Synthesis of Galactosyl-Queuosine and Distribution of Hypermodified Q-Nucleosides in Mouse Tissues

Article abstract of DOI:10.1002/anie.202002295

Queuosine (Q) is a hypermodified RNA nucleoside that is found in tRNA^His, tRNA^Asn, tRNA^Tyr, and tRNA^Asp. It is located at the wobble position of the tRNA anticodon loop, where it can interact with U as well as C bases located at the respective position of the corresponding mRNA codons. In tRNA^Tyr and tRNA^Asp of higher eukaryotes, including humans, the Q base is for yet unknown reasons further modified by the addition of a galactose and a mannose sugar, respectively. The reason for this additional modification, and how the sugar modification is orchestrated with Q formation and insertion, is unknown. Here, we report a total synthesis of the hypermodified nucleoside galactosyl-queuosine (galQ). The availability of the compound enabled us to study the absolute levels of the Q-family nucleosides in six different organs of newborn and adult mice, and also in human cytosolic tRNA. Our synthesis now paves the way to a more detailed analysis of the biological function of the Q-nucleoside family.

Full text of DOI:10.1002/anie.202002295

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Angewandte
Chemie
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Accepted Article
Title: Synthesis of galactosyl-queuosine and distribution of
hypermodified Q-nucleosides in mouse tissues
Authors: Peter Thumbs, Timm T. Ensfelder, Markus Hillmeier, Mirko
Wagner, Matthias Heiss, Constanze Scheel, Alexander
Schön, Markus Müller, Stylianos Michalakis, Stefanie Kellner,
and Thomas Carell
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002295
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10.1002/anie.202002295
Angewandte Chemie International Edition
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Synthesis of galactosyl-queuosine and distribution of
hypermodified Q-nucleosides in mouse tissues
Peter Thumbsa,#, Timm T. Ensfeldera,#, Markus Hillmeiera,#, Mirko Wagnera,#, Matthias Heissa, Constanze Scheelb,
Alexander Schöna, Markus Müllera, Stylianos Michalakisb,c, Stefanie Kellnera and Thomas Carella,*
Abstract: Queuosine (Q) is a hypermodified RNA nucleoside that is
found in tRNAHis, tRNAAsn, tRNATyr, and tRNAAsp. It is located at the
wobble position of the tRNA anticodon loop, where it can interact both
with U or C bases located at the respective position of the
corresponding mRNA codons. In higher eukaryotes, including
humans, the Q base is for yet unknown reasons further modified in
tRNATyr and tRNAAsp by the addition of a galactose or mannose sugar,
respectively. The reason for this additional modification, and how the
sugar modification is orchestrated with Q-formation and insertion, is
unknown. Here, we report a total synthesis of the hypermodified
nucleoside galactosyl-queuosine (galQ). The availability of the
compound enabled us to study the absolute levels of the Q-family
nucleosides in six different organs of new-born and adult mice, and
also in human cytosolic tRNA. Our synthesis now paves the way to a
more detailed analysis of the biological function of the Q-nucleoside
family.
is unknown. In addition, we do not know to which extent the
corresponding tRNAs are modified with different Q-family nucleosides,
and how the G/Q-exchange process and the sugar derivatisation is
orchestrated. Furthermore, quantitative data about Q-modification
levels in different organs is also lacking.
Figure 1. Depiction of the hypermodified base queuosine (1, Q) and of the
galactosylated and mannosylated Q-derivatives galQ (2) and manQ (3) present
in human cytosolic tRNAAsp and tRNATyr, respectively.
In all three domains of life, RNA contains next to the canonical bases
(A, C, G, and U) a large variety of modified nucleosides.[1] Most of
these are chemically simple derivatives of the canonical nucleosides.
