Steroid hormones and nuclear receptors Flashcards
Which enzyme carries out steroid synthesis?
cytochrome p450 system: a a large superfamily of mixed function oxidases.
What is the main job of the cytochrome p450 system?
xenobiotic detox system: oxidizes highly hydrophobic molecules that are otherwise toxic to the cell. This is done in the mito and ER.
Where are cyt p450 system found?
mito and ER
Describe the steps of metabolite (such as lipids and steroid hormones) oxidation by cyt p450.
- CYP contains heme group with iron. Initially iron is oxidized as Fe3+. The CYP protein binds its hydrophobic substrate.
- NADPH CYP reductase moves electrons from NADPH to iron, reducing it and making it ready to accept O2
- The O2 oxidizes the substrate and creates H2O, and the oxidized substrate can leave CYP.
What is another name for nuclear receptors?
txn factors
How is cholesterol transported to the mito for oxidation by CYP?
Once in the cell, StAR transporter (gets across outer mito membrane) and translocator protein TPSO moves cholesterol across the membranes into the mito matrix.
Which steroid hormone precursor does CYP make from cholesterol?
pregnenolone (serves as prohormone to make other steroid hormones)
What are the major signals in steroid hormone synthesis, and what do they do?
- corticotropin releasing hormone made in hypothalamus stimulates anterior pituitary to secrete ACTH
- ACTH stimulate adrenal cortex to release steroid hormones, such as cortisol (steroid hormones can also be made in the sex glands).
- cortisol negatively regulates hypothalamus and anterior pituitary.
How does ACTH hormone stimulate synthesis of steroid hormones?
- ACTH binds G protein coupled receptor, initiating phosphorylation cascade
- cAMP activates PKA cascade, stimulating upregulation of StAR expression and increased cholesterol transport into the mitochondria.
Describe aldosterone.
principal mineralcorticoid produced from progesterone. raises blood pressure and fluid volume, increases sodium uptake.
describe testosterone
male sex hormone synthesized in testes, responsible for secondary male characteristics, produced from progesterone
describe estradiol.
an estrogen, principle female sex hormone synthesized in the ovary, responsible for secondary female sex characteristics
Describe cortisol.
dominant gluccocorticoid. synthesized from progesterone in adrenal cortex. involved in stress adaptation, metabolic energy signal, elevated blood pressure and sodium absorption, effects on immune system.
Where on the chromosome do nuclear receptors bind?
hormone responsive elements. these are distributed across the chromosome.
Describe the synthesis of pregnenolone from cholesterol.
The prohormone pregnenolone is made from the oxidation of cholesterol’s hydrophobic chain by cytochrome p-450SCC. Involves O2. Pregnenolone is therefore less hydrophbic than cholesterol. This takes place in the inner mito membrane
How are estrogens made?
androgens are used as a template to make estrogens, using aromatase to turn the first ring into an aromatic ring. In breast cancer, aromatase is targeted to lower estrogen levels.
What is cortisol binding globulin and what is its purpose?
It is a protein in the blood that allows cortisol to travel throughout the body. This is needed because cortisol is still relatively hydrophobic.
PKA upregulates StAR expression. What other protein involved in cholesterol uptake does it upregulate?
lipoprotein lipases to free up cholesterol from lipid droplet
Describe binding of steroid hormone to nuclear receptor.
The receptor is normally bound to heat shock protein in absence of ligand, keeping it inactive. Once the steroid hormone enters the cell and binds the receptor, HSP is shed and the receptor is activated and translocated to the nucleus via NLS. It then binds to hormone response element on the DNA and elicits a change in protein expression.
How do general and specific txn factors differ?
GTFs are used throughout all of txn and activate promotors at a low, basal level. Specific transcription factors can up/down regulate the levels and rates of protein expression beyond the GTFs.
Describe the structure of a nuclear receptor (specific transcription factor)
- scaffold domain/activation domain for accessory proteins (these will allow the complex to interact with general txn factors)
- DNA binding domain
- hinge
- ligand binding domain
What are the nuclear receptor superfamilies?
- type one: steroid ligands
- type two: ligands are thyroid hormone, vitamin D, retinoic acid, lipid derivatives
- type three: orphan receptors (ligands unknown)
Which is the fight or flight steroid hormone?
cortisole
How does cortisol carry out its function even during low energy?
-It stimulates gluconeogenic enzymes to generate energy for fight or flight. This is why it is called a gluocorticoid.
