistic geochemical and environmental
conditions on a prebiotic Earth.
[
*] Dr. B. Burcar, Dr. B. J. Cafferty, Prof. Dr. N. V. Hud,
Dr. C. Menor-Salvꢀn
School of Chemistry and Biochemistry
Georgia Institute of Technology
Atlanta, GA 30033 (USA)
E-mail: hud@chemistry.gatech.edu
cesar.menor@chemistry.gatech.edu
Prof. Dr. M. Pasek, Dr. M. Gull
School of Geosciences
University of South Florida
Tampa, FL (USA)
Prof. Dr. F. Velasco
Department of Mineralogy and Petrology
Universidad del Paꢁs Vasco
Campus de Leioa, Vizcaya (Spain)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606239.
Scheme 1. Proposed mechanism for urea-catalyzed synthesis of phos-
phate esters.
[
6,7f,10]
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Eutectic solvents with no water, or low water activity, have
recently been shown to exhibit properties that could have
facilitated prebiotic RNA synthesis. Specifically, the 3:1
urea:choline chloride eutectic supports Watson–Crick base
[
12]
pairing and can serve as a milieu for the phosphorylation of
[8a]
sugars and nucleosides at 60–708C. However, the prebiotic
relevance of choline eutectics is questionable and phosphor-
ylation is limited by competitive phosphorylation of the
choline in the eutectic itself. We therefore decided to
investigate the effectiveness of a urea/ammonium formate/
water (UAFW) eutectic solvent system (molar ratio of
[
13]
1
:2:4) as a milieu for direct phosphorylation from soluble
phosphate sources and for the solubilization of secondary
phosphate minerals formed by urea-driven remobilization of
primary phosphates accumulated in an evaporitic environ-
ment. The UAFW eutectic is a prebiotically plausible solvent.
1
Figure 1. H-NMR spectra of UAFW eutectic heated, open, at 858C as
a function of time. The appearance of formamide in UAFW is observed
beginning at 1 day after the preparation of the solvent. Sequential
spectra are offset by 0.2 ppm. Spectra are normalized to the intensity
of the urea resonances at 5.5 ppm.
[
14]
Urea is produced in Miller-Urey type reactions,
when
[15]
ammonium cyanide is exposed to sunlight, and is a hydrol-
[
16]
ysis product of cyanamide; ammonium formate is a hydrol-
[
17]
ysis product of HCN. Upon heating, the UAFW eutectic is
partially converted to formamide (Figure 1, Table S1), creat-
ing a four-component solvent, and providing a facile pathway
for generating this co-solvent of considerable prebiotic
[8c,18]
interest
that has also been shown, by itself, to enhance
[
8b]
phosphorylation from mineral sources.
This UAFW/for-
mamide solvent system provides a fluidic, low-water environ-
ment that can be generated by the moderate heating of urea/
ammonium formate solutions of various concentrations.
Dilute urea/ammonium formate solutions initially stabilize
near the UAFW eutectic point through evaporative loss of
water and ammonium formate, or precipitative loss of urea,
ensuring a consistent starting concentration of components
regardless of their initial abundances (Table S2).
Figure 2. HPLC-MS chromatogram of a representative adenosine phos-
phorylation reaction carried out in the UAFW eutectic at 858C for
To investigate organophosphate synthesis in the UAFW
eutectic, adenosine was mixed separately with Na HPO and
2
4
5
days with Na HPO as the phosphate source. Masses and presump-
2 4
hydroxyapatite Ca(PO ) OH (believed to be one of the most
4
3
tive compounds for uncharacterized species: 309, adenosine–form-
amide; 330/345, 5’-amidophosphate adenosine; 408, monophosphory-
lated 2’,3’-cAMP; 426, mixed diphosphates of adenosine.
[19]
common Hadean phosphate minerals) in the eutectic and
heated, open, for multiple days at 65 or 858C. Efficient
phosphorylation was observed for
this reaction with Na HPO at both
2
4
temperatures, yielding a diverse col-
lection of phosphorylated species
Table 1: Phosphorylation (%adenine by HPLC) in urea solution vs. UAFW.
(
Figure 2), and for all of the canon-
ical ribonucleotides (Table S3).