They often carry methylations at various positions of the heterocycle
or the sugar, but others are heavily modified involving multi-step
biosynthesis pathways. Queuosine 1 (Q) is one of the most complex
of these so-called hypermodified nucleosides. (Fig. 1). It is found in a
large number of different species and also present in the cytosolic and
mitochondrial tRNATyr, tRNAAsp, tRNAHis and tRNAAsn of humans.[2-8]
Interestingly, in the human cytosolic tRNATyr and tRNAAsp, Q is further
modified with galactose (galQ) or mannose (manQ), respectively.[9, 10]
In these tRNAs, the sugar is proposed to be attached to the homo-
allylic hydroxyl-group of the cyclopentene ring system that is linked to
the 7-deazaheterocycle.[11] While the chemical synthesis of Q has
been achieved,[12-14] no reports exist about the preparation of its sugar-
modified derivatives galQ 2 and manQ 3, which has hamperered
investigations of their biological role. Accordingly, the exact function
of galQ and manQ as part of the human cytosolic tRNATyr and tRNAAsp
To address these questions, we performed the first total synthesis of
galactosyl-queuosine 2. This allowed us to confirm its proposed
structure, and to report the absolute levels of all Q-family members in
different tissues of new-born and adult mice. Finally, we were able to
measure to which extent human cytosolic tRNAs are modified with the
three Q-family nucleosides.
[a]
Dr. P. Thumbs, M. Sc. T. T. Ensfelder, M. Sc. M. Hillmeier,
Dr. M. Wagner, M. Sc. M. Heiss, M. Sc. A. Schön, Dr. M. Müller,
Dr. S. Kellner, Prof. Dr. T. Carell
Figure 2. Retrosynthetic analysis for galQ 2, showing the three key-precursors
4, 5, and 6.
Department of Chemistry, Ludwig-Maximilians-Universität München,
Butenandtstr. 5-13, 81377 Munich, Germany. www.carellgroup.de
M. Sc. C. Scheel, Prof. Dr. S. Michalakis
[b]
[c]
Department of Pharmacy, Ludwig-Maximilians-Universität München,
Butenandtstr. 5-13, 81377 Munich, Germany
Department of Ophthalmology, Ludwig-Maximilians-Universität
München, Mathildenstr. 8, 80336 Munich, Germany
Galactosyl-Q 2 was constructed from three appropriately protected
parts (Fig. 2): The 7-formyl-7-deazaguanosine 6 was prepared, as
reported by us, with Bz-protected hydroxyl-groups at the ribose, and
a
pivaloylate protection group at the 2-amino residue.[14] The
[*]
[#]
corresponding author: Thomas.Carell@lmu.de
These authors contributed equally to this work.
galactose sugar was introduced as a TBS- and 2-chloroisobutyryl-
protected trichloroacetimidate 4, and the cyclopentene unit 5 was
used with Fmoc-protected allyl amine and a TBS-protected allylic
alcohol. We choose the 2-chlorobutyryl protecting group for the sugar-
donor 4 because of its bulkiness in order to avoid unwanted orthoester
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202002295
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formation as the main product of the glycosylation reaction as shown
was followed by Fmoc-protection of the free amine using a standard
procedure. We finally opened the acetal and protected the allylic
hydroxyl-group selectively with TBS-OTf in DMF at -55 °C. In this
reaction, the temperature is particularly important. If the reaction was
performed at higher temperatures and with prolonged reaction times,
we noted selective protection of the homoallylic position.
by Szpilman et al.[15]
The galactosyl-donor 4 itself was prepared from D-galactal 7, which
was first TBS-protected (Scheme 1A).[16] cis-dihydroxylation of the
double bond from the sterically less demanding side furnished
compound 8.[17] This step was followed by protection of the two newly-
introduced hydroxyl-groups with 2-chlorobutyric acid to give the
galactose-donor-precursor 9. Deprotection of the anomeric hydroxyl-
group with hydrazine provided the galactose precursor with a free
anomeric hydroxyl-group which was subsequently converted into the
trichloroacetimidate donor 4 using a standard procedure.
Assembly of the galQ nucleoside 2 from the precursors 4-6 is shown
in Scheme 2. We first galactosylated the cyclopentene derivative.
