The Thyroid

BCH 120 — Metabolic & Endocrine Biochemistry · Dr. Radi

build Jul 17 · 11:10 · CC BY-NC-SA 4.0 · owned figures (RDKit / matplotlib / PyMOL)
Dr. Radi

By the end of this unit, you can…

  • Describe the thyroid gland/follicle and the systemic actions of thyroid hormone, and draw the structures of T4 and T3
  • Explain thyroid hormone synthesis on thyroglobulin — iodide trapping, TPO-catalyzed iodination (MIT/DIT) and coupling to T3/T4 — plus storage, secretion, and the inhibitors of synthesis
  • Explain plasma transport (bound reservoir vs active free fraction; T4 vs T3) and peripheral deiodination (selenium deiodinases; T4 → active T3 vs inactive reverse-T3)
  • Trace the hypothalamic–pituitary–thyroid axis and its feedback, and how T3 regulates transcription by flipping the thyroid receptor from repressor to activator
  • Describe the biological actions of T3 and the major thyroid disorders (hyperthyroidism/Graves', hypothyroidism/Hashimoto's, CIDS), their symptoms, and treatment
Dr. Radi

Today's route 🗺️

  1. The Thyroid Gland & Its Hormones
  2. Making Thyroid Hormone — Iodination & Coupling
  3. Transport & Deiodination
  4. The HPT Axis & T₃'s Gene Switch
  5. T₃ Actions & Thyroid Disorders
Dr. Radi

1 · The Thyroid Gland & Its Hormones

"The thyroid is the body's metabolic thermostat — a butterfly-shaped gland that touches nearly every cell. It makes two iodine-studded hormones, T4 and T3, and you need to know both their jobs and their structures."

Dr. Radi

A gland built from follicles

The thyroid sits over your trachea — two lobes joined by an isthmus, about 20 grams. Its working unit is the follicle: a single ring of epithelial cells wrapped around a lake of colloid. The epithelial cells are the factory (they trap iodine and build hormone); the colloid is the warehouse (stored hormone, weeks' worth). Scattered between the follicles are C cells, which make calcitonin — a calcium hormone we'll meet in its own unit.

Dr. Radi

The body's metabolic thermostat

Why does the thyroid matter so much? Because its hormone acts on nearly every cell. It sets your basal metabolic rate and heat production, tunes carbohydrate, fat, and protein metabolism, drives long-bone growth and neural maturation (critical in infancy), and sharpens your response to catecholamines like adrenaline. When it's off — too high or too low — the whole body feels it. That's why thyroid disease is so common and so consequential.

Dr. Radi

T4 and T3 — know these structures

Here are the two hormones, and you need to be able to draw them. Both are built from two tyrosine-derived rings joined by an ether, studded with iodine. T4 (thyroxine) carries four iodines — positions 3, 5, 3′, 5′ — and is the main form released, a long-lived pro-hormone. T3 carries three iodines (3, 5, 3′) and is the active hormone. The count is the whole story: four = storage, three = go.

Dr. Radi

2 · Making Thyroid Hormone — Iodination & Coupling

"Thyroid hormone is unique — it's built on a giant scaffold protein, thyroglobulin, one iodine at a time. Learn the four steps and one enzyme (thyroid peroxidase), and you'll understand both the biochemistry and every drug that treats an overactive thyroid."

Dr. Radi

Built on thyroglobulin, step by step

Thyroid hormone synthesis is a four-step assembly line, and it all happens on a scaffold protein, thyroglobulin. ① Trap — a pump (NIS) concentrates iodide ~30× from the blood. ② Iodinate — thyroid peroxidase (TPO), using H₂O₂, tacks iodine onto tyrosines in thyroglobulin (making MIT and DIT). ③ Couple — TPO joins those iodotyrosines into T3 and T4. ④ Store & secrete — the hormone waits in the colloid until the cell takes it back in and cuts it loose. One enzyme, TPO, runs the two chemistry steps.

Dr. Radi

The coupling arithmetic

Here's the part students love, because it's just addition. Iodinated tyrosines come in two sizes: MIT (one iodine) and DIT (two iodines). Couple a MIT + DIT and you get T3 — three iodines, the active hormone. Couple DIT + DIT and you get T4 — four iodines, the pro-hormone. That's it: the number of iodines on each partner adds up to the hormone. TPO does the joining.

Dr. Radi

Two places to block it

Because synthesis is a defined pathway, we can stop it at two points — which is exactly how we treat an overactive thyroid. Block iodide uptake: perchlorate and thiocyanate compete with iodide at the NIS pump. Block TPO: the thioureas — propylthiouracil (PTU) and methimazole — shut down iodination and coupling directly. Know the two targets and you know the drug classes: no iodine in, or no enzyme to use it.

Dr. Radi

3 · Transport & Deiodination

"Once thyroid hormone hits the blood, two things happen that shape its whole biology: almost all of it rides bound to carrier proteins (only the free bit works), and the tissues get the final say — activating T4 into T3, or shutting it down into reverse-T3."

