S1: Hormone Synthesis and Action of Hormones Flashcards
What are the two main hormones synthesised?
- Peptide/Protein hormones
2. Steroids and iondinated tyrosines
What are the characteristics of peptide hormones and steroids and iodinated tyrosines?
Peptide/Protein hormones
- Water soluble
- Made from large precursor molecules (prehormones)
- Can’t transverse plasma membrane –> have to use cell surface receptors
Steroids and Iondinated tyrosines (thyroid hormones)
- Lipid soluble
- Made from low molecular weight precursors
- Can transverse plasma membrane –> bind to intracellular receptors
Describe the generalised scheme for the synthesis of protein/peptide hormones
1) Transcription of DNA to RNA
2) Post transcriptional processing, where the RNA is converted to mature RNA, introns excised, modification of 3’ and 5’ ends
3) Translation of mature RNA into protein using tRNA to transfer the amino acids
4) Post translational processing, cleavage of large pre-hormone, folding of proteins, addition of sugars (glycosylation)
Explain how the protein being translated is directed inside cellular membrane so pieces of the membrane form secretory granules
- There is signal peptide at the (N terminal) of the polypeptide being synthesised by the ribosomes
- Signal peptide binds to SRP (signal recognition protein)
- SRP binds to an SRP receptor on the rough endoplasmic reticulum
- Signal sequence is passed through ER membrane into the lumen of the ER through a protein channel
- The signal peptide sequence is removed by peptidases and protein synthesis continues
Where is the signal peptide found?
The N-terminal of the polypeptide being synthesised by the ribosome
What does signal peptide bind to?
Signal peptide binds to SRP (signal recognition protein)
What does SRP bind to?
SRP binds to an SRP receptor on the rough endoplasmic reticulum
How does signal sequence pass through ER membrane into lumen?
Through protein channel
What is the function of signal peptide?
The signal peptide allows the protein to be incorporated into the lumen of the ER and subsequently the Golgi apparatus.
What is a pre-prohormone?
Signal sequence plus the prohormone
What is a prohormone?
It consists of active hormone and redundant sequence
The signal sequence has been cleaved off from the pre-prohormone
Describe synthesis of insulin
- Transcription to mRNA
- Excision of introns to mRNA
- Removal of signal sequence and formation of disulphide bonds in RER
- Pre-proinsulin to proinsulin
- Tranfer to golgi apparatus
- Excision of C peptide (redundant part of protein)
- Packaging into secretory vesicles
What is the precursor for all steroid hormones?
Cholesterol molecule
Where is cholesterol stored?
Stored in lipid stores in steroid synthesising cells (bound to sterol carrier protein)
What stimulates a cascade involving cAMP and PKA (secondary messengers)?
Trophic hormone
What does stimulation of cAMP and PKA cause?
StAR protein to become active which binds to mitochondrial wall and transports cholesterol to the inner mitochondrial membrane
What happens to cholesterol inside the mitochondria?
There are enzymes that cleave parts of the cholesterol molecule to produce the steroid
What turns cholesterol into prognenolone?
Pregnenolone is the precursor for many steroid molecules.
The side chain cleavage enzyme P450scc (rate limiting step) turns cholesterol into prognenolone.
What enzymes synthesise steroids?
Hydroxylase enzymes–> between the mitochondria and SER
P450
Dehydrogenases
What genes code for P450 and dehydrogenases?
CYP genes
What can prenenolone be converted into?
Progesterone
17aOH Progesterone
What is progesterone converted into?
Aldosterone
What is 17aOH progesterone converted into?
Cortisol
Androgens
What is androgens converted into?
Oestrogens
What enzyme converts androgens into oestrogens?
Aromatase
List some abnormalities in steroid synthesis
- Deficient in aromatase (enzyme) so they cannot synthesis oestrogens from androgens.
In men = no epiphyseal closure in bones so lone stature
In females= male type characteristics
In boys = early excess androgens
This can be a result of mutations to CYP genes
What are thyroid hormones derived from?
