Biochemistry of Thyroid

Question 1

What is the main physiological role of thyroid hormone?

Answer 1

To regulate cellular metabolism and energy homeostasis

Question 2

What is the secretory unit of the thyroid? Where is thyroid hormone produced?

Answer 2

Thyroid follicle

Question 3

What are the cells that surround the colloid called? What is the side of the cells that face the colloid called?

Answer 3

Thyroid follicular cells

Apical side

Question 4

What comprises colloid?

Answer 4

Thyroglobulin

Question 5

What are the two sides of the thyroid follicle cells?

Answer 5

Apical and basolateral sides

Question 6

What side of the follicular cells is exposed to the bloodstream?

Answer 6

Basolateral side

Question 7

What are the two biologically active thyroid hormones?

Answer 7

Thyroxine (T4)

3,5,3’-triiodothyronine (T3)

Question 8

What is the basic structure of T3 and T4?

Answer 8

A tyrosine molecule linked to a phenyl ring

Question 9

How many phenyl rings are in T3 and T4?

Answer 9

Two

Question 10

T3 has two iodine

atoms on its (phenyl or tyrosine) ring.

Answer 10

Tyrosine

Question 11

What is the significance of removal of an iodine molecule from the tyrosine ring of T3?

Answer 11

Becomes 3,3,5’ triiodothyronine, (reverse T3, rT3) and has NO biological activity

Question 12

Where does the synthesis of T3 and T4 occur?

Answer 12

T4 is solely in the thyroid gland, whereas T3 can occur in other tissues

Question 13

Why is it that T3 can be synthesized in many tissues, but T4 can only be synthesized in the thyroid?

Answer 13

T3 is generated by deiodination of T4

Question 14

What is the major secretion of the thyroid gland: T3 or T4?

Answer 14

T4

Question 15

Where in the thyroid does the biosynthesis of T3 and T4 occur?

Answer 15

On the surface of thyroglobulin

Question 16

Where, besides fortified salt, does iodine come from the diet?

Answer 16

seafood

Plants

Question 17

What is organification?

Answer 17

The process of iodine attachment to the thyroglobulin molecule

Question 18

What is coupling? What is the enzyme that catalyzes this process?

Answer 18

The synthesis of MITs and DITs together to form T3/T4

TPO

Question 19

What is the transporter that bring in iodine to the follicular lumen? Where is the transporter located?

Answer 19

Na/I symporter

Basolateral membrane

Question 20

What does the Na/I symporter do? Is this active or passive?

Answer 20

Brings in one I for every two Na

Secondarily active–relies on Na/K ATPase the constant pumps Na out of the cytoplasm

Question 21

What happens to the iodide once it enters the cell cytoplasm?

Answer 21

transported to the apical side of the cell, where it is transported by a membrane iodide channel protein

Question 22

What is the iodide channel protein on the apical side of thyroid cells called? What happens to the iodide once it is transported into the colloid through this protein?

Answer 22

Pendrin

Goes into exocytotic vesicles fused with the apical cell membrane

Question 23

Where does the organification of iodide occur?

Answer 23

In the exocytotic vesicles

Question 24

What type of bond is the Iodine to tyrosine bond?

Answer 24

Covalent

Question 25

What is the enzyme that catalyzes the bond between iodine and thyroglobulin? Where is this found? What is the electrophile for this reaction?

Answer 25

Thyroid peroxidase It is an integral protein of the apical membrane of follicular cells H2O2

Question 26

What percent of tyrosyl residues of thyroglobulin are iodinated?

Answer 26

20-30%

Question 27

What is the ratio of T4:T3 coupling?

Answer 27

5-7 : 1

Question 28

What are the steps of thyroglobulin secretion?

Answer 28

Thyroglobulin is endocytosed, and then fuse with cell lysosomes forming phagolysosomes. There, thyroglobulin is cleaved (hydrolyzed) to release T4 and T3 but also DIT, and MIT. They are then secreted.

Question 29

Where does the conversion of thyroglobulin to T3/T4 take place?

Answer 29

In the phagolysosomes of the colloid

Question 30

What happens to the MITs and DITs that are hydrolyzed off of thyroglobulin in the lysosome?

Answer 30

Deiodinated by a spseicifc deiodinase, and the iodide is transported back to the apical side of the follicular cells

Question 31

What happens to the thyroglobulin molecule when the iodines are taken off in the lysosome?

Answer 31

most sent back, but some undergo transcytosis, and are excreted

Question 32

What does an increase in serum thyroglobulin levels in indicate?

