Hormone synthesis and action Flashcards
State a disorders of thyroid hormone signalling?
Goitre- enlargement of thyroid gland
What receptor do steroid and thyroid hormones act on and describe their effect?
Lipophilic -> Act on intracellular receptors in cytoplasm
or nucleus by crossing cell membrane
Receptors are transcription factors
State a disorder of steroid hormone signallign
Aromatase deficiency
Describe the overall synthesis of insulin?
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
State disorders of steroid receptor signalling?
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)
Describe the overall process for the synthesis of thyroid hormones?
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
State a disorder of steroid hormone signalling in men?
Aromatase deficiency in men
Unable to synthesise oestrogens from androgens -> no epiphyseal closure ->long stature
Boys show early sexual development due to excess androgens
Describe the 1st change that occurs after the synthesis of a large precursor protein
into an active hormone?
Pre-prohormone is converted into prohormone (hormone + peptide sequence).
- Signal sequence is cleaved
What receptor do peptide and protein hormones act on and describe their effect?
Water soluble -> Act on cell surface receptors
- Activate second messengers and/or enzymes
- Lead to Cytoplasmic and nuclear effects
What molecules are steroids and iodinated tyrosines hormones are made from
Low molecular weight precursors
State the structural organisation of nuclear/steroid hormone receptors?
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
How is goitre caused by?
Lack of iodine in the diet leads to deficiency in T3 and T4 (hypothyroidism) Graves disease (hyperthyroidism) Thyroid adenoma
Goitre- enlargement of thyroid gland
State the 2 secondary messengers involved in GPCR from protein/ peptide hormones
with their effect pathway
Adenyl Cyclase
Phospholipase C
Kinases can activate enzymes or transcription factors
State what hormones are released each gland controlled by the hypothalamic-
pituitary axis/
Thyroid= T3/T4
Adrenal cortex= Aldosterone/cortisol
Gonads= Oestrogen/ testosterone
Describe the strcture of the C region of the steroid hormone/nuclear receptor?
The DNA binding region (C) is made up of 2 zinc fingers which can slot into the helix of the DNA
What is a similarity between peptide, steroid and thyroid hormones?
They all can activate gene transcription
Describe the overall pathway for steroid synthesis from cholestrol?
Describe the control of steroid synthesis from cholestrol?
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
Name the cell surface receptors that protein/peptide hormones bind to?
1) G-protein linked receptors (require G protein guanosine to bind)
2) Receptors with or associated with tyrosine kinase domains
State the name and structure of the large precursor protein once formed?
Pre-prohormone (signal sequence + prohormone)
- Composed of signal + hormone + Peptide sequence
Signal sequence used to direct molecule to right part of cell
State the prohormone processing into active endothelin peptide
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)
How can obesity lead to atherosclerosis?
Obesity drives the development of insulin resistance which is associated with cardiovascular risk factors and atherosclerosis
CVS factors include inflammation, endothelial dysfunction, hypertension
Why is it important to know about hormones, receptors and their signalling pathways?
To understand endocrine disorders and to provide targets for the development of new drugs
State the type of solubility peptides/protein hormones have
vs steroids and iodinated tyrosines hormones?
Peptides and proteins: Water soluble
Steroids and iodinated tyrosines: Lipid soluble
What are the receptors for steroid hormones?
Family of transcription factors
Known as nuclear receptors
State the 5 signalling pathways for protein and peptide hormones in category?
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
State the steroid hormones that can be formed from cholestrol?
Aldosterone
Cortisol
Oestrogen
Androgen
Progestrone
What does Graves’ disease lead to?
Autoantibodies to the TSH receptor act on the thyroid gland, stimulate excess thyroid hormones
- can cause eye disease (Proptosis - bulging of eyes)
How does thyroid adenoma occur by?
Activating mutation of the TSH receptor - a G-protein coupled receptor
- Leads to hyperthyroidism
What molecules are peptides and protein hormones are made from
Large precursor molecules- prohormones
State a disorder of steroid hormone signalling in women?
Aromatase deficiency in women
- Virilisation of XX fetuses
- Clitoromegaly
- Ambiguous genitalia
Girls develop male-type characteristics
State the 4 stages involved in the synthesis of protein/peptide hormones
via transcription?
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)
Describe the mechanism of steroid hormone binding to its receptor?
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
State disorders of protein/peptide hormone signalling?
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
What processes are steroid receptors involved in?
Transactivation
Dimerization
DNA binding
Ligand binding
Nuclear localization signal