This sterically demanding step was successfully achieved by
activation of the trichloroacetimidate with 2-chloro-6-methylpyridinium
triflate in dichloromethane at room temperature.[15, 20] We achieved
selective formation of the β-configured galactoside due to the
neighboring-group effect. Subsequent cleavage of the Fmoc-
protection group gave product 16, which was followed by a two-step
reductive amination. First, the imine was formed in benzene,
subsequently followed by reduction of the imine with NaBH4 in
methanol to afford protected galQ 17. A two-step deprotection
protocol, in which we first removed the TBS-groups with HF•NEt3, was
followed by cleavage of ester-type protecting groups under Zemplén-
conditions. For the cleaving of the pivaloyl-amide protecting group, we
needed to use 0.5 M NaOMe in methanol. This strategy provided the
target compound 2 with a total yield of 0.5 % in 20 linear steps from
the mannose starting molecule for the cyclopentene unit. The
synthesis provided a sufficient amount of material for all further
investigations.
Scheme 1. Synthesis of the key precursors 4 and 5. A) Synthesis of the
galactose precursor 4: a) TBSCl, imidazole, DMF, 55 °C, 2 d; b) K2OsO4∙2 H2O,
NMO, THF, t-BuOH, H2O, rt, 4 h; c) 2-chloroisbutyric acid, DIC, DMAP, 0 °C,
30 min → rt, 2 h; d) N2H4∙AcOH, DMF, -40 °C to rt, 3 h; e) Cl3CCN, Cs2CO3,
DCM, rt, 4 h; B) Synthesis of the cyclopentene precursor 5: a)
2,2-dimethoxypropane, acetone, p-TsOH, rt, 1 h; b) Ac2O, pyridine, 0 °C → rt,
18 h; c) aq. AcOH (66%), 55 °C, 4 h; d) triethyl-orthoformate, 100 °C, 30 min; e)
Ac2O, 130 °C, 5 h; f) t-BuOK, MeOH, 20 min; g) NaH, DMSO, Ph3PMeBr, THF,
rt → 68 °C, 2 h; h) Grubbs-(I)-catalyst, DCM, rt, 26 h; i) Cl3CCN, DBU, DCM, rt,
20 min; k) o-xylene, 150 °C, 5 h; l) NaOH, MeOH, rt, overnight; m) Fmoc-OSu,
NaHCO3, H2O, 1,4-dioxane; n) AcOH, H2O, EtOAc, 50 °C, 24 h; o) TBSOTf,
DMF, -55 °C, 15 min.
Scheme 1B shows the synthesis of the protected 5(S)-amino-
Scheme 2. Depiction of the galQ 2 assembly from the three key-precursors 4,
5, and 6. a) 2-chloro-6-methylpyridinium triflate, DCM, rt, 2 h; b) DBU, MeCN, rt,
1.25 h; c) benzene, rt, 5 h; d) NaBH4, MeOH, 0 °C, 1 h; e) HF∙NEt3, DCM, rt,
4 d; f) NaOMe, MeOH, rt, 2 d.
3(S),4(R)-dihydroxycyclopent-1-ene 5.
Starting
point
was
[18]
mannose 10
which was converted as reported into the double-
acetonide-protected mannofuranoside 11 with an acetyl-protected
anomeric center in two steps. Selective cleavage of the acetonide
protecting group at the primary hydroxyl-group, followed by an
orthoester-based elimination, allowed introduction of a terminal
double bond (12). Anomeric deprotection, followed by a Wittig-
reaction, provided the precursor 13 for the ring-closing metathesis
reaction. The free hydroxyl-group in 14 was then the starting point for
an Overman-rearrangement, providing the amine protected as a
trichloroacetamide 15.[19] Cleavage of this protecting group with NaOH
We next investigated if our synthetic ß-homoallylic galQ 2 is identical
with the natural product, because analytical data available for galQ
was very limited.[11] For this experiment, we isolated total RNA from
mouse liver and performed an enzymatic digestion of the isolated
RNA to the nucleoside level. This nucleoside mixture was analyzed
by HPLC-MS. Indeed, under our HPLC-conditions, we detected two
signals with the appropriate m/z value for galQ and manQ in the
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10.1002/anie.202002295
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extracted ion chromatogram with a retention time of around 32 and
35 min. In the same m/z-range, no other peaks were present. We next
co-injected our synthetic ß-homoallylic galQ 2, which led to a marked
increase of the second signal with a retention time of about 35 min
(Fig. 3). This result unambigously showed that our synthetic
compound galQ 2 and the co-eluting natural compound with the same
retention time are identical. Therefore, this natural compound is
diet,[21, 22] mammals thereby profiting from their gut microbiome.[23] We
therefore speculate that the low levels of Q-family nucleosides in new-
born mice observed here may be caused by a lack of queuine-supply
in new-born mice, which only later establish their microbiome.
