Download Biochemistry Objectives 46

Biochemistry Objectives 46
1.
Iodine incorporation and significance of:
a.
T4: four iodine molecules, two incorporated into each ring; important in
boosting metabolism
b.
T3: synthesized via 5’-deiodinase cleavage of 5’ iodine; ten times more
potent than T4 in boosting metabolism
c.
Reverse T3: synthesized via -deiodinase cleavage of 5 iodine; an inactive
metabolite that functions to lower the pool of free thyroid hormone during
starvation
2.
Synthesis of T4: begins with iodine transport into the cell via the Na+/I- symport
(thyroid iodine pump). The iodine is then pumped out of the cell and oxidized via
peroxidase. The oxidized I+ is then incorporated into tyrosine residues attached
to a thyroglobulin molecule to form either MIT (monoiodotyrosine; one I+
incorporation) or DIT (diiodotyrosine; two I+ incorporation). Extracellular
coupling of two DIT molecules forms a T4 molecule, whereas coupling of a MIT
and DIT forms a T3 molecule. Increased PKA from TSH binding and Gs
signaling stimulates endocytosis of the thyroglobulin/DIT/MIT/T4/T3 aggregate
into a lysosome; subsequent lysosomal hydrolysis of the aggregate releases T4 and
T3 molecules for release (via simple diffusion) into the bloodstream.
3.
TRH-TSH-T4 axis:
a.
Second messengers in target cells:
a. TRH: Thyroid releasing hormone stimulates thyrotrophic release of
TSH via Gq and the IP3/DAG/Ca2+ pathway.
b. TSH: thyroid stimulating hormone
b.
T4 activation to T3 in peripheral target cells: T4 is brought into the cell by
passive diffusion when bound to TBG, and is converted to the more
metabolically active T3 form by 5’ deiodinase.
4.
T3 binding and protein activation: the T3 protein binds to a chromosomal T3
receptor that dimerizes with the RXR receptor to alter gene transcription; it is first
anabolic and causes increased RNA and protein synthesis. The initial period is
followed by a highly catabolic rate to increase metabolism.
a.
Mitochondrial uncoupling protein (UCP): gene transcription leads to an
elevation of UCP, causing an increase in body heat production
b.
Oxidative enzymes: increases shuttling of oxidative enzymes into the
mitochondria to increase basal metabolic rate
c.
Na+/K+ ATPase: increases Na+/K+ ATPase to increase “tertiary” active
transport processes
d.
GH: growth hormone is upregulated to increase metabolism
e.
-adrenergic receptor: 1 upregulation can account for thyroid hormone
increase in heart rate.
5.
Hypothyroidism: hypothyroidism is most often caused by a defect in the
hypothalamus/pituitary/thyroid axis and a resultant decrease in thyroid hormone
secretion. Hypothyroidism presents clinically as a decrease in metabolic rate,
obesity, slow heart rate, goiter, and myxedema (an inelastic edema with dry waxy
skin and facial swelling)
 Note: neonatal hypothyroidism (a failure of the thyroid to descend) is a
major cause of cretinism (severe mental retardation with jaundice,
cyanosis, respiratory failure, and poor feeding)
Hyperthyroidism: an increase in thyroid hormone production caused by
numerous factors including Graves’ disease, excessive iodine intake, and thyroidstimulating immunoglobulin (which is NOT feedback inhibited). Patients often
present with goiter, ophthalmic disorders caused by infiltrative disease of the
orbital muscles, or with thyrotoxic periodic paralysis (flaccid paralysis caused by
excessive renal Na+/K+ ATPase synthesis and a subsequent depletion of plasma
potassium.
6.
Goiter: an enlargement of the thyroid gland
a.
Nutritional deficiency: nutritional goiter is caused by a dietary iodine
deficiency causing an increase in TSH and thyroid hyperplasia in an
attempt to produce more T4. Since there is a lack of iodine, the thyroide
cannot produce T4, and a goiter ensues.
b.
Enzyme defects: cause of hypothyroid goiter; results from a problem with
the thyroid iodine pump, peroxidase, or deiodinase enzymes.
c.
Humoral/immune causes: cause of hyperthyroid goiter; thyroid
stimulating immunoglobulin (TSI) binds to the thyroid and is a long acting
stimulator of the thyroid and thus, increases thyroid production of T4.