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Endocrine > Biochemistry of Thyroid > Flashcards

Biochemistry of Thyroid Flashcards

1
Q

What is the main physiological role of thyroid hormone?

A

To regulate cellular metabolism and energy homeostasis

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2
Q

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

A

Thyroid follicle

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3
Q

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

A

Thyroid follicular cells

Apical side

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4
Q

What comprises colloid?

A

Thyroglobulin

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5
Q

What are the two sides of the thyroid follicle cells?

A

Apical and basolateral sides

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6
Q

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

A

Basolateral side

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7
Q

What are the two biologically active thyroid hormones?

A

Thyroxine (T4)

3,5,3’-triiodothyronine (T3)

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8
Q

What is the basic structure of T3 and T4?

A

A tyrosine molecule linked to a phenyl ring

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9
Q

How many phenyl rings are in T3 and T4?

A

Two

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10
Q

T3 has two iodine

atoms on its (phenyl or tyrosine) ring.

A

Tyrosine

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11
Q

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

A

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

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12
Q

Where does the synthesis of T3 and T4 occur?

A

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

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13
Q

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

A

T3 is generated by deiodination of T4

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14
Q

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

A

T4

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15
Q

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

A

On the surface of thyroglobulin

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16
Q

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

A

seafood

Plants

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17
Q

What is organification?

A

The process of iodine attachment to the thyroglobulin molecule

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18
Q

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

A

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

TPO

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19
Q

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

A

Na/I symporter

Basolateral membrane

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20
Q

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

A

Brings in one I for every two Na

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

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21
Q

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

A

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

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22
Q

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?

A

Pendrin

Goes into exocytotic vesicles fused with the apical cell membrane

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23
Q

Where does the organification of iodide occur?

A

In the exocytotic vesicles

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24
Q

What type of bond is the Iodine to tyrosine bond?

A

Covalent

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25
Q

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

A

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

H2O2

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26
Q

What percent of tyrosyl residues of thyroglobulin are iodinated?

A

20-30%

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27
Q

What is the ratio of T4:T3 coupling?

A

5-7 : 1

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28
Q

What are the steps of thyroglobulin secretion?

A

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.

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29
Q

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

A

In the phagolysosomes of the colloid

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30
Q

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

A

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

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31
Q

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

A

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

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32
Q

What does an increase in serum thyroglobulin levels in indicate?

A

Thyroid pathology

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33
Q

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

A

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

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34
Q

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

A

Peptide hormone

Pyroglutamyl-histidyl-proline residues

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35
Q

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

A

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

Paraventricular nucleus of the hypothalamus

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36
Q

How does TRH get to the anterior pituitary?

A

Portal circulation

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37
Q

What does TRH do to cause TSH release?

A

Gq coupled protein increased PKC.

IP3 stimulates the release of Ca, which stimulates the secretion of TSH

38
Q

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

A

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

39
Q

What is the half life of TRH?

40
Q

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

A

huge glycoprotein with an alpha and beta subunit

41
Q

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

A

Beta is specific to TSH, while the alpha is not

42
Q

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

A

Gs

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

43
Q

What is the half-life of TSH?

A

65 minutes

44
Q

What does TSH do in terms of thyroid growth?

A

Stimulates growth

45
Q

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

46
Q

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

A

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

47
Q

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

A

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

48
Q

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

A
  • Somatostatin
  • Dopamine
  • Glucocorticoids
49
Q

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

A

Bound to thyroid binding proteins

50
Q

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

A

Globulin (70%)

Albumin (30%)

51
Q

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

A

T4

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

52
Q

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

A

little effect

53
Q

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

A

Transthyretin and lipoproteins

T4

54
Q

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

A

T3 is more active
T4 is found in higher concentration

Around 80% of T4 is deiodinated in the periphery to become T3

55
Q

What can happen to T4 and T3 in the periphery?

A

Sequential deiodination to T2 or rT3

56
Q

What is the biological activity of rT3? T2?

57
Q

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

A

Deiodinases

Selenocysteine

58
Q

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?

A

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

59
Q

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

A

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

60
Q

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

A

Converts T4 to rT3, and T3 to T2 (inactivating each)

Inactives thyroid hormone in the brain and placents

61
Q

What are the two main functions of deiodination?

A
  1. Trigger formation of biologically active hormones

2. Deactivate the thyroid hormones when their concentration increases above desirable levels

62
Q

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

A

Glucuronidation

Sulfation

63
Q

How does thyroid hormone get into cells?

A

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

64
Q

Where are the thyroid hormone receptors located?

A

Nucleus, constitutively inhibiting transcription

65
Q

What are the DNA sequences that thyroid receptors sit atop?

A

Thyroid hormone response element (TREs)

66
Q

What are the two components of the thyroid receptor heterodimer?

A

Receptor region and the Retinoid X receptor (RXR)

67
Q

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

A

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

68
Q

What happens when thyroid hormone binds its receptor?

A

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

69
Q

What is the function of HAT complexes?

A

Acetylate histones (makes available for transcription)

70
Q

Does thyroid hormone act outside the nucleus?

A

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

71
Q

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

A

Acceleration of the Basal metabolic rate

72
Q

How does thyroid hormone increase BMR? (2)

A

Stimulation of Na/K ATPase activity

Transcription of uncoupling mitochondrial proteins

73
Q

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

A

Increases d/t increase uncoupling agents

74
Q

What is the effect of thyroid hormone on adipose tissue?

A

Increases lipolysis and activating LPL

75
Q

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

A

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

76
Q

What is the effect of thyroid hormone on bones?

A

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

77
Q

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

A

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

78
Q

What is the effect of thyroid hormone on the liver?

A

Stimulate increased cellular uptake and metabolism of cholesterol and TAGs

79
Q

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

A

Stimulate GH production

80
Q

What is the effect of thyroid hormone on the brain?

A

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

81
Q

What are some common causes of hypothyroidism?

A

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

82
Q

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

A

Thyroid peroxidase
Thyroglobulin
TSH receptors

83
Q

What happens to TSH levels in Hashimoto’s thyroiditis?

84
Q

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

A 
T3 = (3,5,3')
rT3 = (3, 3', 5')
T2 = (3, 3')
85
Q

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

A

homodimer glycoprotein

rER

86
Q

What percent of T3 and T4 does the thyroid synthesize?

A

20% of T3

100% of T4

87
Q

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

A

Alpha
Beta
Gamma

88
Q

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

A

Inhibits:

  • TSH transcription
  • TSH modification
89
Q

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

A

Inhibits:

  • TRH gene expression
  • TRH receptor synthesis
90
Q

Does thyroid hormone secretion impact thyroglobulin synthesis?

91
Q

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

A 
I = both
II = outer
III = Inner

Endocrine (32 decks)

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