Answer 32

Thyroid pathology

Question 33

What are the steps involved in the secretion of T3/T4 in terms of the HPA axis?

Answer 33

TRH from the hypothalamus signals the pituitary to release TSH. TSH acts on the thyroid to increase T3/T4 output.

Question 34

What type of hormone is TRH? What are the components of this?

Answer 34

Peptide hormone | Pyroglutamyl-histidyl-proline residues

Question 35

What is the precursor to TRH? How does this become TRH? Where does this occur?

Answer 35

proTRH peptide, which undergoes cleavage by the action of peptidases and cyclization of glutamine Paraventricular nucleus of the hypothalamus

Question 36

How does TRH get to the anterior pituitary?

Answer 36

Portal circulation

Question 37

What does TRH do to cause TSH release?

Answer 37

Gq coupled protein increased PKC. IP3 stimulates the release of Ca, which stimulates the secretion of TSH

Question 38

What are the two products of PKC activation via Gq proteins?

Answer 38

phosphatidylinositol 4,5- bisphosphate (PIP2) into other second messengers- diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3)

Question 39

What is the half life of TRH?

Answer 39

3 minutes

Question 40

What type of hormone is TSH? What are its components?

Answer 40

huge glycoprotein with an alpha and beta subunit

Question 41

What is the function of the alpha and beta subunit of TSH?

Answer 41

Beta is specific to TSH, while the alpha is not

Question 42

What is the G protein that TSH activates? What does this cause? (3)

Answer 42

Gs This stimulates the iodide transport, transcription of thyroid peroxidase, and transcription of thyroglobulin

Question 43

What is the half-life of TSH?

Answer 43

65 minutes

Question 44

What does TSH do in terms of thyroid growth?

Answer 44

Stimulates growth

Question 45

Which is a more potent inhibitor of TRH and TSH release: T3 or T4?

Answer 45

T3

Question 46

What is the effect of T3 and T4 at the pituitary level?

Answer 46

both T4 and T3 inhibit TSH secretion by decreasing the synthesis and release of TSH

Question 47

What is the effect of T3 and T4 at the hypothalamic level?

Answer 47

T3 inhibits the gene expression of TRH. Additionally, T3 down-regulates the synthesis of TRH receptor thus reducing the ability of thyrotrophs to produce TSH in response to TRH stimulation

Question 48

What three major hormones can alter the serum concentration of TSH?

Answer 48

- Somatostatin - Dopamine - Glucocorticoids

Question 49

What is the vast majority of T3/T4 transported as?

Answer 49

Bound to thyroid binding proteins

Question 50

What are the two major thyroid hormone binding proteins? Which binds more?

Answer 50

Globulin (70%) | Albumin (30%)

Question 51

Which has a higher affinity for thyroid binding globulin: T3 or T4? What is the significance of this?

Answer 51

T4 If thyroid secretion ceases, T4 stored in the serum serves to delay the onset of hypothyroidism.

Question 52

What is the relative magnitude of the effect of a loss of albumin on T3 and T4 levels?

Answer 52

little effect

Question 53

What, besides globulin and albumin, binds thyroid hormones in the serum? Which do these have higher affinity for: T3 or T4?

Answer 53

Transthyretin and lipoproteins T4

Question 54

Which is more biologically active: T3 or T4? Which is found in higher concentration in the serum? Why is there this discrepancy?

Answer 54

T3 is more active T4 is found in higher concentration Around 80% of T4 is deiodinated in the periphery to become T3

Question 55

What can happen to T4 and T3 in the periphery?

Answer 55

Sequential deiodination to T2 or rT3

Question 56

What is the biological activity of rT3? T2?

Answer 56

None

Question 57

What are the enzymes that catalyze the deiodination of T3/T4? What is the cofactor necessary for these?

Answer 57

Deiodinases | Selenocysteine

Question 58

What is the primary deiodinase responsible for the conversion of T4 to T3 or rT3 in the periphery? Where is this found (3 organs)? What regulates this?

Answer 58

Deiodinase I Liver, kidney, thyroid Regulated by TSH-stimulated cAMP production in the thyroid

Question 59

What is the role of type II deiodinase? Where is this found?

Answer 59

Vast tissue distribution--an important source of intracellular T3 in tissues that produce T3 themselves, rather than deriving it from the plasma

Question 60

What is the role of type III deiodinase? What two organs is this found in?

Answer 60

Converts T4 to rT3, and T3 to T2 (inactivating each) | Inactives thyroid hormone in the brain and placents

Question 61

What are the two main functions of deiodination?

