Monday April 9th thyroid

Monday... last week was pituitary, and now we move on to thyroid....

Thyroid hormones, hypothylamic thyroid access.

Tonight some proactice prbomes will be posted to the website. And the first midterm from last quarter will also be listed. Don't assume that this is what you will be tested on from before. There will be different questions. The questions will be totally different and on diffferent topics. But it will show you more or less what the length of the exam is, and what style. Some of the topics wno't be covered in time for our first midterm.

Also, there will be a list of topics you will be responsible for.

first image: hypthalamic-pituitary-thyroid axis....

this is a specific exampe of the heirarcy of control we spoke of on friday. Hypothalaumus makes TRH with stimuclates Ant Pit to make TSH which is released in the systemic blood, and goes into the thyroid glad (front of throat), and triggers growth in the thyroid aand to make thyosine, and tri-iodothyronine (t4 and t3).

All cells in the body respond to the thyroid hormones and we are starting with them rather than with the other pituitary hormones. we are starting with tis particuluar group of hormoneos because it is reasonably straight forward. It illistrates the basic relationships tha tyou will see in the endocrin systems througout the body. The order we will do this in is:
The first thing we will talk about today is the structure of T3and T4, then thri synthesis, then their transport in the blood, and then threir bilological activities, and then their regulation and secretion, and then take a break to talk about hormone mechanism of action, part of that discussion will be directly about the thyroid hormones, but part will be more general. Then we will finish the thyroid hormones by looking at disorders about T3 and T4 secretion.

the first thing to look at is the structure of the molecules. (see page with tyrosine and what it makes in, from eres).

Start with tyrosine. the first step in the biosynthetic pathsway is attaching an iodine to the 3 carbon of the phenol ring. The first carb to accept an Iodine is always called carbon 3. with a 3,5 iodine it is called 3,5 diiodotyrosine (DIT), then with 2 DITs you get T4 (4 means 4 iodines in the structure). If you have a single I, and then attach it to one with 2 I on it (MIT+DIT) you make T3 (3 iodine). Both T4 and T3 are biologically active. Inner ring is the one in the middle, and the outer ring is the one fartherst from the peptide bond. The biologically active molecule with 3 iodines is always an inner ring with 2I, and an outer with 1. If you have a 'reversed' T3, where the inner ring has 1 I, and the outer has 2, is NOT biologically active. T2, and T1 are both NOT biologically active either. (MIT and DIT are NOT biologically active)

Rev T3, is NOT a product made within the thyroid gland, but it is made peripherally.

Now you need to understand how and where it takes place. The thyroid glad consistems mainly of thyroid folicals. A folical is just a sphere of cells. (fig 76-1) The ball is filled with colloid. both the ep cells and the colloid produce thyroid hormones. the colloid contains thyroglobulin (mol wt ~660Kilodaltons) (dimer) It is secreted into the ep cells into the follicle. They thryoglobulin contains about a 100 tyrosine residues. some of which are turned into T3and T4. If you look at fig 7-5 from eres, it shows what has to happen. thyroglobulin is a long chain with tyrosine is part of the chain. they are iodinated (i9o0dine is added) to become DIT molecules. (aka organification) The tyrosine then are in close proximity of each other. the iodinated phenol is hydrolized and is bonede to another DIT. the inner ring is always a DIT, and the outer ring can be either a DIT or an MIT. this is the basic coupling reaction. two things have to happen for the tyrosine to become a T3 or T4. it has to be iodinated, and then coupled. the product is still attached to thyroglobulin molecule. so a peptide bond has to be hydrolized for it to become T3 or T4. (thyroglobulin is the colloid)

fig 76-2 there is an outline that goes with this picture (overview of thyroid hormone biosynthesis)thyroid peroxidase iodinates the tyrosine on thyroglobulin, and it catalyzes the coupling reaciton. if you have read the book, or bgo back, the books talks in one little part talks about an iodinate which is the same, and has both activities.. TG (thyroglobulin) contains MIT, DIT, T3, and T4 (but not RT3 is not normally occuring, that is a typo). the TG just sits there all the peptide bonds are intact, until there is a signal for T3 and T4 to be released, when TSH is present, and reaches out formes it into a vessicle inslide the ep cell (colloid droplet is a membrane bound structure). It them colleses with the lysosomes with contain proteases which hydrolyse the colloid. You have ffree amino accides and T3, T4, MIT and DIT. T3, and T4 are secreted into capilaries. the MIT and DIT are acted on by Diodinaces that remove the iodine and the iodine is recycled into the colloid. thyroglobulin is taken up back into the cell only if TSH is present.

quantitatively:
fewer than 20 tyrosines are iodinated per thryoglobuliln. this is not an efficent process. about 90% of the product that is released from TG is T4, and about 10% is T3, but different books give different numbers. But remember the vast majority is T4, and small amount is T3.

