Remarkable Effect of Chalcogen Substitution on an Enzyme Mimetic for Deiodination of Thyroid Hormones

Article abstract of DOI:10.1002/anie.201502762

Iodothyronine deiodinases are selenoenzymes which regulate the thyroid hormone homeostasis by catalyzing the regioselective deiodination of thyroxine (T4). Synthetic deiodinase mimetics are important not only to understand the mechanism of enzyme catalysis, but also to develop therapeutic agents as abnormal thyroid hormone levels have implications in different diseases, such as hypoxia, myocardial infarction, critical illness, neuronal ischemia, tissue injury, and cancer. Described herein is that the replacement of sulfur/selenium atoms in a series of deiodinase mimetics by tellurium remarkably alters the reactivity as well as regioselectivity toward T4. The tellurium compounds reported in this paper represent the first examples of deiodinase mimetics which mediate sequential deiodination of T4 to produce all the hormone derivatives including T0 under physiologically relevant conditions.

Full text of DOI:10.1002/anie.201502762

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International Edition: DOI: 10.1002/anie.201502762
German Edition: DOI: 10.1002/ange.201502762
Bioorganic Chemistry
Remarkable Effect of Chalcogen Substitution on an Enzyme Mimetic
for Deiodination of Thyroid Hormones**
Karuppusamy Raja and Govindasamy Mugesh*
Abstract: Iodothyronine deiodinases are selenoenzymes which
regulate the thyroid hormone homeostasis by catalyzing the
regioselective deiodination of thyroxine (T4). Synthetic deio-
dinase mimetics are important not only to understand the
mechanism of enzyme catalysis, but also to develop therapeutic
agents as abnormal thyroid hormone levels have implications
in different diseases, such as hypoxia, myocardial infarction,
critical illness, neuronal ischemia, tissue injury, and cancer.
Described herein is that the replacement of sulfur/selenium
atoms in a series of deiodinase mimetics by tellurium
remarkably alters the reactivity as well as regioselectivity
toward T4. The tellurium compounds reported in this paper
represent the first examples of deiodinase mimetics which
mediate sequential deiodination of T4 to produce all the
hormone derivatives including T0 under physiologically
relevant conditions.
Figure 1. The regioselective deiodination reactions of thyroid hormones
catalyzed by three isoforms of iodothyronine deiodinases.
T
hyroid hormones play an important role in growth, devel-
opment, and regulation of energy metabolism.[1] Thyroxine
(T4), the main secretory hormone produced in the thyroid
gland, undergoes peripheral deiodination reactions in various
tissues to form biologically more active 3,5,3’-triiodothyro-
nine (T3; by 5’-deiodination) and an inactive 3,3’,5’-triiodo-
thyronine (rT3; reverse T3, by 5-deiodination).[2] The regio-
selective deiodination reactions are catalyzed by three iso-
forms of the selenocysteine-containing iodothyronine deiodi-
nases (ID-1, ID-2 and ID-3; Figure 1).[3] Although ID-1 can
mediate both 5- and 5’-deiodinations of T4, it is primarily
responsible for the production of plasma T3 by 5’-deiodina-
tion. ID-2 catalyzes only the 5’-deiodination of T4 and is
essential for the local production of intracellular T3. In
contrast, ID-3 mediates only the 5-deiodination and is
important for the inactivation of T4 (Figure 1). The three
isoforms of the enzymes collectively regulate thyroid hor-
mone homeostasis in the body.
thetic selenol that mediates the 5’-deiodination or outer-ring
deiodination (ORD) of N-butyrylthyroxine methyl ester to
give the corresponding triiodo derivative.[5b] We reported that
the compound 1, having two thiol moieties, and the compound
2, having a thiol-selenol pair in the peri-positions, convert T4
and T3 into rT3 and 3,3’-T2, respectively, by 5-deiodination or
inner-ring deiodination (IRD).[6a] Recently, we reported that
the compound 3, bearing two selenol moieties, is more active
than 1 and 2 in the 5-deiodination of T4 and the regioselec-
tivity of deiodination is not altered upon the substitution of
sulfur with selenium.[6b,c] The introduction of an amino group
to 3 increases the nucleophilicity of one of the selenol
moieties, upon deprotonation, but does not alter the regio-
selectivity as the amino-substituted compounds 4–10 which
also mediate the 5-deiodination.[6b,c] Interestingly, 1–6 were
unable to remove additional iodine atoms from either rT3 or
3,3’-T2, even at higher concentrations, and is in contrast to the
ID-3 enzyme, which can remove the second iodine atom from
rT3 and 3,3’-T2 to produce 3’,5’-T2 and 3’-T1, respectively.
