Lecture 2 - synthesis, release, metabolism (Pt. 2) Flashcards
What is a pro-hormone?
Protein synthesized as a large, inactive precursor molecule
e.g. insulin, glucagon
Why are some hormones produced into pro-hormones?
Circulate as inactive molecules but can be cut into several pieces, capable of acting on several different target tissues
- advantageous when these proteins are required at the same time all around the body
Where in the cell are steroid hormones synthesized?
testis, ovary, adrenal cortex
- on the smooth ER and adrenal mitochondria
What is the main enzyme system involved in steroid hormone synthesis?
Cytochrome P450
- al derived from stepwise conversion of cholesterol (involves several hydroxylation and cleavage phases)
How are eicosanoids produced?
Produced locally in cell membranes from arachidonic acid (which is derived from phospholipids)
- act locally in the body (paracrine or autocrine)
What are the functions of eicosanoids?
- stimulate inflammation
- regulate blood flow
- blood clot formation
- affect ion transport
- modulate synaptic transmission
Describe 3 major control pathways for synthesis and release of hormones?
- trophic hormones
- hypothalamus –> pituitary –> target glands - nervous stimuli
- neuroendocrine transduction - integration of nervous and endocrine systems (e.g. light, smell, sound, temperature, stress) - metabolite levels
- glucose –> insulin, glucagon
- AA –> somatotropin
- extracellular calcium –> PTH and calcitonin
Explain how and why carrier proteins are important in modulating the function of lipophilic hormones?
Lipophilic hormones = steroid and thyroid
Carrier proteins = hormone reservoir/buffer, protection and control mechanism –> controls hormone release
- most hormones circulate bound to carrier
- unbound = active, but susceptible to degradation
- carriers play a role in feedback process (free vs. bound as required)
Outline the pathways for degradation and inactivation of peptide hormones
Degraded by peptidases (e.g. cathepsin), mainly in lysosomes of target cells
- endopeptidases degrade at specific internal sites
- exopeptidase degrade from end, one AA at a time
Deamination/reduction of disulphide bonds occurs in target cells (liver, kidney)
Outline the pathways for degradation and inactivation of steroid hormones
Need to be dissociated from carrier
2 step degradation process occurring mainly in kidney and liver
Phase 1: Inactivation
- introduction of extra functional groups by cytochrome P450
Phase 2: increase water solubility
- conjugation to sulfate or glucuronic acid
- increased solubility –> excreted in urine (kidneys) or in bile salts (liver)
Describe the potential roles of sulfation in regulating steroid hormone function
Act to store steroid hormones
- longer half life due to increased binding to plasma proteins
- decreased accumulation of sulfoconjugate in fatty tissue
- sulfatase enzymes regenerate free steroids at target tissues
Not just a degradation product but involved in maintenance as well
Describe the mechanism for the synthesis of protein hormones and the process of movement and processing of newly synthesized protein in the cell
DNA (containing exons = coding region, and introns = spacers helping with stability)
-undergo transcription
RNA transcript
- 5’ capping and RNA splicing
- 3’ poly-adenylation
mRNA
- exported to cytoplasm
- undergo translation
Protein (consisting of a chain of AA)
- post translational modifications –> glycosylation = addition of carbohydrate chains (in golgi apparatus) and phosphorylation = addition of phosphate (by kinases)
In order to be modified, packaged and secreted, protein must be directed to the ER and golgi by signal peptides
- hydrophobic (NP) sequence at the NH2 end of protein
Describe the synthesis of thyroid hormones
Occurs in the thyroid gland
- stimulated by TSH released from the anterior pituitary (released in response to TSH releasing hormone produced from the hypothalamus)
- synthesized by iodination of tyrosine residues in the Tgb protein
- proteases degrade Tgb –> T3 and T4
Discuss factors which regulate hormone release and hormone metabolism and excretion
Steroids are not stored but released immediately to diffuse out of cell vs. Protein and peptide hormones are stored in granules within the gland are are released in response to various stimuli
- Trophic hormone can stimulate hormone release (e.g. FSH and LH –> gonadal steroids)
- In response to nervous stimuli from environmental cues (light, smell, sound, temperature) - neuroendocrine transduction = integration between nervous and endocrine systems
- In response to various metabolites (e.g. glucose –> insulin, glucagon) = stimulus-response coupling
Hormones must be metabolized rapidly and removed so feedback mechanisms can operate and hormones can regulate cell functions
- removal or inactivation follows exponential decay kinetics- half life = measure of the longevity of hormone action