Because the way the process works. the thyroid gland can store colloid for a very long time. if you thyroid were normal, but had a hypphectomy, but the thryoid would holdonto the colloid for several weeks. If tehre isn't a stimulous to be taken up, it just sits there.

so 10% is T3/90% is T4, does that really matter? do they have similar bioactivities, or do they have different roles? they have different roles. if you look at them, most people feel that T3 is physiological releveant thyroid hormone. the reason is because affinity of the thyroid hormone receptor is about 10% higher for T3 than T4. We'll talk next week about a formal def of hormone recptors affinity and their percentage. We make more T4, but the receptor preferes T3. T4 has a different role in the body. aFter T4 is released from thyroid it can have 2 different fates: 1) action of outer ring deiodinase emzyme to make T3, or 2) inner ring deiodinase to produce RT3 (no bioact), or 3) stay T4. which happens dictates whether T3 goes up, or down. T4 acts as a pro-hormone from which T3 is made outside of the thyroid gland. A prohormone is a long peptide string that has protective junk around it, but it is also used as a term to mean it gives rise to something else. where these T4 to T3 changes happen. ther are 2 types of outer ring deiodinases. type 1 in liver, kidneys, and thryoid is responsible for generating T3, that ends up in the blood from T4 that passes through. type 2 deiodinase: taget tissues (thrydoid taget hormone cells) eg pituitary gladn, CNS, placenta, the T4 leaves the blood, enters the cell in the CNS and is converted into T3 within the cell itself. the cell controls when/how much is made.

One more quantitative thing... if you measure the concentration of T3 and T4 in the blood. the total T4 concentration is about 50xs greater than the total T3 concentration. in target cell cytoplasm the estimate is T4 and T3 are relatively equal (inside the target cells). they are both more lypid soluble, not water soluble.

transport in the blood (T3, T4):
this will introduce a topic for thyroid, and steroid hormones. these molecules are very small. maybe one would think that because of their size that they are water sol, but they aren't. that has created during the course of evolution. molecules that are important, but not water soluble makes it difficult to get much of them into the circulation. so they circulate bound to a binding protein. roughly 99.98% of T4, and greater than 99.5% of T3 circulates in the plasma bound to a binding protein. (BP) they are large molecular weight proteins with timpically made by the liver (60-90Kilodaltons) made by the liver and are released into the circulation and present in the plasma. each hormone has their own BP. For T3 and T4 (70%) is called thyroid binding globulin (TBG). and in addition to that some T3 and T4 circulate bound to albumin instead (30%), or a few other proteins. Binding is very specific for TBG, and is non=covalent. nothing else can use it. T3+ TBG=T3-TBG but free T3 is called 'free T3'. Total T3 is free T3 PLUS the stuff bound to BPs. TBG is only in plasma. the Dogma is that only T3 and T4 that are free have biological activity. While it is bound, it is NOT biologically active. the reason for that is, the BP are too large to leave the capillaries, and so it is stuck in the plasma. Only the unbound T3/T4 can make it through the wall to get out of the circ and into the target cell. the binding protein serves the purpose of:
1) raise Hormone solubility in the blood which acts as a reservoir of hormones,
2) increase the half-life/decrease the clearance of hormones from the blood. t1/2 is the shorthand for half-life, which is the time it atkes for 1/2 a compound to be cleared/degraded. (two ways to do this:
a) decrease filtration into urine in kidney (binding proteins can't be filtered because it makes them too big which decreases their excretion).
b)and protect hormones againt attack by degradative enzymes.
both of these mechs work so well in relation of thyrsoid hormones that the t1/2 of T4 is about 7 days, and T3 is about 1 day. Compared with epinephrine (also from tyrosine) estimated t1/2 is 1 min, and others are 20-30 mins! So 1-7 days is super long. the importance of a long half-life is that clinically, you can't instantly change the levels.