Hormone Synthesis & Action Flashcards
Describe peptide/protein hormones.
- water-soluble
- made from large precursor molecules - prohormones
Describe steroid/iodinated tyrosine hormones
- Lipid soluble
- Made from low-weight molecular weight precursors
Describe the generalised scheme for the synthesis of protein/peptide hormones.
FLC REVISION
- 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)
Describe preprohormones.
- Contains the HORMONE
- SIGNAL SEQUENCE - allows the protein to be processed within secretory granules
- REDUNDANT SEQUENCE, both of which will later be cleaved off.
Describe prohormones.
Only contains HORMONE and REDUNDANT SEQUENCE.
Describe the hormonal control of steroid synthesis from cholesterol. PART 1
- 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).
Describe the hormonal control of steroid synthesis from cholesterol. PART 2
- 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.
What are the hormones cholesterol can be converted into?
Aldosterone (from progesterone)
Cortisol + Androgens (from hydroxylated progesterone)
What enzymes do androgens need and what do they do?
- Aromatase
- Converts androgens to estrogens
What is aromatase deficiency in men?
- Unable to synthesize estrogens from androgens
- No epiphyseal closure (bone development)
Describe the synthesis of thyroid hormones. PART 1
- 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.
Describe the synthesis of thyroid hormones. PART 2
- 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.
What is goitre?
Enlargement of the thyroid gland
What is Graves disease?
→ Antibodies to the TSH receptor act on the thyroid gland
→ Stimulates excess thyroid hormones and can cause opthalmopathy
What are properties of peptide and protein hormones?
→ Water soluble → cell surface receptors
→ Activate second messengers/ enzymes with cytoplasmic and nuclear effects
What are properties of steroid hormones?
→ Lipophilic
→ Intracellular receptors in cytoplasm or nucleus
→ Receptors are transcription factors
What are the two surface receptors?
→ G protein-linked receptors
→ Tyrosine kinase domains
What is involved in the G protein signalling pathway?
→ Adenyl cyclase
→ cAMP
→ PKA
- Triggered by GPCRs
What is involved in the PIP pathway?
→ PIP
→ DAG and IP3
→ Ca2+
- Triggered by GPCRs
What are the 2 major pathways in tyrosine kinase?
→ RAF/ MEK/ ERK
→ PI3 kinase / AKT
→ JAK/ STAT
Describe the Raf/MEK/ERK1/2 signalling pathway.
- 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
Describe the phosphatidylinositol kinase/AKT signalling pathway.
- Ligand binds, dimerisation of the receptor
- PI3-kinase activates PIP2 and PIP3
- PIP3 activates Akt (Protein Kinase B)
- Akt activates mTOR
What is mTOR a target for?
Cancer drugs
What does mTOR stimulate and inhibit?
STIMULATE: ribosome production, protein synthesis, nutrient uptake and metabolism
INHIBIT: protein degradation
What are two conditions if you have a defective G coupled receptor?
→ Thyroid adenoma - TSH receptor defective
→ Precocious puberty - LH receptor defective
What are 2 conditions if you have a defective G protein?
→ McCune Albright syndrome
activating syndrome causing continuous activation of adenylate cyclase
fibrous dysplasia of bone
cafe au lait pigmentation
Describe steroid hormone (nuclear) receptors.
- Family of transcription factors
Describe the functional regions of the nuclear receptors.
- 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
What is special about the A/B and E/F domains?
Have transcriptional activity
What is a steroid hormone’s C domain made up of?
2 zinc fingers which slot into the helix of the DNA.
How does a steroid hormone act on its cytoplasmic receptor? PART 1
- 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.
How does a steroid hormone act on its cytoplasmic receptor? PART 2
- 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.
