section
33.2
Thyroid Hormone Synthesis
771
N A D P (NAD )
T h y r o p e r o x id a s e
T h y r o p e r o x id a s e
N a+ /I
S y m p o r te r (In h ib ite d b y C IO ., BF. , S C N ')
E X T R A F O L L IC U L A R
T H Y R O C Y T E
F O L L IC U L A R LU M EN
S P A C E
(B a s o la te r a l)
A p ic al
S u r f a c e
N A D P H (N A D H )+ H
H ,Q , g e n e ra tin g s y s te
lo d o ty ro sin e
N a + . K + - A T P a s e
d e io d in a s e
M IT, DIT
T S H -
llodinatiory
DT
r e c e p to r
KO + % O r^
I— MT
S e c o n d a r y
ly s o so m e
DT
d ig e stio n
M ostly T .,
I C oupling]
I— DIT
sm all a m o u n t
T3—I
Jg
l_
MIT
o f T, a n d
H ,0 +
'kO,
T —
T
o th e r p ro d u c ts
P rim ary
ly s o so m e
Endocytosis
F I G U R E 3 3 - 3
Synthesis of thyroid hormone in the thyrocyte. Tg, Thyroglobulin.
the enzyme probably forms an enzyme-bound
iodinium ion (E-I+) or a free radical of iodine. These
activated derivatives iodinate the tyrosyl residues of
Tg (“organification of iodide”) by the action of
thyroperoxidase and H
2
O
2
. Thionamides (e.g.,
thiourea, thiouracil, propylthiouracil, methimazole)
inhibit this organification of iodide without affecting
iodide uptake. The first position iodinated is
position 3, which forms monoiodotyrosyl-Tg
(MIT-Tg). The second is position 5, which forms
diiodotyrosyl residues (DIT-Tg). Iodination is
accompanied by structural changes (e.g., cystine
formation) and includes a conformational change in
the Tg molecule (illustrated diagrammatically in
Figure 33-3). Activation and organification occur at
the cell-colloid interface where thyroperoxidase
activity is prevalent.
3.
Coupling Reaction and Storage as Colloid.
Iodide
peroxidase or a “coupling enzyme” catalyzes the
“coupling reaction” at the cell-colloid interface by
intramolecular coupling of two iodotyrosyl residues
with formation of an iodothyronyl residue. Coupling
of DIT residues is favored; thus, formation of T
4
residues predominates. The coupling reaction requires
that both substrates be iodinated and that one of the
substrates be DIT-Tg. For this reason, no To, Tj, or T
2
residues are formed. Under normal conditions
less than half of the iodotyrosyl residues in Tg
undergo coupling such that of the total iodinated resi-
dues in Tg, 49% are MIT, 33% DIT, 16% T4, 1% T3,
and a trace amount rT3. The ratio of T
4
to T
3
is >10
on a typical American diet, but it rises or falls with
dietary iodine content. The coupling reaction appears
to be the most sensitive to inhibition by the
thionamides (propylthiouracil, methimazole), being
inhibited at doses that do not inhibit the organification
reactions. As a final note, although proteins other than
Tg are iodinated in nonthyroid tissues that take up
iodine (e.g., salivary gland, mammary gland,
intestinal mucosa), no coupling of the iodinated
residues occurs. Thus, the requirements for the
coupling reaction may be more stringent than
previously believed.
4.
Processing o f TG and Release o f Thyroid Hormone.
Thyroglobulin, with its tetraiodothyronyl residues, is
a pre-prohormone stored in the follicular lumen.
