stimulating hormone, TSH). The latter is a pituitary glycoprotein whose αsubunit is
identical with that of lutropin (LH) and whose specific βmoiety is composed of 112
amino acids carrying a single carbohydrate side chain. The majority of the thyroid
gland contains follicular cells that produce thyroid hormones (iodothyronines). The
thyroid also contains parafollicular cells (sometimes called “C cells”) which biosyn-
thesize another hormone,calcitonin. Four parathyroid glands exist in two pairs, one pair
embedded on the back surface of each of the two thyroid gland lobes. The parathyroid
glands produce parathyroid hormone (PTH).
5.19.1 IodothyroninesL-Thyroxine (5.106, tetraiodothyronine, T 4 ) is 3,5,3',5'-tetraiodo-p-hydroxyphen-
oxy-phenylalanine. The 3,5,3'-triiodo analog (5.107,T 3 ) is also a naturally occurring and
active hormone. In most of its physiological effects, T 3 is more active than T 4. Both hor-
mones are amino acid derivatives, discovered more than 60 years ago and synthesized in
the thyroid gland from tyrosine by inclination and transfer of the iodophenol portion of
a second iodotyrosine molecule. The synthesis takes place in the follicles (acini) of the
thyroid gland, a large endocrine organ weighing about 20 g in adults. The lumen of the
follicle is filled with a colloidal, viscous solution of thyroglobulin.This protein binds T 3
and T 4 with high affinity and is also efficient in binding circulating iodide, which enters
the thyroid gland by active transport coupled to an ATPase. Iodide uptake by the gland
is enhanced by thyrotropin (TSH) and inhibited by large anions such as ClO 4 −. The
iodide is then oxidized and attached to tyrosine by peroxidase and a flavoprotein
monooxygenase in a process that involves NADPH. Thyroglobulin (MW, 650,000; 19 S)
binds the thyronines very strongly, and the hormones can enter the circulation and reach
other cells only after the binding protein is lysed. This proteolysis is stimulated by TSH.
The iodothyronines are very insoluble molecules and are kept in solution by trans-
port proteins.The most important of these is thyroxine binding globulin(TBG), which
carries about 65% T 4 and 70% T 3. It is a small (MW 60,000–65,000) glycoprotein
consisting of four subunits. It has a single, high-affinity binding site for T 4 , with an
estimatedKDof 1.2 × 10 −^10 M.
Thyroxine binding prealbumin(TBPA) carries about 30% T 4 but no T 3. Its affinity is
only of the order of 10−^8 M, but it is much more abundant in serum than is TBG. The
amino acid sequence and the structure of this protein are known. Four identical subunits
(127 amino acids each) form a prolate ellipsoid. Noncovalent interactions between the
subunits form a channel of 1 nm diameter along the long axis, which has a funnel-
shaped opening of 2.5 nm. The T 4 molecule is held in one arm of this channel, binding
360 MEDICINAL CHEMISTRY