Herein we show, for the first time, that the replacement of
either one of the sulfur atoms in 1 or the two selenium atoms
Given the importance of thyroid hormone deiodination in
human metabolism and lack of information about the
mechanism of such deiodination,[4] the development of
simple selenium compounds as deiodinase mimetics has
attracted significant interest.[5–7] Goto et al. reported a syn-
[*] K. Raja, Prof. Dr. G. Mugesh
Department of Inorganic and Physical Chemistry
Indian Institute of Science, Bangalore-560012 (India)
E-mail: mugesh@ipc.iisc.ernet.in
[**] This study was supported by the Department of Science and
Technology (DST), New Delhi. K.R. thanks UGC for a research
fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502762.
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in 3 by tellurium atoms remarkably alters the regioselectivity
of deiodination under physiological conditions.
of deiodination. Similarly, no change in the regioselectivity
was observed when both the sulfur atoms in 1 were replaced
by selenium atoms (3). In contrast, the replacement of the
selenium atom in 2 by a tellurium atom, dramatically
increased the rate of deiodination with a remarkable change
in the regioselectivity.
To confirm the sequential deiodination of T4 (Figure 3),
we treated T4 and its derivatives independently with the test
compounds. The initial rate observed for the IRD of T4 by 13
The dichalcogenides 11 and 12, which were required for
this study, were synthesized by following a procedure
reported for the corresponding sulfur and selenium analogues
(see the Supporting Information, SI). The reduction of 11 and
12 by NaBH4 afforded the compounds 13 and 14, respectively
(Figure 2A). When 13 (0.75 mm) was treated with T4 (300 mm)
in phosphate buffer (pH 7.5) at 378C the immediate forma-
Figure 2. A) Chemical structures of compounds 11–16. B) HPLC chro-
matograms for the reactions of T4 with 13 and 14. C) Initial rates for
the deiodination of T4 and its derivatives by selenium/tellurium
compounds. Assay conditions for 13 and 14: T4, T3, or 3,5-T2
(300 mm), DTT (2.5 mm), 13 or 14 (0.75 mm), and NaBH4 (13 mm).
The reaction mixture was incubated for 10 min in phosphate buffer
(pH 7.5) at 378C. For the deiodination of rT3 and 3,3’-T2, 150 mm of
either rT3 or 3,3’-T2, 75 mm of either 13 or 14, 2.5 mm DTT, and
26 mm of NaBH4 were used. For 3, 16, and PhTeH (17): T4, T3 or 3,5-
T2 (300 mm), DTT (2.5 mm), test compounds (300 mm), and NaBH4
(26 mm) were incubated for 30 min in phosphate buffer (pH 7.5) at
378C and the reactions were followed by HPLC.
Figure 3. Sequential deiodination of T4 by 13 and 14. IRD=inner-ring
deiodination, ORD=outer-ring deiodination, T4=l-thyroxine,
T3=3,5,3’-triiodothyronine, rT3=3,3’,5’-triiodothyronine, 3,3’-T2=3,3’-
diiodothyronine. Stoichiometric amounts of 13 and 14 were required
to observe the formation of T0 from T4.
[(10.6 Æ 0.1) mm minÀ1] at a concentration of 0.75 mm was
much higher than that of 3 [(0.9 Æ 0.1) mm minÀ1] at a concen-
tration of 300 mm (Figure 2C), thus indicating that the activity
of 13 is thousands of times higher than that of 3. The rate of
IRD of T3 or 3,5-T2 by 13 was also found to be much higher
than that of 3. When rT3 and 3,3’-T2 were used, a 100-fold
increase in the concentration of 13 was required to observe an
appreciable deiodination. The compound 14, having two
tellurol groups, was found to be less active [(4.4 Æ
0.1) mm minÀ1] for T4 than 13 in the deiodination of all five
substrates, although a higher concentration of 14 was required
for the IRD of rT3 and 3,3’-T2. This result is surprising
because 3, having two selenol moieties, was found to be
significantly more active than 2 which has a thiol-selenol pair.
