Sulfonium-Based Homolytic Substitution Observed for the Radical SAM Enzyme HemN

Article abstract of DOI:10.1002/anie.202000812

Sulfur-based homolytic substitution (S_H reaction) plays an important role in synthetic chemistry, yet whether such a reaction could occur on the positively charged sulfonium compounds remains unknown. In the study of the anaerobic coproporphyrinogen III oxidase HemN, a radical S-adenosyl-l-methionine (SAM) enzyme involved in heme biosynthesis, we observed the production of di-(5′-deoxyadenosyl)methylsulfonium, which supports a deoxyadenosyl (dAdo) radical-mediated S_H reaction on the sulfonium center of SAM. The sulfonium-based S_H reactions were then investigated in detail by density functional theory calculations and model reactions, which showed that this type of reactions is thermodynamically favorable and kinetically competent. These findings represent the first report of sulfonium-based S_H reactions, which could be useful in synthetic chemistry. Our study also demonstrates the remarkable catalytic promiscuity of the radical SAM superfamily enzymes.

Full text of DOI:10.1002/anie.202000812

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Accepted Article
Title: Sulfonium-based Homolytic Substitution Observed for the Radical
SAM Enzyme HemN
Authors: Wenjuan Ji, Xinjian Ji, Qi Zhang, Dhanaraju Mandalapu, Zixin
Deng, Wei Ding, Peng Sun, and Qi Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000812
Angew. Chem. 10.1002/ange.202000812
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10.1002/anie.202000812
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Sulfonium-based Homolytic Substitution Observed for the
Radical SAM Enzyme HemN
Wenjuan Ji#, Xinjian Ji#, Qi Zhang, Dhanaraju Mandalapu, Zixin Deng, Wei Ding, Peng Sun, and Qi
Zhang*
Abstract: Sulfur-based homolytic substitution (SH) plays an
important role in synthetic chemistry, yet whether such a chemistry
could occur on the positively charged sulfonium compounds remains
unknown. In the study of the anaerobic coproporphyrinogen III
are called radical SAM superfamily enzymes, which represent the
largest known enzyme family consisting of more than 125,000
members found in all three domains of life.[6] Radical SAM
enzymes contain a [4Fe-4S] cluster to bind SAM and reductively
cleave its carbon-sulfur bond to produce a highly reactive 5ˊ-
deoxyadenosyl (dAdo) radical. This alkyl radical then abstracts a
hydrogen from the substrate, thereby initiating diverse reactions
relevant to the modification of nucleic acids and proteins, and the
biosynthesis of cofactors and natural products.[6]
oxidase HemN,
a radical S-adenosyl-L-methionine (SAM)
enzyme involved in Heme biosynthesis, we observed the
production of di-(5′-deoxyadenosyl)methylsulfonium, supporting
a deoxyadenosyl (dAdo) radical-mediated SH reaction on the
sulfonium center of SAM. The sulfonium-based SH reactions were
then investigated in detail by density functional theory calculations
and by model reactions, showing that such a type of reactions is
thermodynamically favorable and kinetically competent. These
findings represent the first report of sulfonium-based SH reactions,
which could be useful in synthetic chemistry. Our study also
demonstrates the remarkable catalytic promiscuity of the radical
SAM superfamily enzymes, which could be a treasury in studying
organic reactions.
We recently investigated the catalytic mechanism of the
anaerobic coproporphyrinogen III oxidase HemN, a radical SAM
enzyme involved in Heme biosynthesis.[7] We showed that in
HemN catalysis, the dAdo radical generated by reductive
cleavage of one SAM molecule (SAM1) abstracts a hydrogen
atom from the methyl group of another SAM (SAM2) in the
enzyme active site (Figure 1). The resulting SAM-based
methylene radical (1) then abstracts the hydrogen from the
propionate side chain of coproporphyrinogen III (2) and initiates
its oxidative decarboxylation (Figure 1). Similar hydrogen transfer
process may also be involved in the reactions of the class C
radical SAM methyltransferases (RSMTs),[8] a group of enzymes
homologous to HemN.[9]
Sulfur-based homolytic substitution (SH) chemistry has
increasingly been recognized as an essential part of the synthetic
toolbox.[1] These reactions have been reported on various sulfur-
containing compounds, including thioethers, thioesters, disulfides,
sulfoxides, sulfinates, sulfonamides, and various S-based acetyl
and ketals.[1-2] It has also been shown that SH reactions cannot
occur on sulfones.[3] However, to date no studies have been
reported to assess whether SH reactions could occur on
sulfoniums, a group of positively charged sulfur-containing
compounds that play important roles in biology and in medicinal
chemistry.[4]
H
H
[4Fe-4S]2+
CH3
dAdo
[4Fe-4S]+
H
[4Fe-4S]+
H3C
R
S
+
dAdoH
R
[4Fe-4S]2+
SAM2
SAM1
N
H
CO2
CH2
COOH
COOH
H
H
H
H
H
S
+
H
H3C
H
H3C
R
R
1
N
H
R
N
R
S-adenosyl-L-methionine (SAM) is ubiquitous in life and
represents the most important sulfonium compound in
biochemistry. This compound serves as a methyl donor for most
methyltransferases and participates in almost every aspects of life
process.[5] Besides the role as a methyl donor, SAM can also
H
2
coproporphyrinogen III ( )
Figure 1. Proposed mechanism for HemN catalysis, in which the second SAM
(SAM2) serves as relay that mediates the dAdo radical-initiated
decarboxylation reactions.
