770
chapter 33
Endocrine Metabolism IV: Thyroid Gland
D ip h en yleth er
!---------------------------------------------
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I
F IG U R E 33-1
Structure of 3,3',5,5'-tetraiodo-L-thyronine (T
4
). T
4
is a substituted
tyrosine or a diphenylether derivative of alanine. Positions in the outer
phenolic ring have prime designations, in contrast to those in the inner
ring. T
4
is iodinated at positions 3 and 5 in both rings. [Modified and
reproduced with permission from V. Cody, Thyroid hormone interactions:
molecular conformation, protein binding, and hormone action.
Endocr.
Rev.
1, 140 ( 1980). © 1980 by the Endocrine Society.]
5. The molecule must be the
L
form.
D
Isomers have
minimal biological activity; for example, D-T
3
has
about 7% the activity of L-T
3
.
33.2
Thyroid Hormone Synthesis
Two substrates are required in the synthesis of thyroid
hormones. The intrinsic substrate is
thyroglobulin
(Tg),
F IG U R E 3 3 -2
Skewed conformation of T
4
. The molecule shown at the top is viewed in
parallel to the plane of the inner phenolic ring, while that shown at the
bottom is viewed perpendicularly to the plane of the inner ring. The ether
linkage between the two rings is angled at about 120°. [Reproduced, with
permission from V. Cody, Thyroid hormone interactions: molecular
conformation, protein binding, and hormone action.
Endocr. Rev.
1, 140
(1980). © 1980 by the Endocrine Society.]
a homodimeric glycoprotein (M.W. 669,000) synthesized
in the rough endoplasmic reticulum of the thyrocytes and
secreted into the follicular lumen by exocytosis. Tg con-
tains 134 tyrosyl residues, only 25-30 of which undergo
iodination and only four of which become a hormonogenic
segment of the molecule.
The extrinsic substrate is elemental
iodine,
present in
food as inorganic iodide. Iodide is readily absorbed via
the small intestine; it is almost entirely removed from the
general circulation by the thyroid and kidney. Iodide that
is taken up by salivary and gastric glands is secreted in
salivary and gastric fluids and is returned to the plasma
iodide pool by intestinal reabsorption. A small amount of
iodide is taken up by the lactating mammary gland and
appears in milk. The synthesis and release of thyroid hor-
mone involves a number of steps (Figure 33-3).
1.
Uptake o f Iodide.
Iodide (I- ) is actively taken up by
the follicular cells against electrical and concentration
gradients. The active uptake of I- is mediated by the
Na+/I- symporter, an intrinsic membrane protein
with approximately 13 transmembrane segments. The
Na+ and I- bound symporter releases both Na+ and
I- on the cytoplasmic side. The empty symporter then
returns to its original conformation exposing binding
sites on the external surface of the cell. The
internalized Na+ is pumped out of the cell by the
ATP-dependent Na+, K+-ATPase (oubain sensitive)
to maintain an appropriate ion gradient. In the normal
gland, the limiting step of thyroid hormone synthesis
is uptake of I- . Both I” and thyroid-stimulating
hormone (TSH) regulate the Na+/I“ symporter
function. TSH promotes I- uptake whereas excess I
decreases I- uptake (discussed later). Anions of
similar charge and ionic volume (e.g., CIO
4
, BF ,
TCO
4
, SCN ) compete with 1“ for transport in the
follicular cell.
2.
Activation and Organification o f Iodide.
Iodide that
enters thyrocytes is “activated” by oxidation that is
catalyzed by thyroperoxidase (TPO). Hydrogen
peroxide is required and is supplied by an
H
2
O
2
-generating system which may be an NADPH
(NADH) oxidase system similar to that of leukocytes
(Chapter 15). Thyroperoxidase is a glycosylated heme
enzyme that is bound to the apical plasma membrane
of the thyrocyte. Thyroperoxidase exists in two
molecular forms (M.W. 105,000 and 110,000) and its
catalytic domain faces the colloid space. In thyroid
autoimmune disorders, one of the major microsomal
antigenic components is thyroperoxidase.
In vitro,
iodide peroxidase catalyzes the reaction
2H++ 21 + H
2
O
2
—>
I
2
+
2
H
2
O. However,
in vivo
