Communications
ID-1 plays an important role in enhancing catalytic efficiency
that ID-1, which deiodinates T4 in the outer-ring to produce
T3, can also remove iodine from the inner-ring of T4
(Scheme 1). It is not clear whether this enzyme uses two
different mechanisms for the deiodination reactions.
Although the imidazolium–selenolate ion pair in ID-1 may
be sufficient for the conversion of T4 into T3, the conserved
Cys residue appears to be important for the inner-ring
deiodination.
for both outer- and inner-ring deiodination.[9] In contrast,
Croteau et al. reported that the conserved Cys residues in ID-
1 are not essential for catalytic activity.[10] However, the
deiodinase activity of compound 4 suggests that the Cys
residue may play a crucial role in the inner-ring deiodination
catalyzed by ID-3.
In addition to the conserved Cys residue, the presence of
histidine (His) residues has been shown to be important for
the deiodinase activity of ID-1. Kꢀhrle and others have shown
that one of the His residues at the active site of ID-1 activates
the selenol by forming an imidazolium–selenolate ion pair.[11]
Goto et al. also reported that the 5’-deiodination of 2 by the
selenol 1 takes place only in the presence of triethylamine.[6]
However, it is not known whether the His residue present at
the active site of ID-3 plays any key role in the enzymatic
reaction. To understand the importance of an amino group,
we carried out the deiodination experiments in the presence
of compound 7, which contains a secondary amino group
adjacent to the selenol moiety. The 77Se NMR spectrum of
compound 7 shows that the signal for this compound is
significantly shifted upfield (d = 109 ppm) relative to that of
compound 4 (d = 162 ppm), indicating that the amino group
abstracts the proton from the selenol moiety to generate a
more nucleophilic selenolate. Unexpectedly, compound 7 was
found to be much less active than 4 in the deiodination of T4
and T3 (Figure 2). Similarly, addition of triethylamine to the
reaction mixture did not enhance the deiodinase activity of 4.
Furthermore, no deiodination was observed when compound
8, which has a tert-amino group capable of deprotonating the
selenol moiety, was employed. It should be noted that
compound 8 has been shown to be an efficient mimic of
glutathione peroxidase (GPx), a Sec-containing enzyme that
acts as an antioxidant.[12] A large upfield shift in the 77Se NMR
signal for compound 8 (3 ppm) suggests that the selenol
moiety in 8 is more nucleophilic than that in compounds 4 and
7. These observations indicate that the presence of an
additional thiol group in proximity to the selenium atom is
more important for the inner-ring deiodination than basic
amino groups.
Interestingly, the deiodination of T4 by compounds 4, 5,
and 7 occurred even in the absence of DTT. When T4 was
treated with an excess amount of compound 4 (5 equiv),
complete conversion of T4 into rT3 was observed. The
deiodination of T4 was also observed in the presence of
compounds 5 and 6, although the activity of these compounds
was found to be much lower than that of 4. During the
deiodination, compounds 4, 5, and 7 were oxidized to 12, 13,
and 14, respectively. As the formation of 12–14 was observed
even under nitrogen atmosphere, the thiol group may act as
an in-built cofactor for the deiodination reaction. It should be
noted that compounds 12–14 are remarkably stable in
aqueous solutions. These compounds can be recovered
quantitatively from the reaction mixture, converted into
compounds 4, 5, and 7, respectively, and then employed for
further deiodination reactions without any noticeable decom-
position.[13] Sun et al. previously suggested that one of the Cys
residues in the active site of ID-1 may interact with the
À
À À
selenium atom to produce a selenenyl sulfide ( Se S )
species.[9] The formation of such a bond has been described
for the selenium-dependent thioredoxin reductase.[14]
The mechanism of deiodination of T4 by compound 4 may
involve the formation of a halogen bond between selenol
group and iodine atom.[15] It should be noted that halogen
bonds play an important role in the recognition of thyroid
hormones. It has been shown that T4 forms short I···O
contacts with its transport protein transthyretin and T4 can
bind to RNA sequences through halogen bonds.[16] The
flavoprotein iodotyrosine deiodinase (IYD),[17] which sal-
vages iodide from mono- and diiodotyrosine formed during
the biosynthesis of T4, may utilize halogen bonds for
deiodination reactions. As S···I interactions are generally
weaker than Se···I interactions,[15] the deiodinase activity of 5
is lower than that of compound 4. Furthermore, the decrease
in the positive charge on the second iodine atom upon
removal of the first may weaken the halogen bond. This
decreased charge may account for the inability of compound 4
to remove iodine from rT3 to produce T2.[7]
Vasil’ev and Engman have shown that the reaction of
PhSeH with the activated diiodophenol 9 affords the deiodi-
nation/substitution product 10, indicating that the substitu-
ents in the phenolic ring modulate the reactivity of the
selenium reagents.[5b] In contrast, Goto et al. reported that
compound 11, which cannot generate the corresponding keto
form, does not undergo any deiodination by selenol 1.[6]
Therefore, the mechanism for the inner-ring deiodination
mediated by compound 4 appears to be different from the one
proposed for the outer-ring deiodination. It should be noted
In conclusion, the first chemical model for the inner-ring
deiodination of thyroxine (T4) and 3,5,3’-triiodothyronine
(T3) by iodothyronine deiodinase ID-3 is demonstrated. This
study suggests that the nature of substituents around the
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9246 –9249
Manna, Debasish