Furthermore, high rates of cell divison and tissue development in
young mice may cause additional queuine supply problems.
indeed
a -galactosylated Q-derivative. Taken together, our
experiment confirms the proposed chemical structure of galQ, in
which the bond between the homoallylic hydroxyl-group of queuosine
and galactose is in ß-configuration.
Figure 3. Results of a co-injection study confirming the identity of our synthetic
ß-homoallylic-galQ 2 with the natural product. Depicted are the extracted-ion
chromatograms (m/z = 572.2148-572.2248) of two HPLC-MS analyses, either
with (right) or without (left) prior spiking of the synthetic galQ 2. The exact mass
[M+H] of galQ (and manQ) is 572.2198 u, showing a perfect match of less than
4 ppm deviation with the two MS-peaks observed by us.
Having identified the HPLC-retention time of galQ and therefore also
of manQ, we finally were able to determine the absolute levels of galQ,
manQ, and Q in different tissues of new-born (post-natal day 1; pd1)
and adult mice (post-natal month 3; pm3). For an initial broad study,
we measured the respective nucleoside levels in cortex, cerebellum,
liver, kidney, heart, and spleen, using the same RNA-isolation and
digestion protocol as for the co-injection experiment (Fig. 4A).
From our data it is clearly evident that the levels of all three
modifications (galQ, manQ, and Q) generally increase with age. This
effect is by far most pronounced with Q, while galQ and manQ only
show a modest increase, if at all. Furthermore, and for all three
modifications investigated, we see differences between the six organs
at the same age. Heart, followed by brain tissues, contain the largest
levels of Q and its sugar-modified derivatives, followed by kidney, liver
and spleen. At gross, the changes of modification levels observed by
us positively correlate with the respective organ-specific protein-
synthesis demands, as we have shown before.[7] Nevertheless, there
are some prominent outliers. These outliers (e.g. heart tissue), seem
to rather correlate with the organ-specific density of mitochondria. It
was shown before that the Q-base in mitochondrial tRNATyr and
tRNAAsp is not sugar-modified.[8] We therefore speculate that the
organ-specific differences in the levels of galQ, manQ, and Q are due
to an overlay of two independent effects: The organ-specific protein-
synthesis ratio, and the organ-specific mitochondrial density.
Figure 4. A) Absolute levels of galQ 2, manQ 3, and Q 1, in six different organs
of new-born (post-natal day 1, pd 1) and adult (post-natal month 3, pm 3) mice.
Values are given as number of xQ-modifications n(X) per 1000 adenosine
nucleosides n(A). Error bars represent the standard deviation of three biological
replicates. For statistical analysis, Student’s unpaired two-tailed t-test was used.
n.s.: not significant, *: p<0.05, **: p<0.01, ***: p<0.001. B) Number of galQ-,
manQ-, and Q-modifications per cytosolic tRNAsAsn, tRNAsHis, tRNAsAsp, and
tRNAsTyr from human HEK 293T cells, respectively. queuine+: cells grown in
queuine-enriched medium, queuine-: cells grown in standard medium. Values
are given as average modifications per tRNA. Error bars represent the standard
deviation of three biological replicates.