a
serve as
a radical precursor to initiate highly diverse
The crystal structure of HemN was reported in 2003 by Layer
et al., showing that two SAM molecules were bound in the enzyme,
while the substrate 2 is not present in the reported structure.[10]
HemN recognizes SAM with both (S)- and (R) configuration at the
chiral sulfonium sulfur, with the former being favored (∼60%
occupancy in the crystal structure) (Figure 2).[10] Interestingly, we
noted that in HemN structure, the methyl group of SAM2 is placed
in the opposite direction and is relatively far away from the C5ˊ of
SAM1, with a distance of 7.0 Å for (S)-SAM (the favored
diastereoisomer) (Figure 2A) and 5.9 Å for (R)-SAM (Figure 2B).
This conformation of SAM2 is apparently not ideally placed for
HemN reaction, and binding of the substrate 2 is likely essential
for tuning SAM in a suitable conformations required for reaction;
similar substrate binding-induced conformational changes were
also noted in the catalysis of the class C RSMT NosN.[8d] The
biotransformations. Enzymes that catalyze these radical reactions
[*] W.Ji, X. Ji, T. Q. Zhang, D. Mandalapu, Prof. Dr. Q. Zhang
Department of Chemistry, Fudan University, Shanghai, 200433, China
E-mail: qizhang@sioc.ac.cn
Prof. Dr. Z. Deng and Prof. Dr. W. Ding
State Key Laboratory of Microbial Metabolism, School of Life Sciences
& Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240,
China
Prof. Dr. P. Sun
School of Pharmacy, Second Military Medical University, 200433,
China
[#] These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202000812
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distances between the SAM1 C5ˊ and the sulfur atom of SAM2 is
5.3 Å for (S)-SAM and 5.4 Å for (R)-SAM, which are within the
reaction range upon conformational fluctuation. This finding
raises a possibility that the dAdo radical produced from SAM1
may attack the sulfonium center of SAM2, which may result in a
sulfonium-based SH reaction. Such a type of reaction, however,
has not been reported in the literature.
sulfonium center of SAM2 to result in the exclusion of the
homoalanine radical (6), which could possibly be quenched to
produce homoalanine (7) (Figure 3C). Consistent with the
proposal, we showed homoalanine was indeed produced in the
reaction (Figure S3), and the yield is roughly similar to that of
compound 3 (Figure S4). These results again strongly support a
dAdo radical-based SH reaction illustrated in Figure 3C.
Figure 2. HemN binds SAM with both (S)- and (R) configuration at the chiral
sulfonium sulfur. (A) Active site of HemN that binds (S)-SAM (∼60% occupancy).
(B) Active site of HemN that binds (R)-SAM (∼40% occupancy).
To test this intriguing possibility, we performed HemN reactions
by incubating the reconstituted HemN with SAM and sodium
dithionite, and the reaction mixtures were analyzed by liquid
chromatography (LC) high-resolution (HR) mass spectrometry
(MS). Careful analysis of the HR-LCMS data revealed a
compound (3) in the reaction, which is clearly absent in the control
reaction with the supernatant of boiled enzyme (Figure 3A, trace
i and ii). 3 exhibited a positive charged molecular ion at m/z =
547.1821, suggesting a molecular formula of C21H27N10O6S
(calculated m/z = 547.1830, 1.8 ppm error). Detailed HR-MS/MS
analysis revealed several key fragments of 3 at m/z = 412.13,
250.10, and 136.06 (Figure S1A), supporting it is di-(5′-
deoxyadenosyl)methylsulfonium,
a sulfonium whose sulfur
connects two dAdo groups and a methyl group.