Iodinated tyrosines
Explain the synthesis of thyroid hormones
- Active uptake of iodine into a follicular cell (in thyroid gland)
- Transport across apical membrane
- Oxidation of iodide to iodide by thyroid peroxidase (TPO)
- Iodination of tyrosine residues
- Coupling of iodinated tyrosine residues - stored in colloid
- Uptake of thyroglobulin droplets into follicle cell where they can be released and secreted as T3 and T4 hormones stimulated by TSH
What enzyme oxidises iodide to iodine?
Thyroid peroxidase (TPO)
Where are iodinated tyrosine residues stored?
Colloid
What stimulates release of T3 and T4 hormone?
TSH
Thyroid stimulating hormone
What is the apical membrane of follicular cell?
Membrane facing the colloid
What is the basolateral membrane of follicular cell?
Membrane facing the capillary
What is goitre?
Enlargement of the thyroid gland
What is Graves disease?
Antibodies to the TSH receptor can act on the thyroid gland and stimulate excess thyroid hormones causing an eye disease
What happens when peptide and protein hormones bind to cell surface receptors?
This activates secondary messengers/enzymes in the cell and results in cytoplasmic and nuclear effects.
What are most steroid receptors?
Transcription factors which are proteins that bind to DNA and initiate transcription
What are the 2 type receptors that proteins and peptide hormones bind to?
- G protein coupled
2. Tyrosine kinase domains
What are the 2 pathways that proteins and peptide hormones produce with GPCR?
Adenyl cyclase
- Gas pathway
- PKA phosphorylates a binding protein that initiates transcription
Phosphinositide
- Gaq pathway
- Releases calcium
What are the 3 pathways that proteins and peptide hormones produce with Tyrosine kinase receptors?
RAF/MEK/ERK1/2 signalling pathway
- cell growth
- downstream phosphorylation
- Activates transcription
Phosphatidylinositol kinase (PI-3)/AKT signalling pathway - Protein synthesis
JAK/STAT signalling pathway
- downstream phosphorylation
- Activates transcription
What can a defective G protein coupled receptor lead to?
Thyroid adenoma due to TSH receptor mutation (activating mutation, meaning overactivated receptor)
Precocious puberty due to LH receptor (activating mutation)
Hypergonadotrophic hypogonadism (inactivating mutation of LH receptor)
What can a defective G protein lead to?
Pseudohypoparaythyroidism due to PTH receptor (inactivating mutation)
McCune Albright syndrome (activating mutations in G proteins) can involve excess hormone secretions which results in fibrous dysplasia of bone or café au lait skin pigmentation
Combined precocious puberty and hypoparathyroidism due to LH receptor (activating) and PTH receptor (inactivating)
Activating mutation of LH receptor (also a G-protein coupled receptor) can lead to testotoxicosis, high levels of testosterone will stimulate penile growth and growth of pubic hair in young children.
What receptors do steroid hormones act on?
Nuclear/ cytoplasmic receptors that are transcription factors that bind to DNA
-They sit in the nucleus or cytosol
What are the different functional regions of steroid hormone receptors?
Domains A-F
C domain is the DNA binding region and is highly conserved and is important for the protein to interact with
A/B (N terminal) and E/F domains have transcriptional activity
What are zinc fingers?
Part of C domain of the transcription factor that allow it to lock into DNA
Explain steroid cell signalling
- Hormone crosses cell membrane as it is lipid soluble
- Transcription factors (steroid receptors) are found in inactive state in the cytoplasm and they are bound to heat shock protein. This can be displaces when steroid enters the cytoplasm as it has higher affinity
- Dimerisation occurs
- Dimor receptor (hormone receptor complex) translocates to the nucleus where it binds to hormone response element of the DNA
- Transcription is initiated
What keeps nuclear receptors inactive?
Repressor proteins
When binding occurs, these repressor proteins are released and along with other co-activators and co-factors. The chromatin will be opened up and allow for gene transcription.
What is androgen insensitivity syndrome .(AIS)?
Someone unable to respond to steroid hormones
So could have an XY genotype but an XX phenotype (i.e. look like a woman).
What type of hormones are T4/T3?
Amino acid derivatives
