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Biochem > Exam3Lec6/7CholesterolMetabolism/SteroidHormoneBiosynth > Flashcards

Exam3Lec6/7CholesterolMetabolism/SteroidHormoneBiosynth Flashcards

1
Q

What is the major sterol in the human body?

A

Cholesterol

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2
Q

Chosleterol biosynthesis

A
  1. Cholesterol is dervided from Acetoacetyl-CoA and this generates HMG-CoA using HMG-CoA.
  2. The rate limiting step is HMG-CoA reductase making mavalonic acid.
    3.** HMG reductase is the site of inhibition of statin drug**
  3. So statins are drugs that inhibits cholesterol being made so its taken to improve cholesterol
  4. 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

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3
Q

What is hedgehog and what is required for hedgehog processing to occur?

A

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

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4
Q

What is Smith-Lemli-Opitx Syndrome?

A

This occurs due to a defect in 7-dehydrocholesterol reductase in the choles. biosynthetic pathway.

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5
Q

Why does a lack of cholesterol result in multigenic manifestions from Smoth-Lemi -Opitz syndrome?

A

HH does tissue differentiona so HH can’t mature and undergo embryogenesis

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6
Q

Explain defect in 7-dehydrocholesterol reductase

A

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.

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7
Q

95% of causes of ambiguous genetalia is due to what?

A

21 hydroxylase deficiency
you get ambigous external genitalia
Male: “fine” unless losing salt
Female: clitoral hypertrophy

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8
Q

What is one of the key hallmarks of diagnosing CAH due to 21 hydroxylase deficiency?

A

elevated levels of 17-alphahydroxyprogesterone levels

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9
Q

What are the metabolic characterists of 21-hydoxylase deficiency?

What can be seen in plasma analysis?

A

LOW sodium
HIGH potassium
LOW cortisol
HIGH 17-alphahydroxyprogesteron

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10
Q

What two main steroid hormones do we see in the adrenal cortex?

A

Aldosterone and cortisol

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11
Q

What are three types of steroids?

A

Mineralcorticoids:aldosterone–> Na+ retention/K+ secretion
Glucocorticoids:cortisol–> gluconeogeneis and major regulator
Androgens: testosterone

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12
Q

All steroid hormones are derived from what?

A

Cholesterol

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13
Q

Stucture of cholesterol

A

27C ring where beta on top and alpha on bottom plane. Attachment of fa in chol ester is on OH branching off 3rd carbon.

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14
Q

What are the obligatory requirements for a mixed function oxidase?

A

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.

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15
Q

What is CSCC?

A

cholesterol side chain cleavage= mixed fxn oxidase rxn= 27 desmolase

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16
Q

What consitutes the RLS of biosynthesis of steroid hormone?

A

the conversion of chol to pregnenolone

occurs in the mitochondria

17
Q

Explain the process of cholesterol to pregenolone

A

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

18
Q

What is the cytochrome P450

A

terminal oxidase in mixed fxn oxidative rxn. So it provides the terminal oxygen

19
Q

What are the three zones of the Adrenal cortex? What are they resp for synthesizing?

A
  1. Zona Glomerulosa is the outer most region resp for making aldosterone
  2. Zona Fasciculata is the middle region and is resp. for making cortisol
  3. Zona reticularis is the inner most region and is resp for making androgens
20
Q

Explain adrenal steroidogenesis

A

location: adrenal gland
CYP21A2=21-hydroxylase
We have 3 zones, of which zone 1 and 2 requires CYP21A2 gene.

  1. CYP21A2 is needed in the Zona Glomerulosa to make aldosterone We see HIGH Na+ and LOW K+. SALTY
  2. CYP21A2 is needed in the Zona Fasciculata to make cortisol so there is high gluconeogenesis activity. SWEET
  3. androgen production, determines sex

Salty, Sweet Sex

21
Q

What serves as a hallmark or indication that CYP21A2 is blocked/inhibited

A

accumulation of 17-OH Progesterone

22
Q

If CYP21A2 is blocked in the Zona Glomerulosa what occurs

A

NO aldosterone is being made. So we see LOW Na+ and HIGH K+. This is dehydration

21-hydroxylase deficiency

23
Q

If CYP21A2 is blocked in the Zona Fasciculata, what occurs?

A

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

24
Q

What is congenital adrenal hyperplasia?

A

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)

25
Q

Explain the mechanism of action of ACTH

A
  1. ACTH binds to receptors on the cortex and cellular signaling occrurs, and PKA is activated and chol esters and esterases are made.
  2. Chol is cytosol is transported to the mitochondria for steroid synthesis.
  3. STAR protein helps brings cholesterol into mictochondria.
26
Q

What is StAR protein responsible for?

A

Loading of cholesterol on to active site of chol side chain cleavage system

27
Q

StAR has a very short half-life, what needs to occur?

A

Concomitant protein biosyntheis is required for steriodgenesis . This means that you must have protein synthesis constantly occuring at the same time to make new StAR.

if you put in an inhibitor for protein synthesis, you cant get steroidgenesis

28
Q

Defect in StAR leads to what

A

Congenital Lipoid Adrenal Hyperplasia. Fat globules are surroindong mitchondiria, and can’t load cholesterol into mitochondria

29
Q

In an experiment, we are going incubute isolated cells from a person suffering from congenital adrenal hyperplasia due to 21 hydroxylase def. In the other test tube, you incubate sick adrenal cells with defect in StAR, Which one of the two cell will produce the most steroids collectively.

A

The first one will have more bc if you have a defect in StAR you scrap the whole steriodgenic pathway bc you cant load chol into mitochondria.

30
Q

Explain Biosynthesis of Estrogens

A

Aromatase is the enzyme that turns adrogens (testosterone) to estrogen

you need an adrogen precursor ( testosterone) to make estradiols

31
Q

What is the fxn, RLS, and Location of sterooid synthesis?

A

FXN: produce multiple types of steroids
RLS: conversion of chol. to pregnenolone (CSCC/27-desmolase)
Location:mitochondria

32
Q

Steroidn Synthesis Summary

A
  1. Cholesterol is transported into mitochondria by StAR protein
  2. CSCC/27-desmolase converts cholesterol into pregnenolne through a mixed-function oxidase rxn.
    -occurs 3 times
    -final O2 comes from CP450
  3. Produce steroid hormones based on location
33
Q

____is the precursor of all steroid hormones.

A

Cholesterol

34
Q

___enzyme complex catalyzes the rate-limiting step in steroidogenesis. The enzyme complex is located on the inner mitochondrial membrane.

A

Cholesterol side-chain cleavage(CSCC)

35
Q

CSCC is a mixed- function oxidase which requires ___and ____. _____ erves as the terminal oxidase

A

NADPH, molecular O2, Cytochrome P450SCC

36
Q

___protein plays an important role in the rate-limiting step of steroidogenesis

A

StAR

37
Q

True or False: Different zones of the adrenal gland synthesis different steroid products

A

True

38
Q

The major cause of Congenital Adrenal Hyperplasia is what?

A

a defect in adrenal 21 hydroxylase

39
Q

____is a P-450 catalyzed reaction converting androgens to
estrogens

A

Aromatase

Biochem (17 decks)

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