To further validate the proposed structure of 3, we chemically
synthesized di-(5′-deoxyadenosyl)methylsulfonium by using a
thioether-based coupling strategy followed by S-methylation
(Figure 3B). LC-HRMS analysis showed the authentic standard 3
was coeluted with the expected product in the HemN-catalyzed
reaction (Figure 3A, trace iii), and exhibited a highly similar HR-
MS/MS spectrum (Figure S1B), confirming that 3 is indeed di-(5′-
deoxyadenosyl)methylsulfonium produced from SAM by HemN
via a unprecedented mechanism.
We also performed the reaction with S-adenosyl-l-[methyl-2H3]-
methionine (d3-SAM), and the expected product 3D was observed
in the reaction, which exhibited a positive charged molecular ion
three mass units higher than 3 (observed m/z= 550.2001,
calculated m/z = 550.2019, 3.3 ppm for a molecular formula of
C21H24D3N10O6S), and the structure is supported by HR-MS/MS
analysis (Figure S2).
Figure 3. Sulfur-based SH reactions catalyzed by HemN. (A) LC−MS analysis
of HemN in vitro activity, showing the extracted ion chromatograms (EICs) of [M
+ H]+ = 547.2 (corresponding to 3) for (i) negative control reaction with SAM and
the supernatant of boiled HemN, (ii) HemN reaction with SAM, (iii) HemN
reaction with SAM (ii) spiked with the synthetic standard of 3, (iv) HemN reaction
with SAM and 2; and the EICs of [M + H]+ = 550.2 (corresponding to 3D) for (v)
negative control reaction with d3-SAM, (vi) HemN reaction with d3-SAM; and the
EICs of [M + H]+ = 549.2 (corresponding to 4) for (vii) negative control reaction
with SAHO, (vii) HemN reaction with SAHO, and HemN reaction with SAHO (viii)
spiked with the synthetic standard of 4. In summary, trace i-iv are reactions with
SAM, trace v-vi are reactions with d3-SAM, and trace vii-viiii are reactions with
SAHO. Dithionite were included in all the reactions. (B) Preparation of the di-
adenosylated products 3, 4, and 5. See Figure S9-S13 for the NMR spectra of
compound 3, 4, and 5. (C) A summary of the HemN-catalyzed SH reactions.
Intriguingly, although theoretically all the three S-C bonds of
SAM2 could be broken in the dAdo radical-based SH reaction, we
did not observe the product corresponding to S-CH3 bond
cleavage (i.e. production of a sulfonium in which the sulfur atom
connects two dAdo moieties and a homoalanine moiety). We were
unable to see whether the S-C(5ˊ) bond of SAM2 was broken
The results presented above support that HemN catalyzes an
unusual sulfonium-based SH reaction. In this reaction, the dAdo
radical generated from reductive cleavage of SAM1 attacks the
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because such a reaction would yield SAM that is exactly the same
with the starting substrate. We would like to point out that 3 was
also observed in the reaction with the substrate 2, albeit with a
decreased (~30%) yield (Figure S4). Apparently, 3 is an off-
pathway shunt product in the reaction resulting from the catalytic
promiscuity of the enzyme. Careful quantification of the reaction
products showed that the yield of 3 in the presence of 2 is about
10% of protoporphyrinogen IX (Figure S4), the on-pathway
product of HemN. The promiscuous activity of HemN is possibly
because the in vitro reaction of HemN was not performed in the
optimized condition, and whether compound 3 is also produced in
vivo remains to be investigated. It also appears that HemN is far
from well-evolved, and a SAM-adduct off-pathway product was
also observed in HemN in vitro reaction.[7]
Figure 4. DFT-calculated potential energy profile of sulfur-based SH reaction
initiated by a methyl radical. Free energies of activation (kcal/mol) were
calculated at the B3LYP/6-31+G(d)/SCRF (water) level of theory with geometry
optimized at the same level of theory. The transition states have been validated
by intrinsic reaction coordinate (IRC) calculations (Figure S5-S8).
