Serine octamer reactions: Indicators of prebiotic relevance

Article abstract of DOI:10.1002/anie.200351210

The earliest molecule of life? Chirally selective reactions relevant to the origin of homochiral life are undergone by serine. Chiral exchange between serine, glyceraldehyde, and glucose occurs, favoring the enantiomers (L-serine, D-sugars) present in modern living systems (see picture).

Full text of DOI:10.1002/anie.200351210

Angewandte
Chemie
The Prebiotic Role of Serine
Serine Octamer Reactions: Indicators of Prebiotic
Relevance**
Zoltan Takats, Sergio C. Nanita, and R. Graham Cooks*
Herein we explore the hypothesis[1,2] that serine played an
important role in the prebiotic chemistry that led to living
organisms. The principal tool used in this study is sonic-spray
ionization (SSI),[3,4] a mild method that facilitates investiga-
tion of chemical species present in concentrated aqueous
solutions.[5,6] It has been reported that serine, alone among the
common a amino acids, forms homochiral magic-number
clusters.[1,2,7–9] These clusters incorporate other amino acids of
like chirality by substitution for serine[10,11] and they are
capable of aggregation.[8] These facts allow a prebiotic
scenario in which serine clusters were involved in chiral
accumulation and in transmission of chirality to other amino
acids. We now report observations that suggest unique
connections between serine and other compounds of funda-
mental importance to biochemistry, including glyceraldehyde,
glucose, phosphoric acid, and some transition-metal ions. We
also suggest a reaction that might have been the locus for
symmetry-breaking in serine.
Serine, the putative product of the reaction between the
interstellar molecules glycine and formaldehyde,[12,13] is one of
the primitive amino acids.[14] It has not been reported in
interstellar space but has been identified in meteorites.[15]
Both the strong preference for homochirality and the stability
of the magic-number cluster set serine apart from other amino
acids.[16,17] Herein we report new experimental facts
(Scheme 1) that confirm the uniqueness of serine: 1) Serine
clusters with glyceraldehyde, undergo chiro-selective reac-
tions involving the octamer, 2) it forms a chirally dependent
magic-number cluster with glucose, 3) it incorporates H3PO4
into its homochiral octamer, 4) the magic-number octamer is
cationized by CuII ions, while other-magic number clusters of
serine are observed with FeII and FeIII ions. In all these
instances serine reacts uniquely compared to other represen-
tative amino acids. Finally, 5) serine is amongst the most easily
racemized a amino acids.
Scheme 1. Reactions of serine and its octamer; chiro-selective reac-
tions, P=serine/glyceraldehyde condensation reaction product.
*
aqueous mixture is heated at approximately 758C for 14 h,
forming a Schiff base. The SSI mass spectrum shows this
serine–glyceraldehyde dehydration product to substitute for
one or two serines in the octamer, in a similar fashion to that
seen for mixtures of serine with a amino acids.[10,11] Remark-
ably, substitution into the serine octamer is chirally selective,
as confirmed by using purified[18] d-glyceraldehyde and
recording the SSI mass spectrum. The l-serine octamer
incorporates the condensation product of l-serine and d-
glyceraldehyde (8% relative abundance for one substitution,
3% for two) whereas no reaction was detectable for the d-
serine/d-glyceraldehyde pair. Other amino acids undergo the
same reaction with glyceraldehyde to form analogous Schiff
base products. Remarkably, serine and threonine were found
to be the only amino acids to incorporate the glyceraldehyde
dehydration product into a magic-number cluster (the
octamers). It is noteworthy that the chiral selection matches
that seen in biological systems (l-amino acids and d-sugars).
Under the mild conditions of the SSI process, a solution
containing l-serine and dl-glyceraldehyde (Sigma, St. Louis,
MO; solid, 90% + purity) exhibits only one prominent
product, a pronounced magic-number cluster, [Ser6Glyc6Na]+
(m/z 1193). Tandem mass-spectrometry experiments show
that [Ser6Glyc6Na]+ fragments by loss of C6H12O6 units which
suggests that glyceraldehyde is present in the form of a dimer
(hexose or an isomer) in the cluster.[19] Evidence for the
structural assignment and information on chiral control of the
reaction was obtained by performing experiments with
hexose/serine mixtures. The SSI mass spectrum of a l-
serine/d-glucose mixture (Figure 1) shows a remarkable
magic-number cluster, nominally the same ion seen with
glyceraldehyde. MS/MS experiments showed that analo-
gously to the cluster with glyceraldehyde, the loss of one
hexose molecule (m/z 1013) yields the dominant fragment.
The strong but incomplete chiral preference for the l-serine/
The recently proposed mechanism for chiral transfer from
serine to other amino acids[10] stimulated the search for a
chemical connection between the l-serine and d-sugars of
living organisms. The interactions of serine with glyceralde-
hyde, the simplest aldose, were examined. The two com-
pounds undergo a condensation reaction when a neutral
[*] Prof. R. G. Cooks, Dr. Z. Takats, S. C. Nanita
Department of Chemistry
Purdue University