The deiodination reactions of T4 by an increasing the
concentration of either 13 or 14 showed the formation of
rT3 and a subsequent deiodination, thus leading to the
formation of 3’,5’-T2 by IRD and 3,3’-T2 by ORD (Figure 3).
tion of rT3 was observed. In contrast, a stoichiometric amount
of 3 (300 mm) was required for the 5-deiodination of T4 under
identical experimental conditions (Figure 2C). Interestingly,
when 13 was treated with T4 in 1:1 molar ratio, the HPLC
chromatograms showed the formation of six different prod-
ucts. A comparison of the HPLC chromatograms with that of
the authentic samples indicated that the reaction generated
most of the deiodination products of T4, that is, rT3, 3,3’-T2,
3’,5’-T2, 3-T1, 3’-T1, and T0 (Figure 2B). Similar products
were obtained when 14 was treated with T4 in 1:1 molar ratio.
These observations indicate that the replacement of sulfur in
1 by a selenium atom (2) increases the reaction rate for the
conversion of T4 into rT3 without altering the regioselectivity
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Although T3 can be converted into 3,3’-T2 by IRD, the
formation of 3,3’-T2 occurs mainly via rT3 as almost all the T4
in the reaction mixture is rapidly converted into rT3 by 13 and
14 (see Figures S14 and S15 in SI). Attempts to detect the
formation of T3 directly from T4 were unsuccessful, as T3
undergoes a rapid deiodination by IRD to produce 3,3’-T2.
However, 13 and 14 do mediate the conversion of T3 into 3,3’-
T2 by IRD when T3 was used as the starting material
(Figure 3). Interestingly, 13 and 14 do not mediate the ORD
of T3 to produce 3,5-T2, but these compounds can remove
iodine from 3,3’-T2 by ORD to produce 3-T1, thus indicating
that the ORD is not a favored process when two iodines are
present in the inner-ring. Similarly, the ORD of 3’-T1 was not
observed at lower concentrations of 13 and 14, whereas the
IRD of 3-T1 produced T0 as the final product (Figure 3).
Therefore, T4 is converted into the fully deiodinated deriv-
ative T0 through the rT3!3,3’-T2!3-T1 pathway, involving
two IRD reactions and two ORD reactions. When 13 and 14
were used in large excess (50 equiv), a complete conversion of
T4 into T0 was observed, an indication that 3’-T1 also
undergoes deiodination to give T0. The diiodo derivative 3,3’-
T2 serves as a common intermediate for both 3-T1 and 3’-T1.
Figure 4. Path A: ORD of 18 involving a nucleophilic attack of the
tellurium reagent at iodine atom in the keto form 21. Path B: Conver-
sion of T4 into rT3 by 13 involving a cooperative halogen and
chalcogen bonding. A similar mechanism is applicable for ORD.
supported by another study involving a selective conversion
of 18 into 19 by a sterically protected selenol.[5b] However, the
sequential removal of all the iodine atoms in T4 by 13 and 14
suggests that the deiodination of T4 may proceed by
a cooperative halogen and chalcogen bonding mechanism as
proposed earlier for 1–3 (Figure 4, Path B).[6c,d]
Recent evidence suggests that another mammalian deio-
dinase enzyme, iodotyrosine deiodinase (IYD), plays an
important role in thyroid gland.[9] This enzyme is responsible
for recovering iodide for subsequent reuse in T4 biosynthesis
and its mutation can lead to iodide deficiency and ultimately
hypothyroidism.[9b] IYD catalyzes the reductive deiodination
of 3,5-diiodo-l-tyrosine (DIT; Figure 5), which is produced as
À
These observations reveal that the reactivity of C I bonds in
T4 is remarkably altered upon deiodination.
The facile deiodination of T4 and its derivatives by 13 and
14 prompted us to check whether compounds having one
tellurol moiety without any additional thiol group can
mediate such deiodination. We treated T4 with the tellur-
ocysteine derivative 16 (obtained from the corresponding
ditelluride 15 by reduction with NaBH4; Figure 2) in 1:1 molar
ratio and monitored the reaction by HPLC. Interestingly, 16
was able to deiodinate T4, T3, and 3,5-T2, although the rate of
the reaction was much lower than that of 13 and 14
(Figure 2C). Almost no deiodination was observed when
either rT3 or 3,3’-T2 was used as a substrate. However, the
initial rate for the deiodination of T4 and T3 by 16 was found
to be significantly higher than that of 3 under identical
reaction conditions. Similarly, tellurophenol (PhTeH; 17;
obtained in situ by treatment of diphenyl ditelluride with
NaBH4) was able to deiodinate T4 and T3 and the activity was
lower than that of the other compounds (Figure 2C). In
contrast, no deiodination was observed when either T4 or T3
was treated with selenocysteine or selenophenol (PhSeH)
under similar experimental conditions.