Answer 61

1. Trigger formation of biologically active hormones | 2. Deactivate the thyroid hormones when their concentration increases above desirable levels

Question 62

What reaction do the phenolic hydroxyl groups of T4/T3 undergo to be secreted in the urine/bile?

Answer 62

Glucuronidation | Sulfation

Question 63

How does thyroid hormone get into cells?

Answer 63

Through specific high affinity transport proteins that is dependent on Na gradient

Question 64

Where are the thyroid hormone receptors located?

Answer 64

Nucleus, constitutively inhibiting transcription

Question 65

What are the DNA sequences that thyroid receptors sit atop?

Answer 65

Thyroid hormone response element (TREs)

Question 66

What are the two components of the thyroid receptor heterodimer?

Answer 66

Receptor region and the Retinoid X receptor (RXR)

Question 67

What is the function of the RXR region of the thyroid receptor?

Answer 67

Recruits HDAC activity to maintain chromatin in a condensed state, and prevent transcription

Question 68

What happens when thyroid hormone binds its receptor?

Answer 68

Conformational change, displacing the HDAC, and binding of a HAT complex.

Question 69

What is the function of HAT complexes?

Answer 69

Acetylate histones (makes available for transcription)

Question 70

Does thyroid hormone act outside the nucleus?

Answer 70

Yes--regulation of ion channels and protein kinase signaling cascades that increase cAMP

Question 71

There are thyroid hormone receptors in nearly all tissues. What is the significance of this?

Answer 71

Acceleration of the Basal metabolic rate

Question 72

How does thyroid hormone increase BMR? (2)

Answer 72

Stimulation of Na/K ATPase activity | Transcription of uncoupling mitochondrial proteins

Question 73

What is the effect of thyroid hormone on oxygen consumption by mitochondria? Why?

Answer 73

Increases d/t increase uncoupling agents

Question 74

What is the effect of thyroid hormone on adipose tissue?

Answer 74

Increases lipolysis and activating LPL

Question 75

What is the effect of thyroid hormone on glycogenolysis and gluconeogenesis?

Answer 75

Increase to balance the increased use of glucose as a fuel for thermogenesis

Question 76

What is the effect of thyroid hormone on bones?

Answer 76

Control osteoclast and osteoblast activity, and thus growth (slow growth vs osteoporosis)

Question 77

What is the effect of thyroid hormone on the CV system?

Answer 77

Increases cardiac output d/t increase in the transcription of Ca ATPase, myosin, and adenylate cyclase

Question 78

What is the effect of thyroid hormone on the liver?

Answer 78

Stimulate increased cellular uptake and metabolism of cholesterol and TAGs

Question 79

What is the effect of thyroid hormone on the pituitary (beside negative feedback)?

Answer 79

Stimulate GH production

Question 80

What is the effect of thyroid hormone on the brain?

Answer 80

Involved in the process of neurogenesis, neuronal migration, differentiation, and synaptogenesis

Question 81

What are some common causes of hypothyroidism?

Answer 81

Autoimmune disorders (e.g. Hashimoto's thyroiditis)

Question 82

What are the autoantibodies found in Hashimoto's thyroiditis? (3)

Answer 82

Thyroid peroxidase Thyroglobulin TSH receptors

Question 83

What happens to TSH levels in Hashimoto's thyroiditis?

Answer 83

Increase

Question 84

What is the biochemical name of T3? rT3? T2?

Answer 84

``` T3 = (3,5,3') rT3 = (3, 3', 5') T2 = (3, 3') ```

Question 85

What type of molecule is thyroglobulin? Where in the follicular cells is this synthesized?

Answer 85

homodimer glycoprotein rER

Question 86

What percent of T3 and T4 does the thyroid synthesize?

Answer 86

20% of T3 | 100% of T4

Question 87

What are the subunits that comprise the G protein coupled receptors?

Answer 87

Alpha Beta Gamma

Question 88

What is the effect of T3/T4 on the pituitary?

Answer 88

Inhibits: - TSH transcription - TSH modification

Question 89

What is the effect of T3/T4 on the hypothalamus?

Answer 89

Inhibits: - TRH gene expression - TRH receptor synthesis

Question 90

Does thyroid hormone secretion impact thyroglobulin synthesis?

Answer 90

No

Question 91

Inner, outer, or dual ring activity: Type I, II, and III deiodinases?

Answer 91

``` I = both II = outer III = Inner ```