Steroids

Question 1

How is cholesterol synthesised?

Answer 1

cholesterol is synthesised from acetyl CoA in a reaction mediated by HMG-CoA reductase

squalene is converted to squalene epoxide via squalene epoxidase
squalene epoxide is converted to lanosterol via squalene cyclase
lanosterol is converted to cholesterol

Question 2

How does oestradiol bind to its oestrogen receptor?

Answer 2

must be hydrophobic/lipophilic enough to pass through the cell membrane

flat planar aromatic ring must be able to fit into the narrow slit of the active site
- allow hydroxy group to interact with Glu353 and Arg394

hydroxyl group binds to His524

receptor pocket is hydrophobic so hydrophobic skeleton is needed

Question 3

How do steroid bind to DNA? How is it specific to steroids?

Answer 3

steroids bind to receptors found in the cytoplasm
- they diffuse into the cell through the membranes and bind to receptors

receptor-ligand complexes dimerise and migrate to the nucleus where they bind to specific hormone response elements (HRE) on DNA
- they cause gene expression via increasing or decreasing gene transcription and translation

the HRE regions in DNA are highly conserved
- contain structures described as zinc fingers that bind ligands specifically
= mutations in zinc fingers change HRE specificity

Question 4

What are the characteristic features of oestrogens?

Answer 4

oestrone, oestradiol and oestriol

C18 estrane skeleton

flat aromatic A ring

no side chains

Question 5

What are the characteristic features of progesterone?

Answer 5

C21 pregnane skeleton

double bond at position 4
- keto

Question 6

How does oestrogen and progesterone travel in the blood?

Answer 6

oestrogen is bound to sex hormone binding globulin

progesterone is bound to corticosteroid binding globulin

hormone concentration measures free (unbound) steroids
- only unbound steroids are active

Question 7

What are phytoestrogens? What do they do?

Answer 7

phytoestrogens are non-steroidal compounds of plant origin displaying oestrogenic properties

they
- bind to oestrogen receptors
- stimulate oestrogenic response

Question 8

What are the different oestrogen agonists and antagonists?

Answer 8

agonist
- phytoestrogens
- oestradiol
- flavonoids

antagonists
- tamoxifen

Question 9

What are the features of oestrogen agonists that allow binding to oestrogen receptors?

Answer 9

large complementary surfaces between the molecule and receptor

hydrophobic skeleton
= binding pocket is hydrophobic so allows entry and binding

flat aromatic portions
- aromatic ring A in oestradiol and aromatic rings in flavonoids
= allows access to narrow slit in binding pocket allowing hydrophilic portions to bind to amino acids

no side chains
= allows H12 protein to fold and close over the binding pocket

Question 10

What are the features of oestrogen antagonists that block binding to oestrogen receptors?

Answer 10

large complementary surfaces between the molecule and receptor

hydrophobic skeleton
= binding pocket is hydrophobic so allows entry and binding

flat aromatic portions
- aromatic rings in tamoxifen
= allows access to narrow slit in binding pocket allowing hydrophilic portions to bind to amino acids

side chains
= prevents folding of H12 protein over the binding pocket stopping activity

Question 11

What features do oestrogen agonists and antagonists share? How do they differ?

Answer 11

share
- large complementary surfaces between the molecule and receptor
- hydrophobic skeleton
- flat aromatic portions

differ
- antagonists have a side chain while agonists do not
= side chain presence is what blocks activity as it stops H12 protein from closing over the binding pocket in the receptor thereby stopping activity

Question 12

What are characteristics features of androgens?

Answer 12

C19 androstane skeleton
no side chain
double bond at position 4
- keto
17 beta hydroxyl