Midterm II: Steroid Hormone Synthesis (Ben) Flashcards Preview

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Flashcards in Midterm II: Steroid Hormone Synthesis (Ben) Deck (45)
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1

What kind of reactions are most of the reactions in steroid synthesis?

Catalyzed by what type of enzymes?

And what is the general formula for these rxns?

Hydroxylations catalyzed by CYP450 enzymes

 

2

Where are steroid hormone synthesis reactions located within the cell?

ER or Mitochondria

3

What is the 2nd most frequent reaction type in steroid hormone synthesis?

Via what kind of enzyme + co-factor?

Oxidoreduction reactions

Via dehyrogenase enzymes using NAD+

4

What is the electron donor molecule in the CYP450 enzymes?

And what special part of the enzyme transfers the electrons?

NADPH donates electrons

Heme-iron in CYP450 enzyme transfers electrons twice during the hydroxylation reactions

5

CYP450 needs another enzyme to transfer key elements of the reaction to it.

What is the enyzme?

What does it transfer and how?

CYP450 Reductase

- transfers 2 electrons one by one from NADPH

6

What is the general name of the entire enzyme complex shown here?

Microsomal Electron Transport Chain

- because it consists of the CYP450 reductase enzyme which transfers electrons to the CYP450 enzyme

7

What are the components of the mitochondrial (not microsomal) electron transport chain involved in some CYP450 steroid synthesis reactions?

In what organ is this chain found?

Found on adrenal mitochondria...

Adrenodoxin Reductase - takes electrons from NADPH to adrenodoxin

Adrenodoxin - an iron-sulfur protein which transfers electrons to the CYP450

8

What is the first step in the synthesis of all steroid hormones?

Reactants?

Enyzme?

Product?

(Include # of Cs)

Cleavage of cholesterols side chain...

Reactants: Cholesterol (27C) + 3 NADPH + 3 O2

Enzyme: P450SCC Side Chain Cleavage Enyzme

Product: Pregnenolone + Isocaproaldehyde + 3 NADP+ + 3 H2O

 

9

Why are 3 NADPH used in the side chain cleavage enzyme reaction?

Because it is a 3 step reaction:

  1. Hydroxylation of C22
  2. Hydroxylation of C20
  3. Cleavage of bond between C20 and 22

10

Where is P450SCC located?

the inner mitochondrial membrane

11

How is cholesterol transported into the mitochondria for steroid hormone synthesis?

What is the name of the condition resulting from a lack of the molecule necessary for this?

StAR

(Steroidogenic Acute Regulatory Protein)

- if this is missing = Congenital Lipoid Adrenal Hyperplasia

12

What two hormones signal increased steroid hormone production?

In which tissues?

  1. ACTH - adrenal gland
  2. LH - testes, ovaries

13

How do LH and ACTH induce steroid hormone synthesis?

(One route leading to 2 effects)

induction of cAMP increase

  1. induces StAR activation
  2. activates PKA which phosphorylates/activates cholesterol esterase

14

What two actions does the P450c17 enyzme have?

17-hydroxylase

and 

17,20 lyase

15

What two reactions are performed by the 17 hydroxylase activity of the P450c17 enzyme?

 

Pregnenolone ----> 17OH Pregnenolone

Progesterone ----> 17OH Progesterone

16

What two reactions are performed by the 17,20-lyase activity of P450c17?

17OH Pregnenolone ---> DHEA (dehydroepiandrosterone)

17OH Progesterone ---> androstenedione

17

What 3 reactions are catalyzed by 3-Hydroxysteroid Dehydrogenase (3OHSDH)?

And what happens in these reactions?

Transfers double bond from B ring to A ring + dehydrogenates the 3-OH

Pregnenenolone ---> Progesterone

17OH Pregnen ---> 17 OH Progest

DHEA ---> Androstenedione

 

18

What is the activity of the P450c21 enyzme?

21 hydroxylase

- hydroxylates the LAST carbon of progesterone and 17OH progesterone

19

What two reactions does P450c21 perform via its 21-OHase activity?

Progesterone ---> 11-Deoxycorticosterone

17OH Progesterone ---> Deoxycortisol

20

What one enzyme catalyzes two different reactions with 3 different activities to make a final product of steroid hormone synthesis?

Aldosterone Synthase

  1. Reactions:
    • 11-deoxycorticosterone > corticosterone
    • corticosterone > aldosterone
  2. Activities:
    • 11-hydroxylase
    • 18-hydroxylase
    • 18-dehydrogenase

21

Where is aldosterone synthase found (specific cell layer) and what kind of hormone does it produce?

What gene encodes it?

- found in the zona glomerulosa

- produces mineralocorticoid (specifically aldosterone)

- encoded by CYP11B2

22

Lack of which enzyme/enzyme activities determines the production of only mineralocorticoids by the zona glomerulosa?

P450c17

with its 17-OHase and 17,20 Lyase activities

- this keeps steroid synthesis in the glomerulosa to the pregnenolone-to-aldosterone path only

23

What gene/enyzme performs the last reaction in the glucocorticoid path?

11-Hydroxylase

encoded by CYP11B1

(does not have 18-OHase/DHase activity of CYP11B2)

24

What is the last reaction in the glucocorticoid pathway?

11-Deoxycortisol ---> Cortisol

via CYP11B1 gene's 11-Hydroxylase activity

25

In what cells does the CYP11B1 gene express the glucocorticoid-producing enzyme with only 11-OHase activity?

Zona Fasciculata

and

Zona Reticularis

26

Where do the reactions for the synthesis of mineralocorticoids take place?

(starting from pregnenolone)

(2 locations)

  1. ER surface
    • Pregnen > Progest
    • Progest > 11-deoxycorticosterone (DOC)
  2. Inner Mitochondrial Membrane
    • DOC > Corticosterone
    • Corticosterone > Aldosterone

27

Which enzyme activities are preferred in the zona fasciculata?

And thus what are its primary products?

 

21-OHase / P450c21

- so reactions proceed in the direction of glucocorticoids (cortisol)

 

- weak mineralocorticoids (ie corticosterone) can also be made, BUT the zona fasciculata lacks 18-OHase/Dehydrogenase activity so aldosterone can't be made

28

Which enyzme activity is preferred in the zona reticularis?

And thus what are its primary products?

17,20 Lyase activity

- reactions proceed in the direction of weak androgens

 

29

Where within the cells of the zona fasciculata/reticularis are the main products of these cells made?

  • Fasciculata - cortisol/corticosterone are completed on the mitochondrial inner membrane (but made on the ER until their DOC/11-deoxycortisol intermediates)
  • Reticularis - weak androgens are completed on the ER surface

30

What is adrenarche?

development of the zona reticularis around age 10-11

- this is seen enzymatically as an increase in 17,20-Lyase activity

- results in 100-fold increase in weak androgen (DHEA) production