These products, when compared to
dry-down reactions with water and
urea instead of the UAFW eutectic,
show an increase in total phosphor-
ylation at both temperatures, with
a marked increase in phosphoryla-
tion for all of the characterized
species that were observed at 658C
[
c]
Temp. [8C]
Solvent
P-Source
Na HPO
5’-AMP [%]
2’,3’-cAMP [%]
T-Org-PO [%]
4
[
a]
6
5
water/urea
UAFW
water/urea
UAFW
3.7
21.7
6.9
58
N.D.
N.D.
2
4
Na HPO
9.4
2
4
hydroxyapatite
hydroxyapatite
(
Table 1,
Figure S1).
Upon
extended heating, a transition from
noncyclic to cyclic nucleotides was
observed (Tables S4 and S5), and
oligomers with masses correspond-
ing to dimers and trimers are
[
b]
85
water/urea
UAFW
water/urea
UAFW
Na HPO
14.5
14.4
6.2
4.8
27
34
N.D.
4.0
2
4
Na
HPO
2
4
hydroxyapatite
hydroxyapatite
2.9
0.8
detected (Figure S2). Phosphoryla- [a] 19 days. [b] 5 days. [c] Total organic phosphate. N.D.: None Detected.
2
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Given the importance of mobile phosphate for these
phosphorylation reactions, we hypothesize that the UAFW
eutectic formed from urea- and ammonia-rich ponds could be
vital for generating moderately soluble struvite and new-
beryite on the prebiotic Earth, as these minerals commonly
form on the present Earth in urea-rich solutions from
[20]
biological sources. Simulating an evaporitic environment
with urea or UAFW eutectic as an ammonium source, along
with initial concentrations of 50 mm MgSO and 10 mm free
4
phosphate (concentrations within the ranges found in modern
seawater and geological systems, with phosphate provided,
Figure 3. Negative mode ESI-MS spectrum of a glycerol (Gly) phos-
phorylation (p) reaction carried out in the UAFW eutectic with
Na HPO after 22 days. cpGly, cyclic glycerol monophosphate; pGly,
glycerol monophosphate; GlypGly, diglycerol monophosphate; (pGly)2,
diglycerol diphosphate. Additional peaks are the major side products
resulting from carbamylation of glycerol phosphates (Figure S3).
for example, from apatite dissolution by acidic steam-heated
[21]
surface
waters),
the
formation
of
struvite
2
4
(
NH MgPO ·6H O) and newberyite (MgHPO ·2H O) is
4
4
2
4
2
observed for both solutions after three days of drying-
rewetting cycles (Figure S5). The formation of newberyite
or struvite is pH- and redox-dependent and struvite even-
[
20b,22]
tually loses ammonia to form newberyite (Figure S6).
In
tion with dimerization is also observed for glycerol under
identical conditions (Figure 3). Both the phosphorylation and
oligomerization of nucleosides is consistent with reported
the presence of 50 mm CaCl , this solution forms a combina-
2
tion of brushite (CaHPO ·H O) and newberyite.
4
2
In addition to generating struvite and newberyite, it is
important to know if the eutectic can release phosphate from
insoluble source minerals. The conversion of hydroxyapatite
to struvite is calculated to be thermodynamically favorable in
[7d]
higher temperature, urea-catalyzed results,
but with the
current reactions taking place at lower temperatures than
these previous reports. Control experiments run without urea
showed no detectable phosphorylation at either temperature,
for any solvent composition, or any phosphate source.
5
9
the presence of water, urea, and MgSO , with K = 10 at
4
298 K:
Following these experiments, the impact of the UAFW
eutectic on insoluble mineral phosphate sources was
explored. Emulating conditions similar to those used for the
phosphorylation reactions, an increase in solubilization was
observed for representative phosphate minerals (Table S6).
Correlating with their observed solubility in water, an impact
on phosphorylation efficacy is also observed for different
synthetic mineral phosphate sources in the UAFW eutectic
þ
þ 1:5 ðNH Þ CO þ 30 H O þ 4:5 Mg þ 5 SO42ꢁ
2þ
H
2
2
2
þCa
5
ðPO
4
Þ
3
OH ðhydroxyapatiteÞ !