To further study the influence of queuine-availability on Q-family
modification levels, cell culture experiments were performed: Human
embryonic kidney 293T (HEK 293T) cells were grown either in culture
medium supplemented with 20 nM of the queuine enriched medium)
or in medium without additional queuine (standard medium). Queuine
is the substrate of the TGT-enzyme, which performs the exchange of
It is well-established that for biosynthesis of Q (and its sugar-modified
derivatives), eukaryotes have to take up the queuine-base from their
a
guanine base by the queuine heterocycle during tRNA-
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10.1002/anie.202002295
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COMMUNICATION
maturation.[24-26] From both cell populations, cytosolic tRNATyr, tRNAAsp
tRNAHis, and tRNAAsn were isolated and digested to the nucleoside
level. For each of these four individual tRNA-species, the number of
galQ-, manQ-, and Q-modifications per tRNA was then determined by
,
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[7]
a
mass spectrometry-based isotope-dilution method using the
reference compound synthesized here (see supporting information).
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position of cytosolic tRNATyr, tRNAAsp, tRNAHis, and tRNAAsn is strongly
dependent on queuine availability (Fig. 4B).[27] In case of tRNATyr
(galQ), tRNAHis and tRNAAsn (Q), the difference in modification extent
between cells grown in enriched versus standard medium is threefold,
while for tRNAAsp (manQ) it is 1.7 fold. These results are well in line
with our hypothesis and might therefore explain the lower modification
levels in new-born mice. Of note, in all of our experiments even a
sufficient queuine-supply did not lead to fully modified tRNAs. This
might again be an indication of the modification machinery lagging
behind the de novo-synthesis of tRNA in highly proliferating cells.
Furthermore, we detected a Q-only-modified tRNATyr-form in our
experiments lacking the galactose sugar, while tRNAAsp was always
found to be either modified with manQ or completely unmodified. It
seems that, in our experimental setup, mannosylation of tRNAAsp may
be more tightly connected to G/Q-exchange than the galactosylation
of Q-only-bearing tRNATyr. Testing this exciting hypothesis is an
interesting starting point for future studies.
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[24]
In summary, we here report the first total synthesis of the human
natural product galactosyl-queuosine 2. Our synthetic material
allowed us to confirm the proposed galQ structure by direct
comparison with natural material, and we show that this hypermodfied
nucleoside is present in all tissues of new-born and adult mice. We
furthermore report the absolute levels of all three Q-family-members
in six different mouse organs and in human cytosolic tRNAs. Taken
together, our results confirm the crucial importance of tRNA galQ- and
manQ-modification.
[25]
[26]
[27]
F. Tuorto, C. Legrand, C. Cirzi, G. Federico, R. Liebers, M. Müller,
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Acknowledgements
Funded by the Deutsche Forschungsgemeinschaft (DFG, German
Research Foundation) –Project-ID 255344185 – SPP 1784; Project-
ID 325871075 – SFB 1309, and Project-ID 393547839 – SFB 1361.
This project has received additional funding from the European
Union's Horizon 2020 research and innovation programme under the
Marie
Skłodowska-Curie
grant
agreement
No
765266
(LightDyNAmics) and from the European Research Council (ERC)
under the European Union's Horizon 2020 research and innovation
programme under grant agreement No 741912 (EPiR).
Keywords: RNA modifications, epitranscriptome, queuosine,
galactosylation, mannosylation, mannosyl-queuosine.
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COMMUNICATION
COMMUNICATION
The first total synthesis of the
Peter Thumbs *, Timm T. Ensfelder *,
Markus Hillmeier *, Mirko Wagner *,
Matthias Heiss, Constanze Scheel,
Alexander Schön, Markus Müller,
Stylianos Michalakis, Stefanie Kellner,
and Thomas Carell #
hypermodified
RNA
nucleoside
galactosyl-queuosine (galQ) was
achieved. Moreover, the distribution of
this nucleoside, and, in addition, of
mannosyl-queuosine and queuosine,
was determined in tissues of new-born
and adult mice, and in human
cytosolic tRNAs.
Page No. – Page No.
Synthesis of galactosyl-queuosine
and distribution of hypermodified
Q-nucleosides in mouse tissues
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