A previous study on the deiodination of a T4 derivative,
the N-butyrylthyroxine methyl ester 18, revealed that tellu-
rium reagents such as NaHTe can remove iodine from the
outer-ring (Figure 4, Path A).[8] When 18 was treated with
4 equivalents of NaHTe in ethanol at 508C for 4 hours, the T3
derivative 19 (R = Me, R’ = COnPr) and 3,5-T2 derivative 20
(R = Me, R’ = COnPr) were obtained in 45 and 5% yield,
respectively, along with unreacted starting material (50%).[8]
The reason for the formation of 19 and 20 has been ascribed to
higher reactivity of the two outer-ring iodines as compared to
the inner-ring ones. It has been postulated that one of the
possible mechanistic pathways may involve an enol–keto
tautomerism of 18 into 21, and allows the tellurium nucleo-
phile to selectively attack at the outer-ring iodines to produce
19 and 20 (Figure 4, Path A).[8] This assumption was further
Figure 5. A) Deiodination of 3,5-diiodo-l-tyrosine (DIT) to 3-iodo-l-
tyrosine (MIT) by iodotyrosine deiodinase (IYD) using NADPH as
cofactor. The enzyme also catalyzes the deiodination of MIT to l-
tyrosine. B) Active site of IYD indicating the binding of MIT near the
flavin (FMN; PDB ID 3GFD).
a byproduct of T4 biosynthesis. In contrast to the iodothyr-
onine deiodinases, IYD does not use selenocysteine for the
deiodination. This enzyme belongs to the group of flavopro-
teins of the NADH oxidase/flavin reductase family. The
NADPH/FMNH2-dependent deiodination of DIT produces
3-iodo-l-tyrosine (MIT), which can be further deiodinated by
the same enzyme to produce l-tyrosine.[10] To understand
whether the selenium and tellurium compounds that deiodi-
nate T4 and its derivatives can mimic the function of IYD, we
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treated 1–3, PhSeH, 16, and 17 with DITand MIT in 1:1 molar
ratio. However, no deiodination of DIT and MIT by these
compounds was observed. Particularly, 3, 16, and 17, which
were able to remove an iodine from 3,5-T2 (Figure 2C), could
not mediate the deiodination of DIT, thus indicating that the
0.03) mm minÀ1 and (0.37 Æ 0.03) mm minÀ1, for 13 and 14,
respectively]. Similarly, the inability of 13 and 14 to remove
iodine from 3-MIT is due to much weaker Te···I interactions
of 3-MIT with tellurium reagent as compared to that of 3-T1.
In summary, we showed that the introduction of tellurium
atoms in place of either sulfur or selenium in deiodinase
mimetics alters not only the reactivity but also the regiose-
lectivity of the deiodination. We also showed for the first time
that compounds having two tellurol moieties or a thiol-
tellurol pair can mediate sequential deiodination of T4 to
produce all the possible thyroid hormone derivatives under
physiologically relevant conditions. This study provides the
first experimental evidence that the regioselectivity of thyroid
hormone deiodination is controlled by the nucleophilicity and
the strength of halogen bond between the iodine and
chalcogen atoms.
À
reactivity of the C I bond in DIT is significantly different
from that of 3,5-T2 because of the presence of phenolic group.
Interestingly, when DIT was treated either 13 or 14 in 1:1
molar ratio, a significant monodeiodination of DIT was
observed. The initial rate for the deiodination of DIT by 14
[(0.37 Æ 0.03) mm minÀ1] was found to be higher than that
observed for 13 [(0.24 Æ 0.03) mm minÀ1]. This difference is in
contrast to the deiodination of T4, in which 13 was found to be
more active than 14 (Figure 2C). While N-butyryl-3,5-diio-
dotyrosine methyl ester has been shown to be monodeiodi-
nated by NaHTe in ethanol at higher temperatures,[8] 13 and
14 represent the first examples of compounds that mediate
the monodeiodination of DIT under physiological conditions.
The mechanism of deiodination of DIT by 13 and 14 appears
to be similar to that of T4 and its derivatives. However, 13 and
14 do not mediate the deiodination of MIT under identical
reaction conditions, although these compounds are able to
remove iodine from 3-T1 (Figure 3).
Keywords: enzymes · halogens · hormones · iodine · tellurium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 7674–7678
Angew. Chem. 2015, 127, 7784–7788
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Compound
ESe···I [kcalmolÀ1
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ETe···I [kcalmolÀ1
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3,5-T2
3-T1
3,5-DIT
3-MIT
3.50
2.62
2.60
2.15
4.31
3.39
3.37
2.78
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much higher than that observed for 3,5-DIT [(0.24 Æ
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Received: March 25, 2015
Published online: May 12, 2015
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