Hormone Synthesis and Action Flashcards
How are protein/peptide hormones synthesised by transcription?
a) Transcription of DNA to RNA
b) Post-transcriptional processing RNA -> mature RNA – excision of introns, modifications of 3’ and 5’ ends
c) Translation of mature RNA into protein using tRNA to transfer amino acids
d) Post-translational processing cleavage of large pre-prohormone, folding of proteins, the addition of sugars (glycosylation)
What are the different stages of protein hormones?
Synthesis of large precursor proteins —> active hormone
Pre-prohormone (signal sequence + prohormone + additional accessory peptide sequences)
The signal sequence will usually direct the larger precursor molecule to the right part of the cell
These get cleaved to form:
Prohormone (hormone + peptide sequence(s))
How is insulin synthesised?
Transcription to mRNA
Excision of introns to messenger RNA
Removal of signal sequence and formation of disulphide bonds in RER.
Pre-proinsulin -> proinsulin
Transfer to Golgi apparatus, excision of C peptide and packaging into secretory granules
So insulin is made by A chain and B chain and held together by disulphide bonds
What glands controlled by the hypothalamic-pituitary axis?
Our hypothalamus will release releasing/inhibiting hormones that act on the anterior pituitary gland which secrete trophic hormones
Thyroid stimulating hormone acts on the thyroid to release T3 and T4 (thyroid hormone)
ACTH acts on the adrenal cortex to release cortisol and aldosterone
LH and FSH act on the gonads to secrete oestrogen/testosterone
How are steroids synthesised from cholesterol?
Processing of cholesterol occur in steroidogenic cell in those glands/gonads
The trophic hormone stimulates the cell to activate second messengers like cAMP to activate a further molecule like protein kinase A
Cholesterol bound to sterol carrier protein- transported to mitochondria
Once it gets synthesised, StAR (steroidogenic acute regulatory protein) protein transports cholesterol to inner mitochondrial membrane (rate limiting)
At this point cholesterol can be cleaved
Cholesterol cleaved to pregnenolone by side chain cleavage enzyme P450scc (rate limiting)
Between mitochondria and smooth endoplasmic reticulum steroids synthesised by hydroxylase enzymes that allow it to be converted to the different steroid hormones
How are thyroid hormones synthesised?
Occurs in the thyroid gland
Upon the action of thyroid stimulating hormone:
1. Active uptake of iodide into follicular cell by an NIS symporter
2. Transport across the apical membrane
3. Oxidation of iodide to iodinated intermediate by thyroid peroxidase (TPO) which is activated by H2O2
4. Iodination of tyrosine residues from thyroglobulin molecule to form MIT (mono-iodinated) or DIT
5. Coupling of iodinated tyrosine residues to produce T3 and T4 (the no. referring to the no. of iodine molecules)
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 by getting cleaved from the thyroglobulin
How does each group of hormones action?
Peptide and protein hormones
Water soluble —–> cell surface receptors
Activate second messengers and/or enzymes
Cytoplasmic and nuclear effects
Steroid and thyroid hormones
Lipophilic ——> intracellular receptors in cytoplasm or nucleus.
Receptors are transcription factors
How do G-protein linked receptors work?
We have a pathway known as the adenyl and cAMP signalling pathway and the phosphoinositide signalling pathway
In the first one, on binding to the receptor we have translocation of the alpha subunit to bind with the adenyl cyclase to activate cAMP which goes on to activate protein kinase A which gets phosphorylated which wither result in phosphorylation of an enzyme or a nuclear effect with activation of transcription
In the second pathway, the alpha subunit binds to the PLC to activate it which will convert PIP2 to PIP3 and PIP3 to DAG where protein kinase C is phosphorylated to activate cytosolic enzymes
PIP3 can be converted to IP3 which can act on the SER to release calcium from intracellular stores
How do tyrosine kinase receptors work?
One class is called the Raf/MEK/ERK1/2 signalling pathway and the PI3 kinase/AKT signalling pathway
In the first one, upon ligand binding, you have a tyrosine kinase receptor that gets phosphorylated which will then go on to activate second messengers
Raf gets phosphorylated then MEK gets phosphorylated and then ERK 1/2 gets phosphorylated to activate transcription factors, mutation of one of those three can cause cancer
In the second one, when the receptor gets phosphorylated, you get phosphorylation of second messengers where AKT gets phosphorylated to activate mTOR which regulates a lot of functions in other cells
These include promoting ribosome production, inhibiting protein degradation, and stimulating nutrient uptake and metabolism
How does the JAK/STAT receptor pathway work?
One last one is called the JAK/STAT pathway involved in our immune system
Upon stimulation, we have dimerisation and phosphorylation of the receptor
The STAT protein will get phosphorylated, ultimately translocate to the nucleus, and bind to response elements to activate transcription
How are steroid hormone receptors structured?
Steroid hormone receptors are a family of transcription factors
Different functional regions of the receptor are defined as domains - A-F
The C domain is the DNA binding region and is highly conserved
The E domain is the ligand-binding domain; ligand sits within the pocket of the ligand-binding domain
Both the A/B domains and E/F domains have transcriptional activity (AF-1/AF-2)
Different steroid receptors are continually being discovered
The C domain is the DNA binding domain
It has 2 zinc fingers that allow that part of the receptor/TF to bind to the DNA
What happens after the thyroid hormone crosses the cell membrane?
Hormone crosses cell membrane
Heat shock protein dissociates from receptor
Hormone binds to receptor and dimerization occurs
Dimerized receptors translocate to the nucleus
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
What are the two types of peptide hormone signalling disorders?
Type 1 – autoimmune destruction of the pancreatic islets: absolute insulin deficiency
Type 2 – insulin resistance, partial loss of insulin production (insulinopenia) – often associated with obesity
What are the disorders of steroid hormone signalling?
Aromatase deficiency in men
Unable to synthesise oestrogens from androgens -> no epiphyseal closure
-> long stature/long bones
Aromatase deficiency in women
Virilisation of XX foetuses so they will have male type characteristics
Clitoromegaly
Ambiguous genitalia with enlarged clitoris
Girls develop male-type characteristics and boys show early sexual development due to excess androgens
Resistance to hormone action: when you cannot respond to steroid hormones
Inactivating mutations of steroid receptors e.g. Androgen receptor (nuclear receptor)
Androgen insensitivity syndrome (AIS)
What are some disorders of thyroid hormone signalling?
Goitre – enlargement of the thyroid gland
Causes of a goitre:
Lack of iodine in the diet leads to deficiency in T3 and T4 (hypothyroidism)
Graves disease (hyperthyroidism)
Thyroid adenoma
Proptosis – bulging of eye
Graves’ Disease Autoantibodies to the TSH receptor act on the thyroid gland, stimulate excess thyroid hormones, and can cause eye disease
Activating mutation of the TSH receptor - a G-protein coupled receptor
