Hormone Synthesis & Action

Question 1

Describe peptide/protein hormones.

Answer 1

• water-soluble
• made from large precursor molecules - prohormones

Question 2

Describe steroid/iodinated tyrosine hormones

Answer 2

• Lipid soluble
• Made from low-weight molecular weight precursors

Question 3

Describe the generalised scheme for the synthesis of protein/peptide hormones.

FLC REVISION

Answer 3

• TRANSCRIPTION: of the DNA to RNA
• POST-TRANSCRIPTIONAL PROCESSING: conversion of RNA to mature RNA with the excision of introns and modifications of the 3’ and 5’ ends
• TRANSLATION: of mature RNA into protein using tRNA to transfer amino acids
• POST-TRANSLATIONAL PROCESSING: cleavage of large-prehormone, folding of proteins, an addition of sugars (glycosylation)

Question 4

Describe preprohormones.

Answer 4

• Contains the HORMONE
• SIGNAL SEQUENCE - allows the protein to be processed within secretory granules
• REDUNDANT SEQUENCE, both of which will later be cleaved off.

Question 5

Describe prohormones.

Answer 5

Only contains HORMONE and REDUNDANT SEQUENCE.

Question 6

Describe the hormonal control of steroid synthesis from cholesterol. PART 1

Answer 6

• Hormone activates GPCR which activates cAMP - increases amount of activated PKA.
• Increases cholesterol ester hydrolase activity - releases cholesterol from cytoplasmic store.
• Increases the synthesis of StAR protein (Steroidogenic Acute Regulatory protein).

Question 7

Describe the hormonal control of steroid synthesis from cholesterol. PART 2

Answer 7

• Cholesterol is cleaved into pregnenolone by the side chain cleaving enzyme, P450scc
• Pregnenolone is a precursor to other steroid hormones.
• Between the mitochondria and SER, the steroids are synthesised by hydrolase enzymes.

Question 8

What are the hormones cholesterol can be converted into?

Answer 8

Aldosterone (from progesterone)
Cortisol + Androgens (from hydroxylated progesterone)

Question 9

What enzymes do androgens need and what do they do?

Answer 9

• Aromatase
• Converts androgens to estrogens

Question 10

What is aromatase deficiency in men?

Answer 10

• Unable to synthesize estrogens from androgens
• No epiphyseal closure (bone development)

Question 11

Describe the synthesis of thyroid hormones. PART 1

Answer 11

• Upon the stimulation of TSH, active uptake of iodide into the follicular cell.
• Iodide moves through the apical membrane via a transporter called pendrin
• Iodide oxidised to an iodinated intermediate by thyroid peroxidase (TPO), activated by H2O2.

Question 12

Describe the synthesis of thyroid hormones. PART 2

Answer 12

• Components iodinate a thyroglobulin molecule (on the tyrosine residues)
• Coupling of the iodinated residues to make T3 or T4.
• T3 /T4 are stored in the colloid.
• When stimulated by TSH , release and secretion of T3 and T4 into the blood circulation.

Question 13

What is goitre?

Answer 13

Enlargement of the thyroid gland

Question 14

What is Graves disease?

Answer 14

→ Antibodies to the TSH receptor act on the thyroid gland
→ Stimulates excess thyroid hormones and can cause opthalmopathy

Question 15

What are properties of peptide and protein hormones?

Answer 15

→ Water soluble → cell surface receptors
→ Activate second messengers/ enzymes with cytoplasmic and nuclear effects

Question 16

What are properties of steroid hormones?

Answer 16

→ Lipophilic
→ Intracellular receptors in cytoplasm or nucleus
→ Receptors are transcription factors

Question 17

What are the two surface receptors?

Answer 17

→ G protein-linked receptors
→ Tyrosine kinase domains

Question 18

What is involved in the G protein signalling pathway?

Answer 18

→ Adenyl cyclase
→ cAMP
→ PKA
- Triggered by GPCRs

Question 19

What is involved in the PIP pathway?

Answer 19

→ PIP
→ DAG and IP3
→ Ca2+
- Triggered by GPCRs

Question 20

What are the 2 major pathways in tyrosine kinase?

Answer 20

→ RAF/ MEK/ ERK
→ PI3 kinase / AKT
→ JAK/ STAT

Question 21

Describe the Raf/MEK/ERK1/2 signalling pathway.

Answer 21

• Ligand binds to the tyrosine kinase receptor, receptor dimerises and becomes phosphorylated
• Ras GTP is activated, which activates Raf
• Activated Raf activates MEK, which activates ERK1/2
• Activated ERK1/2 enters the nucleus and initiates transcription

Question 22

Describe the phosphatidylinositol kinase/AKT signalling pathway.

Answer 22

• Ligand binds, dimerisation of the receptor
• PI3-kinase activates PIP2 and PIP3
• PIP3 activates Akt (Protein Kinase B)
• Akt activates mTOR

Question 23

What is mTOR a target for?

Answer 23

Cancer drugs

Question 24

What does mTOR stimulate and inhibit?

Answer 24

STIMULATE: ribosome production, protein synthesis, nutrient uptake and metabolism
INHIBIT: protein degradation

Question 25

What are two conditions if you have a defective G coupled receptor?

Answer 25

→ Thyroid adenoma - TSH receptor defective → Precocious puberty - LH receptor defective

Question 26

What are 2 conditions if you have a defective G protein?

Answer 26

→ McCune Albright syndrome activating syndrome causing continuous activation of adenylate cyclase fibrous dysplasia of bone cafe au lait pigmentation

Question 27

Describe steroid hormone (nuclear) receptors.

Answer 27

- Family of transcription factors

Question 28

Describe the functional regions of the nuclear receptors.

Answer 28

- A/B domain is the N-terminal domain - C domain is the DNA binding region and is highly conserved - D domain is the hinge region - E domain is the ligand binding domain - F domain is the C-terminal domain

Question 29

What is special about the A/B and E/F domains?

Answer 29

Have transcriptional activity

Question 30

What is a steroid hormone’s C domain made up of?

Answer 30

2 zinc fingers which slot into the helix of the DNA.

Question 31

How does a steroid hormone act on its cytoplasmic receptor? PART 1

Answer 31

- Hormone is lipophilic so passes through cell membrane. - Hormone causes heat shock protein (HSP) (that is sitting in the steroid receptors (SR’s) place) dissociate and will take its place, causing dimerisation to occur.

Question 32

How does a steroid hormone act on its cytoplasmic receptor? PART 2

Answer 32

- Dimerised SRs will translocate to the nucleus, where they bind to the steroid response element (SRE) on the DNA. - Along with other transcription factors, transcription is initiated.