We recently showed that the radical SAM enzymes NosL and
NosN are able to cleave a sulfoxide SAHO and a sulfone SAHO2,
both of which are structurally homologous to SAM (Figure 3C).[11]
To test whether HemN can catalyze similar SH reaction on
sulfoxide and sulfone, we performed HemN reactions with SAHO
and SAHO2 respectively. This analysis showed that HemN can
efficiently cleave both SAM analogues and produce 5ˊ-
deoxyadenosine (dAdoH) (Figure S5). Further analysis revealed
a compound (4) in the reaction with SAHO, which is clearly absent
in the negative control reactions (Figure 3A, trace vii and viii). 4 is
consistent with the proposed product of the dAdo radical-based
SH reaction on SAHO (Figure 3C), and this is supported by HR-
MS/MS analysis (Figure S6A). To further validate the proposed
structure of 4, we chemically synthesized the authentic standard
and ran LC and HRMS/MS analysis for comparison. These
analyses showed the synthetic standard 4 was coeluted with the
enzyme-produced product (Figure 3A, trace viiii), and exhibited a
highly similar HR-MS/MS spectrum (Figure S6B). These results
confirm that HemN is able to catalyze a dAdo-based SH reaction
on a sulfoxide SAHO. We did not find a similar SH reaction product
5 in the reaction with SAHO2 (Figure 3C), and this observation is
consistent with the early studies showing that SH reactions cannot
occur on sulfones.[3]
Early studies showed that SH reactions proceeded smoothly on
sulfide and sulfoxide.[2c, 12] In these reactions, photolysis of an
iodophenyl moiety led to generation of a phenyl radical, which
subsequently attacked the sulfur center to result in SH reactions.
However, these analyses were carried only on sulfide and
sulfoxide, but not on a sulfonium. To test whether a similar SH
reaction can also occur on sulfonium, we synthesized dimethyl 2-
(o-iodophenyl)ethyl sulfonium (8) and performed a photolysis
reaction similar to those reported by Kampmeier et al.[12] HPLC
analysis of the photolysis product of 8 clearly revealed the
production of 1-methyl-2,3-dihydrobenzothiophenium (10), a SH
reaction product of the radical intermediate 9 (Figure 5). We also
observed the production of 1-methylbenzothiophenium 11, an
oxidized product that is also found in a control reaction in which
the synthetic standard 10 was treated with the same reaction
condition. This analysis again validates that SH reaction can
readily occur at the sulfur atom of a sulfonium.
To further investigate the sulfonium-based SH reactions, we
selected methyl radical and trimethylsulfonium as a quantum
reaction model and performed a density functional theory (DFT)
calculation. For comparative analyses, calculations were also
performed on dimethyl sulfide, dimethyl sulfoxide and dimethyl
sulfones. These calculations showed the attacking methyl group
approaches the sulfur center with the synergistic leave of the
backside methyl group, and the free energy along the reaction
coordinate reached the maximum when the sulfur atom is in the
middle of the attacking radical and the leaving group (Figure S5-
S8). The activation barrier is 21.1 kcal/mol for dimethyl sulfide,
19.5 kcal/mol for dimethyl sulfoxide, and has an exceptional high
value of 54.2 kcal/mol for dimethyl sulfone. Notably, the activation
barrier for trimethylsulfonium is 18.0 kcal/mol, about 3 kcal/mol
lower than that of dimethyl sulfide, suggesting that SH reaction on
a sulfonium could be thermodynamically more favorable than the
corresponding sulfide.
Figure 5. A model sulfonium-based SH reaction. (A) Photolysis reaction of
dimethyl 2-(o-iodophenyl)ethyl sulfonium (8). (B) HPLC analysis of (i) the
standard 8, (ii) the photolysis reaction mixture of 8, and (iii) synthetic standard
of 10 treated with the same reaction condition used in (ii). UV absorbance at
254 nm.
In summary, we observed the production of 3 in the reaction
mixture of HemN, suggesting a dAdo radical-based SH reaction
on the SAM sulfonium center. This finding inspired us to further
investigate the sulfonium-based SH reaction by DFT calculation
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Keywords: catalytic promiscuity • S-adenosylmethionine • SAM
analogue • sulfonium radical • biosynthesis
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Text for Table of Contents
Wenjuan Ji#, Xinjian Ji#, Qi Zhang,
Dhanaraju Mandalapu, Zixin Deng, Wei
Ding, and Qi Zhang*
Sulfonium-based homolytic
substitution (SH) was observed in the
reaction of a radical SAM enzyme
HemN. Subsequent DFT and model
chemistry analysis showed that this
type of chemistry is
thermodynamically favorable and
could be further explored in chemical
synthesis.
Page No. – Page No.
Sulfonium-based Homolytic
Substitution Revealed in the Study of
the Radical S-adenosyl-L-methionine
Enzyme HemN
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