Hormone synthesis and action

Question 1

State a disorders of thyroid hormone signalling?

Answer 1

Goitre- enlargement of thyroid gland

Question 2

What receptor do steroid and thyroid hormones act on and describe their effect?

Answer 2

Lipophilic -> Act on intracellular receptors in cytoplasm
or nucleus by crossing cell membrane
Receptors are transcription factors

Question 3

State a disorder of steroid hormone signallign

Answer 3

Aromatase deficiency

Question 4

Describe the overall synthesis of insulin?

Answer 4

Insulin is a peptide/protein hormone remember

1) Transcription to mRNA
2) Excision of introns to messenger RNA
3) Translation of mature RNA into protein to form pre-proinsulin.
- Moves to RER
3) Removal of signal sequence and formation of disulphide bonds in RER.
4) Pre-proinsulin -> proinsulin
5) Transfer to Golgi apparatus, excision of C peptide and packaging into secretory granules.
Forms active insulin

Question 5

State disorders of steroid receptor signalling?

Answer 5

1) Resistance to hormone action: when you cannot respond to steroid hormones
2) Inactivating mutations of steroid receptors e.g. Androgen receptor (nuclear receptor)
3) Androgen insensitivity syndrome (AIS)

Question 6

Describe the overall process for the synthesis of thyroid hormones?

Answer 6

1) Active uptake of iodide into follicular cell
2) Transport across the apical membrane
3) Oxidation of iodide to iodinated intermediate by thyroid peroxidase (TPO)
- TPO is activated by H2O2
4) Iodination of tyrosine residues of thyroglobulin
5) Coupling of iodinated tyrosine residues
6) Storage of T3 and T4 in colloid
7) Uptake of thyroglobulin droplets into follicle cell
8) Release and secretion of T3 and T4 stimulated by TSH

Question 7

State a disorder of steroid hormone signalling in men?

Answer 7

Aromatase deficiency in men

Unable to synthesise oestrogens from androgens -> no epiphyseal closure ->long stature

Boys show early sexual development due to excess androgens

Question 8

Describe the 1st change that occurs after the synthesis of a large precursor protein
into an active hormone?

Answer 8

Pre-prohormone is converted into prohormone (hormone + peptide sequence).
- Signal sequence is cleaved

Question 9

What receptor do peptide and protein hormones act on and describe their effect?

Answer 9

Water soluble -> Act on cell surface receptors

• Activate second messengers and/or enzymes
• Lead to Cytoplasmic and nuclear effects

Question 10

What molecules are steroids and iodinated tyrosines hormones are made from

Answer 10

Low molecular weight precursors

Question 11

State the structural organisation of nuclear/steroid hormone receptors?

Answer 11

Different functional regions of the receptor are defined as domains - A-F

• A/B= N-terminal domain
• C= DNA binding region (highly conserved)
• D= Hinge region
• E= Ligand binding domain
• F= C-terminal domain

The C domain is the DNA binding region and is highly conserved
Both the A/B domains and E/F domains have transcriptional activity (AF-1/AF-2)

Different steroid receptors are continually being discovered

Question 12

How is goitre caused by?

Answer 12

Lack of iodine in the diet leads to deficiency in T3 and T4 (hypothyroidism)
Graves disease (hyperthyroidism)
Thyroid adenoma

Goitre- enlargement of thyroid gland

Question 13

State the 2 secondary messengers involved in GPCR from protein/ peptide hormones
with their effect pathway

Answer 13

Adenyl Cyclase
Phospholipase C

Kinases can activate enzymes or transcription factors

Question 14

State what hormones are released each gland controlled by the hypothalamic-
pituitary axis/

Answer 14

Thyroid= T3/T4
Adrenal cortex= Aldosterone/cortisol
Gonads= Oestrogen/ testosterone

Question 15

Describe the strcture of the C region of the steroid hormone/nuclear receptor?

Answer 15

The DNA binding region (C) is made up of 2 zinc fingers which can slot into the helix of the DNA

Question 16

What is a similarity between peptide, steroid and thyroid hormones?

Answer 16

They all can activate gene transcription

Question 17

Describe the overall pathway for steroid synthesis from cholestrol?

Answer 17

Question 18

Describe the control of steroid synthesis from cholestrol?

Answer 18

1) Cholesterol bound to sterol carrier protein
- transported to mitochondria
2) StAR protein transports cholesterol to inner mitochondrial membrane (rate limiting)
3) Cholesterol -> pregnenolone by side chain cleavage enzyme, P450scc (rate limiting)
4) Between mitochondria and smooth endoplasmic reticulum
- Pregnenolone is synthesised into steroids by hydroxylase enzymes

StAR = steroidogenic acute regulatory protein

Question 19

Name the cell surface receptors that protein/peptide hormones bind to?

