The Thyroid hormones:
3,5,3’,5’-tetraiodothyronine (thyroxine T4)
small amounts of 3,5,3 ́-triiodothyronine (T3)
traces of 3,3 ́,5 ́-T3 (reverse T3).
The Thyroid hormones:
3,5,3’,5’-tetraiodothyronine (thyroxine T4)
small amounts of 3,5,3 ́-triiodothyronine (T3)
traces of 3,3 ́,5 ́-T3 (reverse T3).
- T4 is converted to T3 and rT3 in peripheral tissues
- T3 is the major hormone bound to the thyroid hormone (TH) receptors.
- control of metabolic processes and heat production, and normal growth and development.
- T4 is converted to T3 and rT3 in peripheral tissues
- T3 is the major hormone bound to the thyroid hormone (TH) receptors.
- control of metabolic processes and heat production, and normal growth and development.
What are the cell surface transporters that transport T3 and T4 into cells? Which one often has mutations?
• TH transporters
o monocarboxylate transporter (MCT) protein family
o organic anionic transport protein family (OATPs).
• mutation in the MCT8 gene have impairments in both neurological development and thyroid function.
• Target cells contain nuclear TH receptors (TRs), which have an affinity for T3 that is five to ten times that for T4.
Compare Ligand-TR vs unbound TR activity.
• Ligand-TRs bind to TH-response elements (TREs) results in enhancement or suppression of transcription.
• In the absence of ligand, TRs can have the opposite effect to that which it exerts in the presence of ligand.
o For example if the liganded TR stimulates the transcription of specific gene, transcription may be suppressed in the absence of ligand.
o The effects of the unliganded receptors are thought to be acritical in TH-dependent brain development.
What are the steps of TH biosynthesis?
- plasma iodide by the sodium-iodide symporter (NIS).
- Peroxidation of thyroidal I- to form an iodinating agent (I2 or I+).
- Iodination of tyrosine residues contained in the thyroidal protein (thyroglobulin) to yield monoiodotyrosine and diiodotyrosine (MIT and DIT).
- Coupling of two DIT or one DIT and one MIT molecules to form T4 or T3, respectively
- Enzymic hydrolysis of thyroglobulin release T4 and T3, MIT and, DIT.
- Some T3 may be also formed by the intrathyroidal deiodination of T4 to yield T3.
- The T4 and T3 are released into the serum when the appropriate signal is given.
What happens when MIT and DIT are released from thyroglobin in the thyroid?
• The MIT and DIT released from the thyroglobulin are rapidly deiodinated within the thyroid by a specific iodotyrosine deiodinase and are NOT released into the circulation.
What is autoregulation of the thyroid?
- Increased Iodine offers negative feedback in iodine uptake, organification, and release of T4 and T3
- This is autoregulation because it is independent of TSH
What is organification?
- the incorporation of iodine into thyroglobulin for the production of thyroid hormone, a step done after the oxidation of iodide by peroxide.
- The term refers to Iodine as an inorganic compound becoming attached to an organic compound thyroglobulin.
How long does autoregulation last?
- 48-72 hours.
* If the iodine level is maintained, TH synthesis and release resume.
What is Extrathyroidal Regulation?
• TSH binds to receptors in the membrane of the thyroid cell, and most of its effects are mediated by cAMP • effects include o hormone biosynthesis o thyroidal intermediary metabolism o phospholipid and RNA synthesis o growth and vascularity of the gland.
What is the effect of autoantibodies on TSH?
• autoantibodies can bind to the TSH receptor and mimic OR block the effects of TSH.
Describe the differences between T3 and T4 negative feedback.
- T3 inhibits the pituitary the transcription TSH-α and the TSH-β subunits.
- T4 inhibits the hypothalamus and pituitary is dependent on its intrapituitary conversion to T3.
What percent of T4 and T3 is bound to plasma proteins?
- Greater than 99.95% of T4
* 99.5% of T3
T4 is normally bound to what three proteins?
- 60% thyroxine-binding globulin (TBG), which in contrast to the TRs has a higher affinity for T4 than for T3
- 30% thyroxine-binding prealbumin (TBPA)
- 10% albumin
What proteins is T3 bound to?
• TBG
albumin
How long are T4 and T3 usually bound to their plasma proteins?
- T4: 9 days; T3: 1 day
- Reversible
- the extent of the binding governs the residence time of each hormone in plasma
- Only free (unbound) T4 or T3 is available to the target cells.
How much role do TH binding proteins have in levels of free T4 and T3 in the plasma?
- None that we know of. They are carrier proteins only.
* change in the plasma free T4 concentration is governed by the pituitary-thyroid feedback mechanism.
Are T4 and T3 bound to other proteins in plasma and cells? Do these binding sites play any role in hormone action?
- T4 and T3 are also bound to non-receptor proteins in extracellular fluids, the plasma membrane, cytosol, and nucleus
- are not thought to serve any direct role in hormone action.
- low affinity and high capacity for T4 and T3
- higher affinity for T4 than for T3
T4 and T3 are present in every tissue of the body. Most of the TH secreted by thyroid is T4. T4 is often converted to T3 in cells.
T4 and T3 are present in every tissue of the body. Most of the TH secreted by thyroid is T4. T4 is often converted to T3 in cells.
What are Deiodinase?
• T4 and other iodothyronines are metabolized by three types of deiodinase: D1, D2, and D3
Where is D1 found? What is its function?
- liver, kidney and thyroid
- responsible T4 ==> T3 circulating in plasma to maintain plasma T3 levels
- also has substrate preference for the sulfate conjugates of the iodothyronines due to its additional inner deiodinase activity (explained below)
Where is D2 found? What is its function?
- pituitary, CNS, and brown fat
* responsible for the local generation of T3 from T4 in these local tissues.
Where is D3 found? What is its function?
- placenta and pregnant uterus (high levels)
- Brain and other tissues (low levels)
- converts T4 and T3 to their inactive derivatives, rT3 and 3,3’-T2, respectively.
- Protects brain from excess TH
Compare D1, D2, and D3 in terms of outer vs inner ring deiodinating enzymes?
- D1 and D2 are both outer-ring or 5’-deiodinating enzymes
- D3 is an inner-ring or 5-monodeiodinating enzyme
- D1 also has inner ring deiodinase activity