560 Oval Drive, West Lafayette, IN 47907 (USA)
Fax: (+1)765-4949-421
E-mail: cooks@purdue.edu
[**] This workwas supported by the National Science Foundation
(CHE 97-32670) and by the U.S. Department of Energy, Office of
Basic Energy Sciences (DE-FG02-94ER14470). We thankJeffrey
Patrick(Eli Lilly Co.) for helpful discussions.
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DOI: 10.1002/anie.200351210
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Communications
FeII, and FeIII readily cationize serine clusters. For CuII,
deprotonation is needed for charge balance and CuII chloride
yields the octamer [Ser8 + Cu-H]+ as well as the analogous
tetrameric complex. As expected, FeII behaves analogously
but it also yields an abundant intact adduct [Ser10 + Fe]2+.
Other amino acids generally form dimeric or trimeric clusters
with transition-metal ions.
Serine was found to racemize under mild conditions at
pH ꢀ 6, as shown by a study of 2,3,3-[D3]-l-serine. An
aqueous solution heated in a sealed ampoule showed that
the 2,3,3-[D3]-l-serine was converted into [D2]-dl-serine. This
is evident from the ESI mass spectra in Figure 3, which shows
Figure 1. Magic-number cluster at m/z 1193 corresponding to
[Ser6Glc3Na]+ in the SSI mass spectrum of a l-serine /d-glucose
mixture.
d-glucose and d-serine/l-glucose combinations over the
homoclusters is evident in both tandem and single-stage
mass spectra (Figure 2). Isotopic effects can be ruled out since
data taken with 2,3,3-[D3]-l-serine confirmed the chiral
preference. In contrast, magic-number heteroclusters
(amino acid/hexose) were not observed for other common
amino acids, with the exception of threonine, which behaves
similarly to serine.
Figure 3. ESI mass spectra of 2,3,3-[D3]-l-serine reference
solution (a; before heating) and a solution of 2,3,3-[D3]-l-serine
after heating for 30 h at approximately 1608C (solid line). Approxi-
mately half of the l-serine (c) has racemized (dl, c), as indicated
by the final composition of the sample, about 25% d- and 75% l-
serine.
peaks arising from the protonated form of 3,3-[D2]-dl-serine
at m/z 108 and the remaining protonated 2,3,3-[D3]-l-serine
at m/z 109. At shorter times or lower temperatures, con-
version was less complete. Confirmation that the product was
racemic [D2]-serine was obtained by performing chiral
analysis by tandem mass spectrometry[20] and by polarimetry
on a l-serine solution heated at 1608C for 30 h. These
experiments showed 24 Æ 6% conversion into d-serine, in
agreement with the data of Figure 3. Aspartic acid and
threonine were also racemized relatively easily, for example
l-threonine showed the formation of 10 Æ 3% of d-threonine
under identical conditions. The facile racemization of serine
has been previously reported.[21,22] It could be the result of
dehydration of the hydroxy group with loss of the hydrogen at
the a carbon and formation of a vinylic group. The influence
of an external chiral agent upon such a low-energy equili-
brium process might have resulted in a preference for d- or l-
serine, so allowing symmetry breaking.
Figure 2. SSI mass spectra for serine/glucose nonameric cluster ions
showing the preferential formation of the d-glucose/l-serine and l-glu-
cose/d-serine pairs over their l/l and d/d counterparts using isotopic
labeling. Blue: SSI-MS of a solution containing l-serine (5.0 mm), l-
glucose (2.5 mm), and d-glucose-U-13C6 (2.5 mm). Red: d-serine
(5.0 mm), l-glucose (2.5 mm), and d-glucose-U-13C6 (2.5 mm), where n
is the number of d-glucose-U-13C6 in the cluster [Ser6Glc3Na]+.
Further tests of the hypothesis that serine played a unique
role in prebiotic chemistry involved examining its reactions
with phosphoric acid and transition-metal ions. Phosphoric
acid incorporates readily into serine clusters by substituting
for serine; it gives a series of ions [Ser8Àn + (H3PO4)n +
H]+,(n = 1–3). Sulfuric acid, by contrast, was not incorporated
into clusters of serine under analogous conditions. With other
natural amino acids, only single incorporations of phosphoric
acid occurred into statistically distributed amino acid clusters,
without preferred magic-number effects. The unusual stability
of the serine octamer is further indicated by the fact that CuII,
Significant features related to modern biochemical sys-
tems are displayed uniquely by serine. The other amino acids
examined fail to show these types of reactions or do so to a
smaller extent and without the tell-tale chiral preferences.
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Angewandte
Chemie
Serine might have separated into its homochiral forms in the
course of forming the octamer and its higher clusters in
concentrated aqueous solutions; this might then have served
as a site for essential prebiotic reactions, which include the
binding of C3 sugars and their dimerization, uptake of
phosphoric acid in a form suited to controlled phosphoryla-
tion, and transition-metal-ion binding and oxidation. The
facile racemization of serine offers a specific chemical process
in the context of which symmetry breaking might have
occurred.
Received: February 18, 2003 [Z51210]
Keywords: amino acids · chemical evolution · chirality ·
.
mass spectrometry · serine
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