Download Steroid and Thyroid Hormones

CLASS: 11-12
DATE: 9-17
PROFESSOR: Whikehart
I.
Steroid and Thyroid Hormones
Scribe: Spencer Terry
Proof:Megan Guthman
Page 1 of 3
Steroid & Thyroid Hormones [S1]
a. I put these together because they are largely an insoluble class of hormones.
b. Have particular problems the other group doesn’t
II. Introduction [S2]
a. Will look and different types and origins
b. Will discus synthesis of different groups: Steroids and T3/T4 which are made in different molecules
c. Some carriers go through bloodstream unbound, but some are bound
d. Mechanisms are quite different than peptide hormones
III. Steroid Hormones (Derived from Cholesterol) [S3]
IV. Types [S4]
a. Read slide
b. Most of the hormones are short lived
c. Glucocorticoids: Should say anti-inflammatory instead of inflammatory
V. Origins of Steroidal Synthesis [S5]
a. Steroids are made in 3 locations: The adrenal glands and the sexual organs (ovaries and testes). This is
done through the synthesis of adrenocorticotropic hormone in the pituitary gland.
b. The hormone is made here and travels to the various targets (pecking order)
VI. Origins [S6]
a. We’re going to focus on the adrenal’s because they are very important.
b. These are organs that are next to the kidneys. Two of each per person
c. This is done under the influence of ACTH.
d. In the adrenals, we find 3 classes of steroids: corticosterone, cortisol, and androgens.
e. ACTH is largely involved in making glucocorticoids, but not exclusively.
f.
VII. Steroid Synthetic Pathways [S7]
a. Don’t be concerned, because he is going to pick out what he wants us to know.
b. All of this begins with cholesterol. All the steroids are made from cholesterol through numerous enzymatic
pathways.
c. The principal enzymes belong to the P450 class. The name means particulate matter visible at 450nm.
These P450 enzymes are involved in oxidation reactions, and what they do largely is pick off and break down
the tail end of the cholesterol molecule.
d. The produce a lot of hydroxy groups on the substituent that we call steroid hormones.
e. You see the Types of P450 enzymes on the left.
f. Each one of these reactions where you see a separate arrow involves a separate enzyme.
g. In the pathway that involves or winds up with the sex steroids, goes through one or two pathways and ends
up with the precursor androstenedione.
h. The other classes to be familiar with are corticosterone (ultimately produces aldosterone), and finally cortisol
(indicated by red arrow)
VIII. Notes: DHEA [S8]
a. Don’t worry about what DHEA stands for.
b. NADPH comes from the pentose phosphate shunt. It’s a source of electrons for steroid synthesis. Also
requires molecular oxygen.
c. Only wants us to know about the main 3.
d. Many of these have both mineralo and glucocortico activity
e. Glucocorticoid is concerned with energy production via stimulating glucose, lipid, and protein metabolism.
f. Minerolocorticoids are involved in water retention
g. READ SLIDE
IX. P450 Enzymes [S9]
a. Pathway on the right: One of the first things that occurs in the production of steroid is to chop of the tail –
begins at carbons number 20 and 22.
b. Cytochrome p450 has both oxidase and desmolase activity will put hydroxy groups on carbons 20 and 22
using NADPH and 2 molecules of oxygen
CLASS: 11-12
Scribe: Spencer Terry
DATE: 9-17
Proof:Megan Guthman
PROFESSOR: Whikehart
Steroid and Thyroid Hormones
Page 2 of 3
c. Cytochromes contain Iron atoms and iron atoms are responsible for moving electrons back and forth to get it
off a substrate.
d. The product is 20,22-dihydroxy cholesterol
e. More oxygen and more NADPH is then used to produce pregnenolone (one of the steroids isolated from
tissue of pregnant women).
f. This whole process is called mixed function oxidation because there is both oxidation and reduction going on
at the same time.
g. If you look closely up top, you need two molecules of oxygen, and one of the products was water and the
other is the hydroxy groups incorporated into cholesterol.
X. Glucocorticoid vs. Mineralocorticoid Activity [S10]
a. The numerous functions of steroids is a primary reason why, if you prescribe to a patient, you should be
conservative due to the side effects. If you aren’t conservative, a patient might get a cataract for example.
Also, steroids can mask conditions that the patient has. Cutting back, all of a sudden this condition will
suddenly cause problems.
b. Glucocorticoids involve increases in metabolism
c. Aldosterone primarily has Mineralocorticoid functions, but could have Glucocorticoid functions as well.
XI. Anti-inflammatory Activity [S11]
a. It is one of the primary reasons steroids are prescribed to patients. They reduce inflammation.
b. Can look at cortisol and see what mixed function oxidation has done to the molecule. It has cut it back, so
that we have the keto group, but also have the 3 hydroxy groups.
c. READ SLIDE
XII. Transport [S12]
a. Most of the cortisol is carried by transcortin, and remainder by albumin.
b. The structure here doesn’t show anything about how the transport works
c. Has lots of beta pleated sheets and some alpha helices.
d. Don’t know how or where it binds
e. READ SLIDE
XIII. Hormones of the Thyroid Gland [S13]
a. The second group of hormones are those derived from the thyroid gland
XIV.