Answer 19

1) G-protein linked receptors (require G protein guanosine to bind)
2) Receptors with or associated with tyrosine kinase domains

Question 20

State the name and structure of the large precursor protein once formed?

Answer 20

Pre-prohormone (signal sequence + prohormone)
- Composed of signal + hormone + Peptide sequence

Signal sequence used to direct molecule to right part of cell

Question 21

State the prohormone processing into active endothelin peptide

Answer 21

1) Prepro-endothelin -> Pro-endothelin via furin protease (removal of signal)
2) Pro-endothelin -> Big-endothelin via furin protease (removal of C terminus)
3) Big endothelin -> Endothelin via endothelin converting enzyme (removal of rest of inactive peptide components)

Question 22

How can obesity lead to atherosclerosis?

Answer 22

Obesity drives the development of insulin resistance which is associated with cardiovascular risk factors and atherosclerosis

CVS factors include inflammation, endothelial dysfunction, hypertension

Question 23

Why is it important to know about hormones, receptors and their signalling pathways?

Answer 23

To understand endocrine disorders and to provide targets for the development of new drugs

Question 24

State the type of solubility peptides/protein hormones have
vs steroids and iodinated tyrosines hormones?

Answer 24

Peptides and proteins: Water soluble
Steroids and iodinated tyrosines: Lipid soluble

Question 25

What are the receptors for steroid hormones?

Answer 25

Family of transcription factors
Known as nuclear receptors

Question 26

State the 5 signalling pathways for protein and peptide hormones in category?

Answer 26

GPCR:

1) Adenyl cyclase and cAMP (Gs protein)
- AC stimulates -> Causes ATP -> cAMP -> Increases PKA
2) Phosphoinositide pathway (Gg protein)
- PLC + PIP 2 = (PIP3) -> DAG + IP3 -> Increased PKA + Ca2+

Receptors with tyrosine kinase activity

3) Raf/MEK ERK pathway
4) PI3-Kinase/Akt pathway
5) JAK STAT pathway

Question 27

State the steroid hormones that can be formed from cholestrol?

Answer 27

Aldosterone
Cortisol
Oestrogen
Androgen
Progestrone

Question 28

What does Graves’ disease lead to?

Answer 28

Autoantibodies to the TSH receptor act on the thyroid gland, stimulate excess thyroid hormones
- can cause eye disease (Proptosis - bulging of eyes)

Question 29

How does thyroid adenoma occur by?

Answer 29

Activating mutation of the TSH receptor - a G-protein coupled receptor
- Leads to hyperthyroidism

Question 30

What molecules are peptides and protein hormones are made from

Answer 30

Large precursor molecules- prohormones

Question 31

State a disorder of steroid hormone signalling in women?

Answer 31

Aromatase deficiency in women

• Virilisation of XX fetuses
• Clitoromegaly
• Ambiguous genitalia

Girls develop male-type characteristics

Question 32

State the 4 stages involved in the synthesis of protein/peptide hormones
via transcription?

Answer 32

1) Transcription of DNA to RNA

2) Post-transcriptional processing RNA -> mature RNA
- Excision of introns (splicing)
- Modifications of 3’ and 5’ ends (capping and polyadenylation)

3) Translation of mature RNA into protein using tRNA to transfer amino acids
- Large pre-prohormone is formed here

4) Post-translational processing cleavage of large pre-prohormone (in golgi apparatus)
- Folding of proteins
- Addition of sugars (glycosylation)

Question 33

Describe the mechanism of steroid hormone binding to its receptor?

Answer 33

1) Hormone crosses cell membrane
2) Heat shock protein dissociates from receptor
3) Hormone binds to receptor and dimerization occurs
4) Dimerized receptors translocate to the nucleus
5) Binds to the hormone response element on the DNA, along with other transcription factors
- Transcription is initiated

Some receptors located within the nucleus not the cytoplasm

Question 34

State disorders of protein/peptide hormone signalling?

Answer 34

Diabetes
Type 1 – autoimmune destruction of the pancreatic islets: absolute insulin deficiency
Type 2 – insulin resistance, partial loss of insulin production (insulinopaenia) – often associated with obesity

Obese class III ≥ 40 BMI

Question 35

What processes are steroid receptors involved in?

Answer 35

Transactivation
Dimerization
DNA binding
Ligand binding
Nuclear localization signal