Dr. Radi

A big bound reservoir, a tiny active pool

In the blood, over 99% of thyroid hormone rides bound to carrier proteins (thyroxine-binding globulin and friends) — and while it's bound, it's inactive. Only the small free fraction can enter cells and act. That's why the lab measures free T4/T3, not total. And the two hormones play different roles: T4 is the large, slow reservoir (half-life ~7 days); T3 is the small, fast, active pool (half-life ~1 day). Bulk storage versus the working currency.

Dr. Radi

Tissues activate — or silence — T4

Here's the elegant control: T4 is a pro-hormone, and each tissue decides what to do with it using deiodinases (which are selenium enzymes — so you need dietary selenium). Chop an iodine off the outer ring (D1/D2) → T3, the active hormone. Chop one off the inner ring (D1/D3) → reverse T3 (rT3), which is inactive. So the same T4 can be turned up or down locally. In starvation and serious illness, the body shunts toward rT3 — dialing metabolism down to conserve fuel.

Dr. Radi

4 · The HPT Axis & T₃'s Gene Switch

"Thyroid output is governed by the classic three-tier feedback loop — hypothalamus, pituitary, thyroid. And down at the molecule, T₃ does something clever: it doesn't just turn a gene on, it releases a brake that was actively holding it off."

Dr. Radi

The HPT axis and its feedback

Thyroid hormone runs on a three-tier axis. The hypothalamus sends TRH, which tells the anterior pituitary to release TSH, which drives the thyroid to make T3 and T4. Then comes the control knob: circulating T3/T4 feed back negatively on both the pituitary and hypothalamus, throttling TSH so levels stay steady. A neat detail — the pituitary makes its own T3 (via deiodinase) so it can sense the T4 in your blood. Somatostatin and dopamine nudge TSH down too.

Dr. Radi

How T₃ flips a gene ON

Now the molecular trick, and it's not what you'd guess. The thyroid receptor (TR) is already sitting on the DNA at a thyroid response element — but with a co-repressor bound, it's actively holding the gene OFF. When T3 arrives and binds the receptor, it triggers a shape change that kicks the co-repressor off and pulls in co-activators and RNA polymerase, switching the gene ON. So T3 doesn't push the gas — it releases the brake. Elegant, and worth remembering.

Dr. Radi

5 · T₃ Actions & Thyroid Disorders

"Put it together: what T₃ actually does in your tissues, and what happens when the thyroid runs too hot or too cold. Two of the most common autoimmune diseases in medicine live here — Graves' and Hashimoto's — and they're mirror images."

Dr. Radi

What T₃ does in the tissues

Once T3 is inside and switching genes, the effects are body-wide. It raises oxygen consumption and BMR (the metabolic engine). It boosts protein synthesis — but also catabolism, so in excess it pushes you into negative nitrogen balance. It's essential for nervous-system growth and development and cranks up neurotransmitter sensitivity. And it integrates with insulin, glucagon, and catecholamines to touch all of intermediary metabolism. One hormone, wired into everything.

Dr. Radi

Too hot, too cold — and the antibodies

When the thyroid misfires, it's often autoimmune, and the two big diseases are mirror images. Hyperthyroidism — usually Graves' — is antibodies (TSI) that mimic TSH and won't stop: goiter, bulging eyes (exophthalmos), weight loss, heat intolerance, racing heart. (A hot nodule or adenoma can also do it.) Hypothyroidism — often Hashimoto's — is antibodies that destroy the gland (iodine deficiency does it too → CIDS in infants): weight gain, cold intolerance, slow heart, lethargy, myxedema. One antibody flips it on, the other tears it out — and TSH is the first test that tells them apart.

Dr. Radi

Fixing it: block, ablate, or replace

Treatment follows straight from the biochemistry. For a thyroid that's too active, you block synthesis (PTU, methimazole — the TPO inhibitors), or you ablate the gland with radioactive iodine or surgery. For a thyroid that's too quiet, you simply replace the hormone: oral thyroxine (T4), taken for life, which the body deiodinates to T3 as needed. And because untreated infant hypothyroidism is devastating, every newborn is screened — catching CIDS before it can do harm.

Dr. Radi

Can you…?

  • ☐ describe the thyroid gland/follicle and the systemic actions of thyroid hormone, and draw the structures of T4 and T3?
  • ☐ explain thyroid hormone synthesis on thyroglobulin — iodide trapping, TPO-catalyzed iodination (MIT/DIT) and coupling to T3/T4 — plus storage, secretion, and the inhibitors of synthesis?
  • ☐ explain plasma transport (bound reservoir vs active free fraction; T4 vs T3) and peripheral deiodination (selenium deiodinases; T4 → active T3 vs inactive reverse-T3)?
  • ☐ trace the hypothalamic–pituitary–thyroid axis and its feedback, and how T3 regulates transcription by flipping the thyroid receptor from repressor to activator?
  • ☐ describe the biological actions of T3 and the major thyroid disorders (hyperthyroidism/Graves', hypothyroidism/Hashimoto's, CIDS), their symptoms, and treatment?

If any box stays empty, the practice site has a drill for it. 🧪

Dr. Radi