Synthesis of T3 and T4 [S14]
a. Read Slide
b. With some variation in the production of T3 and T4, it may have an effect on how fast we do things and how
high the temperature in the room should be
XV. Cuboidal Epithelial Cells
a. Here is a cross section of the principal cells of the thyroid gland and what they do is take up iodine as iodide
and transport them through the cell.
b. Also take up amino acids and be involved in the production of a protein called thyroglobulin. This is in the
colloid region of the apical side of the cell. It is in this region that iodination of the thyroglobulin takes place.
c. We have amino acid uptake, then incorporation and synthesis, the thyroglobulin is transported to the colloid
where iodination takes place. Thyroglobulin is reabsorbed into the cell. Inside the cell, it is digested by
lysosomal enzymes inside the lysosomes, releasing T3 and T4 inside the cell. They are eventually released
into the bloodstream.
XVI.
This Scheme Shows How:
a. The tyrosine amino acids are used to make up T3 and T4
b. Tyrosine amino acids are part of the thyroglobulin molecule (140 Tyr residues per molecule – 28 of these are
iodinated)
c. An enzyme called iodoperoxidase that incorporates iodine by means of hydrogen peroxide onto the ends of
the Tyr residue.
d. The squiggly lines are the remainders of the thyroglobulin molecule.
e. It occurs in 2 ways. You can have double iodination, giving you 2 di-iodotyrosine, or you can have
monoiodination giving you mono-iodotyrosine.
f. Then there is an enzyme called a coupling enzyme that will piggyback one of these tyrosines on top of the
other. It will transfer a portion of the iodinated tyrosine onto a second one. This gives you 3,5-3’-triiodothyronyl residue still hooked onto the protein, or it will ive 3,5,3’ 5’ tetraiodothyronyl residue. This protein
in its iodinated form is then taken into a lysosome and broken down by a protease, releasing the individual
hormones.
g. 2 of these are shown here, but there are actually 6 or 7 ways the iodination could take place
XVII. Iodinated ThyroGlobulin
CLASS: 11-12
Scribe: Spencer Terry
DATE: 9-17
Proof:Megan Guthman
PROFESSOR: Whikehart
Steroid and Thyroid Hormones
Page 3 of 3
a. Read Slide
b. TSH = thyroid stimulating hormone
c. There are 4 or 5 different hormones that effect the activity of the thyroid gland itself. Some of those are
feedback mechanisms which are important because the possible consequences of uncontrollable thyroid
gland.
XVIII. Thyroid Hormones Released into the blood
a. There are 8 forms (had said 6 earlier).
b. This shows 4 forms, and he said 2 of these are important.
c. For example, T3 has 300-800 % the biological activity of T4
d. Other forms have less than 1% of the activity.
XIX.
What Happens when these hormones arrive at their target cells?
a. They all operate by basically the same mechanism.
b. They bind to some receptor protein.
c. A problem that occurs that is still not resolved (drawing on board).
d. Have a hormone such as T3 or T4 carried to the plasma membrane of the cell by a protein and easily enter
the cell. They are then assumed to bind to a receptor protein in the cytoplasm. These hormones then go as a
complex with the receptor into the nucleus where they eventually bind with DNA.
e. Some people believe that the hormones enter the nucleus without a receptor (Whikehart doesn’t believe this
because of a solubility problem of being transported from the plasma membrane to the nucleus).
f. The receptor protein, before bind to the hormone, is bound to a blocking protein. The hormone binds to a
hormone binding site. When this happens, the blocking protein dissociates from the receptor. It is then
possible for the complex to bind to DNA at the DNA binding domain (which contains zinc fingers). Zinc fingers
bind to the DNA.
g. The gene activating/inhibiting domain is where the action takes place.
XX. General Scheme of a Steroid/Thyroid Receptor
a. Hormone binds at the hetero or homo dimerization domain
b. The ligand-independent transacitvation domain is the area where the action takes place.
c. The receptor binds to two sections of DNA (one in the DNA binding domain, and the other at the end of the
transactivation domain)
XXI.
General Diagrams of Steroid Receptor Proteins
a. The transactivation domain has a variable length. Sometimes it is long, sometimes short. Long in case of
progesterone receptor, Glucocorticoid receptor.
b. Short with thyroid hormone receptors.
c. The amino acid identity in this region is very low (indicated as 0). This means that the amino acid sequences
in each of these is very different.
d. What is really important about the regions is the length.
e. The DNA binding domain doesn’t vary much (usually about 68 a.a. long)
f. Hormone-binding domain doesn’t vary greatly either.
XXII. Mechanism for Transcription Activation
a. In transcription, the synthesis of RNA, we have a promoter region, and we have a region where the chain is
located.
b. RNA polymerase binds at the promoter region. What happens here as far as binding can be complex
because there are a number of factors that will bind at the promoter region. These factors determine whether
synthesis takes place or not, and the rate at which it takes place.
c. To complicate this matter, we have the protein receptor hormone complex with its variable region located
here, also has a say in whether RNA synthesis begins.
d. There are 2 locations where the receptor binds. It binds at the enhancer region as well as the promoter
region.
XXIII. Notes on Transcription Effects
a. Read Slide
XXIV. Summary
a. Read Slide
b. Carrier proteins are need in ALL cases for steroids, and in some cases for thyroid hormones
c. Question: The main reason carrier proteins are required is that the steroid hormones are not soluble and
won’t go through the blood unless they have a carrier protein. With T3 and T4, some are bound to carrier
proteins and some are not.
[End 31:40 mins]