3 MgNH PO ꢂ 6 H O ðstruviteÞ þ 5 CaSO ꢂ 2 H O ðgypsumÞþ
4
4
2
4
2
1
:5 MgCO ðmagnesiteÞ
3
Experimentally, the UAFW eutectic with an initial con-
centration of 50 mm of MgSO was found to alter the
hydroxyapatite (Ca (PO (OH)) upon drying and rewetting
with 50 mm MgSO , mobilizing the phosphate and forming an
assemblage of secondary evaporitic mineral phases, mainly
struvite, gypsum (CaSO ·2H O), and ammonium sulfates.
4
(
Table 2, Figure S4). These results are indicative of phosphor-
5
)
4 3
ylation in the UAFW eutectic being primarily limited only by
the availability of phosphate in solution.
4
4
2
XRD analysis of the converted hydroxyapatite shows 60%
unreacted hydroxyapatite, 25% struvite, and 10% gypsum
comprising the solid residue (Figure 4). Without MgSO the
treatment of hydroxyapatite with urea or UAFW under the
4
Table 2: Phosphorylation (%adenine by HPLC) of adenosine in UAFW at
8
58C with different PO sources.
4
same conditions, or in the presence of MgCl , was not found to
2
P-Source
5’-AMP [%]
2’,3’-cAMP [%]
T-Org-PO [%]
4
alter the original mineral phase, suggesting that phosphate
solubilization is due to phosphate substitution by sulfate.
Urea-negative experiments showed no phosphate solubiliza-
Na HPO4
14.4
4.8
33.8
25.2
23.8
12.8
2
Struvite
11.2
10.4
6.8
4.3
3.9
2.9
tion from hydroxyapatite in the presence of MgSO . These
4
results demonstrate that urea-rich solutions, such as a UAFW
eutectic, not only increase the solubility of phosphate
minerals, but also allow the formation of a secondary
evaporitic paragenesis of urea-soluble classic “cave minerals”
Newberyite
Struvite/Brushite/
[
a]
Gypsum
2
+
from primary phosphate sources, even in the presence of Ca
and the absence of biological agents (Figures S5–S9).
Processed
Hydroxyapatite
4.1
2.9
1.3
0.8
6.9
4.0
[
b]
These experiments suggest that an environment rich in
ammonia, small organics such as urea and formate, MgSO4,
and phosphate could be an ideal location for prebiotic
organophosphate synthesis. These organics would theoret-
ically be abundant near prebiotic geothermal fields and from
Hydroxyapatite
[a] Mixture from precipitation by H PO by equimolar CaCl and MgSO
3 4 2 4
in urea solution. [b] Processed by successive additions of MgSO4
followed by drying to a suspension of hydroxyapatite in urea solution at
58C.
[
14,16]
6
Miller-Urey type reactions,
with magnesium as the
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To test this evaporative scenario, we conducted experi-
ments in which we allowed samples to completely dry during
heating, followed by reforming the UAFW eutectic by
rewetting with either deionized water or an aqueous solution
containing 50 mm MgSO . These reactions exhibited signifi-
4
cant phosphorylation at 65 and 858C for Na HPO and
2
4
struvite, with a 3–6 ꢀ increase in phosphorylation for apatite
when rewet with 50 mm MgSO (Table 3). These reaction
4
conditions simulate environmental drying–rewetting cycles
that are useful for providing extreme dehydrating conditions
to facilitate condensation reactions followed by increased
mobility within a fluidic phase to promote solution-based
chemistry. These conditions are particularly interesting as
they simulate some of the best environments for the
formation of struvite and newberyite minerals from apatites,
and may be the most prebiotically viable scenario.
For these reactions, the addition of MgSO to the system
4
inhibits phosphorylation in the presence of soluble Na HPO
2
4
while promoting phosphorylation when moderately soluble
struvite or insoluble apatite is used (Tables 3 and S7). These
results are indicative of magnesium sequestering phosphate
when only soluble phosphate is present, while promoting the
solubility of phosphate when less soluble minerals are used as
the phosphate source. In fact, the MgSO -doped phosphor-
4
ylation reactions with Na HPO4 and struvite are nearly
2
identical, supporting the premise that equilibrium is reached
with these ions in solution regardless of their initial source.
