Exam3Lec6/7CholesterolMetabolism/SteroidHormoneBiosynth Flashcards
What is the major sterol in the human body?
Cholesterol
Chosleterol biosynthesis
- Cholesterol is dervided from Acetoacetyl-CoA and this generates HMG-CoA using HMG-CoA.
- The rate limiting step is HMG-CoA reductase making mavalonic acid.
3.** HMG reductase is the site of inhibition of statin drug** - So statins are drugs that inhibits cholesterol being made so its taken to improve cholesterol
- Then we get lanosterol and then finally cholesterol.
HMG-CoA reductase pathwau
de-novo synthesis of cholestero begins with Acetyl coA which then makes acetoacetyl-CoA, Cholesterol is req for biological membranes, bile acid, steroid hormons, and proper embryomic development
HMG-CoA is the RLE in Ketones
What is hedgehog and what is required for hedgehog processing to occur?
A secreted protein involved in embryonic development, developing forebrain, tissue differentiation etc and CHOLESTEROL is required for processing to occur.
HH proteins requre chol from maturation and normal embryonic fxns
What is Smith-Lemli-Opitx Syndrome?
This occurs due to a defect in 7-dehydrocholesterol reductase in the choles. biosynthetic pathway.
Why does a lack of cholesterol result in multigenic manifestions from Smoth-Lemi -Opitz syndrome?
HH does tissue differentiona so HH can’t mature and undergo embryogenesis
Explain defect in 7-dehydrocholesterol reductase
We go from 7-dehydrocholesterol to cholesterol by the 7-dehydrocholesterol reductase enzyme. If there is a defect here, we get a buildup of 7-dehydrocholesterol and no cholesterol is being made. If no cholest is being made, there is no HH processing. If there is no HH processing, Smith-Lemli-Opitx Syndrome can occur and we get different clinical manifestations.
95% of causes of ambiguous genetalia is due to what?
21 hydroxylase deficiency
you get ambigous external genitalia
Male: “fine” unless losing salt
Female: clitoral hypertrophy
What is one of the key hallmarks of diagnosing CAH due to 21 hydroxylase deficiency?
elevated levels of 17-alphahydroxyprogesterone levels
What are the metabolic characterists of 21-hydoxylase deficiency?
What can be seen in plasma analysis?
LOW sodium
HIGH potassium
LOW cortisol
HIGH 17-alphahydroxyprogesteron
What two main steroid hormones do we see in the adrenal cortex?
Aldosterone and cortisol
What are three types of steroids?
Mineralcorticoids:aldosterone–> Na+ retention/K+ secretion
Glucocorticoids:cortisol–> gluconeogeneis and major regulator
Androgens: testosterone
All steroid hormones are derived from what?
Cholesterol
Stucture of cholesterol
27C ring where beta on top and alpha on bottom plane. Attachment of fa in chol ester is on OH branching off 3rd carbon.
What are the obligatory requirements for a mixed function oxidase?
NADPH and Molecular oxygen (O2)
One atom of the O2 goes to substrate, the other goes to water hence the name mixed fxn. Oxidatiom and reduction occurs.
What is CSCC?
cholesterol side chain cleavage= mixed fxn oxidase rxn= 27 desmolase
What consitutes the RLS of biosynthesis of steroid hormone?
the conversion of chol to pregnenolone
occurs in the mitochondria
Explain the process of cholesterol to pregenolone
This requires 3 mixed fxn oxidative pathways on cholesterol.
1. Choles to 22-hydroxycholesterol ( We did CSCC and hydroxylized Chol at position 2)
2. 22-hydroxycholesterol to 20, 22-hydroxycholesterol (we did CSCC at postion 20)
3. 20, 22-hydroxycholesterol to pregnenolone 21 ( we did CSCC and cleaved b/w 20 and 22; which is the side chain of isocaproic aldehyde)
remember that CSCC requires NADPH and O2)
this opccurs in the mitochondria
What is the cytochrome P450
terminal oxidase in mixed fxn oxidative rxn. So it provides the terminal oxygen
What are the three zones of the Adrenal cortex? What are they resp for synthesizing?
- Zona Glomerulosa is the outer most region resp for making aldosterone
- Zona Fasciculata is the middle region and is resp. for making cortisol
- Zona reticularis is the inner most region and is resp for making androgens
Explain adrenal steroidogenesis
location: adrenal gland
CYP21A2=21-hydroxylase
We have 3 zones, of which zone 1 and 2 requires CYP21A2 gene.
- CYP21A2 is needed in the Zona Glomerulosa to make aldosterone We see HIGH Na+ and LOW K+. SALTY
- CYP21A2 is needed in the Zona Fasciculata to make cortisol so there is high gluconeogenesis activity. SWEET
- androgen production, determines sex
Salty, Sweet Sex
What serves as a hallmark or indication that CYP21A2 is blocked/inhibited
accumulation of 17-OH Progesterone
If CYP21A2 is blocked in the Zona Glomerulosa what occurs
NO aldosterone is being made. So we see LOW Na+ and HIGH K+. This is dehydration
21-hydroxylase deficiency
If CYP21A2 is blocked in the Zona Fasciculata, what occurs?
NO cortisol is being made so we see no neg feedback to hypothalamus and pit, so we see HIGH CRH and HIGH ACTH stimulation–> hyperplasia (incr size of gland)
21-hydroxylase deficiency
Body says okay you need more cortisol, so it tell hypthal and ant pit to make more ACTH and CRH and there is a high buildup of this bc CYP21A2 is blocked so we cant make more cortisol. This shunts it dows to make androgens
What is congenital adrenal hyperplasia?
An incr in adrenal activtity due to high ACTH stimulation, incr in cell proliferation, leads to incr size of adrenal gland
Caused by MULTIPLE steroid enzyme deficienies NOT JUST 21-hydroxylase deficiency (but it IS 95% of cases)