Overall, our observations suggest that a simple evaporitic
environment rich in urea, whose formation is plausible during
the Early Archean, could address the phosphate problem by
promoting thermodynamically favored phosphate solubility
or by forming secondary phosphate species with higher
solubility in a UAFW eutectic solvent. Also, it is shown that
newberyite is equivalent to struvite as a phosphate source for
the phosphorylation of nucleosides, extending the redox, pH,
and composition spaces for the formation of efficient
phosphate donors. Most importantly, these reactions are
shown to work efficiently even under one-pot synthetic
conditions by solubilization of phosphate from plausibly
abundant prebiotic minerals, such as hydroxyapatite, making
prebiotic organophosphate synthesis possible under mild
conditions with enhanced yields, and much less complicated
than multi-environment synthetic scenarios. Finally, we have
shown that Darwinꢁs intuition regarding a “warm little pond”
could be right, as an evaporating urea-rich pond with
ammonium salts and phosphates (even water-insoluble phos-
phates) could be the ideal environment for the origin of
organophosphates.
Figure 4. Phosphate solubilization from hydroxyapatite in ure-
a+MgSO solutions. a) Raman spectrum of hydroxyapatite before
4
(
lower line) and after (upper line) drying-rewetting cycles at 658C with
urea solution and MgSO . Note the formation of gypsum (Gp) and
4
ꢁ
1
struvite (S). b) Deconvolution of the 900–1050 cm zone of the
Raman spectrum. The sum of contributions of the main phosphate
vibrations of hydroxylapatite (Hap), newberyite (Nw), gypsum, and
struvite fits with the observed spectrum. c) Powder X-ray diffractogram
of the partially converted hydroxyapatite in UAFW+MgSO . Character-
4
ized conversion products: struvite (S), gypsum (Gp), boussingaultite
(
Bs), and mascagnite (M). Original hydroxyapatite and reference
reflections (blue vertical lines) are shown for comparison.
dominant divalent cation due to the higher solubility of its
salts and an abundant source from weathering of mafic and
[
23]
2ꢁ
ultramafic rocks. Additionally, the availability of SO4 on
a prebiotic Earth is possible through disproportionation of
[24]
volcanic SO2. Even if phosphate was initially present in
insoluble apatites or similar minerals, successive evaporative
inflows with urea-rich water containing MgSO would greatly
4
[
23b]
enhance the solubility of these phosphate minerals.
Local
heating from the hydrothermal systems along with evapora-
tion would form the UAFWeutectic in this pond, which would
then act to dissolve and convert the insoluble phosphate
minerals to struvite, newberyite, and brushite, which can then
be readily utilized for organophosphate synthesis (Fig-
ure S10).
Experimental Section
Identification of mineral phases was done by Raman and X-ray
diffraction spectroscopy. Analysis of nucleoside phosphates and the
1
UAFW eutectic was done by HPLC-DAD, ESI-MS, and H-NMR.
Method information and synthesis of mineral phases are described in
the Supporting Information.
4
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Angewandte
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Phosphate Source
5’-XMP
%]
2’,3’-cXMP
T-Organic-
[
[%]
PO [%]
4
[
a]
[b]
[a]
[b]
[a]
[b]
A
U
A
U
A
U
6
5
5
Na HPO4
struvite
10.0 13.3 1.5
5.4 10.5 1.3
0.6 0.9 N.D. 0.3
1.2 1.4
2.7
3.4
18.8
10.2
0.6
27.0
20.4
1.2
2
hydroxyapatite
hydroxyapatite with MgSO4 2.8 2.5
4.9
4.7
20167.
8
Na HPO4
17.0 22.0 5.5
7.4 5.3 4.6
2.3 2.6 N.D. 1.5
4.6 3.8
12.9 39.9
3.4
55.4
14.2
5.2
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16.8
4.1
15.8
14.1
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Received: June 27, 2016
Revised: July 25, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Origins of Life
B. Burcar, M. Pasek, M. Gull, B. J. Cafferty,
F. Velasco, N. V. Hud,*
C. Menor-Salvꢁn*
&&&& — &&&&
Darwin’s Warm Little Pond: A One-Pot
Reaction for Prebiotic Phosphorylation
and the Mobilization of Phosphate from
Minerals in a Urea-based Solvent
Phosphate in the prebiotic pond:
solvent is excellent for nucleoside phos-
phorylation from solubilized phosphate,
and would have been regularly generated
as urea-rich aqueous pools evaporated on
the early Earth.
Hydroxyapatite is shown to undergo
alternation, producing an evaporitic
paragenesis of more soluble minerals in
a urea/ammonium formate/water eutec-
tic containing magnesium sulfate. This
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!