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Biochemistry II > Steroids (Ben) > Flashcards

Steroids (Ben) Flashcards

1
Q

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?

A

Hydroxylations** catalyzed by **CYP450 enzymes

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2
Q

Where are steroid hormone synthesis reactions located within the cell?

A

ER or Mitochondria

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3
Q

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

Via what kind of enzyme + co-factor?

A

Oxidoreduction reactions

Via dehydrogenases** using **NAD+

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4
Q

What is the electron donor molecule in the CYP450 enzymes?

And what special part of the enzyme transfers the electrons?

A

NADPH donates electrons

  • Heme-iron in CYP450 enzyme transfers electrons twice during the hydroxylation reactions
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5
Q

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

What is the enyzme?

What does it transfer and how?

A

CYP450 Reductase

  • transfers 2 electrons** **one by one from NADPH
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6
Q

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

A

Microsomal Electron Transport Chain

  • because it consists of the CYP450 reductase enzyme which transfers electrons to the CYP450 enzyme
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7
Q

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?

A

Found on adrenal mitochondria…

Adrenodoxin Reductase - takes electrons from NADPH to adrenodoxin

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

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8
Q

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

Reactants?

Enyzme?

Product?

(Include # of Cs)

A

Cleavage of cholesterols side chain…

P450SCC Side Chain Cleavage Enyzme

Cholesterol (27C) + 3 NADPH + 3 O2 →
Pregnenolone (21C) + Isocaproaldehyde + 3 NADP+ + 3 H2O

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9
Q

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

A

Because it is a 3 step reaction:

  1. Hydroxylation of C22
  2. Hydroxylation of C20
  3. Cleavage of bond between C20 and 22
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10
Q

Where is P450SCC located?

A

the inner mitochondrial membrane

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11
Q

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?

A

StAR

(Steroidogenic Acute Regulatory Protein)

  • if this is missing = Congenital Lipoid Adrenal Hyperplasia
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12
Q

What two hormones signal increased steroid hormone production?

In which tissues?

A
  1. ACTH - adrenal gland
  2. LH - testes, ovaries
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13
Q

How do LH and ACTH induce steroid hormone synthesis?

(One route leading to 2 effects)

A

induction of cAMP increase

  1. induces StAR activation
  2. activates PKA which phosphorylates/activates cholesterol esterase
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14
Q

What two actions does the P450c17 enyzme have?

A

17-hydroxylase

and

17,20 lyase

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15
Q

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

A
  • Pregnenolone → 17OH Pregnenolone
  • Progesterone → 17OH Progesterone
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16
Q

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

A
  • 17OH Pregnenolone → DHEA (dehydroepiandrosterone)
  • 17OH Progesterone → androstenedione
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17
Q

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

And what happens in these reactions?

A

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

  • Pregnenenolone → Progesterone
  • 17OH Pregnen → 17 OH Progest
  • DHEA → Androstenedione
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18
Q

What is the activity of the P450c21 enyzme?

A

21 hydroxylase

hydroxylates the LAST carbon of progesterone and 17OH progesterone

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19
Q

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

A
  • Progesterone → 11-Deoxycorticosterone
  • 17OH Progesterone → Deoxycortisol
20
Q

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

A

Aldosterone Synthase

  1. 11-hydroxylase
    11-deoxycorticosterone > corticosterone
  2. 18-hydroxylase/dehydrogenase
    corticosterone > aldosterone
21
Q

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

What gene encodes it?

A
  • found in the zona glomerulosa
  • produces mineralocorticoid (specifically aldosterone)
  • encoded by CYP11B2
22
Q

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

A

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
Q

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

A

11-Hydroxylase

encoded by CYP11B1**

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

24
Q

What is the last reaction in the glucocorticoid pathway?

A

11-Deoxycortisol → Cortisol

via CYP11B1 gene’s 11-Hydroxylase activity

25
Q

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

A

Zona Fasciculata

and

Zona Reticularis

26
Q

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

(starting from pregnenolone)

(2 locations)

A
  1. ER surface
    • Pregnen > Progest
    • Progest > 11-deoxycorticosterone (DOC)
  2. Inner Mitochondrial Membrane
    • DOC > Corticosterone
    • Corticosterone > Aldosterone
27
Q

Which enzyme activities are preferred in the zona fasciculata?

And thus what are its primary products?

A

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
Q

Which enyzme activity is preferred in the zona reticularis?

And thus what are its primary products?

A

17,20 Lyase activity

  • reactions proceed in the direction of weak androgens
29
Q

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

A
  • 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
Q

What is adrenarche?

A

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
31
Q

What are the 3 mechanisms that favor 17,20-Lyase activity?

A
  1. High [CYP450 Reductase]/[P450c17] ratio
  2. Cytochrome B5 - allosterically increases the reductase-to-P450c17 electron donation efficiency
  3. Phosphorylation - of Ser/Thr residues on P450c17
    • only 17,20-lyase, not 17-OHase enhancement
32
Q

What are the general effects of aldosterone?

What organ/part of the organ and how?

A

Kidney Collecting Ducts

Increases expression of…

  • Na/K-ATPase
  • Na + K Channels
  • H+-ATPase

Resulting in…

  • Na+ reabsorption
  • K+ secretion
  • H+ secretion
33
Q

What are signs of aldosterone excess?

And deficiency?

A

Excess:

  • hypertension
  • hypokalemia
  • alkalosis

Deficiency:

  • water/salt loss
  • hyperkalemia
  • acidosis (high H+)
34
Q

What is the receptor for aldosterone?

A

Mineralocorticoid Receptor

(Steroid Receptor Type I)

35
Q

What is steroid receptor promiscuity?

A

tendency of multiple different steroid hormones to bind to the mineralocorticoid receptor

36
Q

How is the problem of steroid receptor “promiscuity” solved?

Hint: an enzyme

A

11βOH-steroid dehydrogenase 2

inactivates cortisol (→ cortisone) and corticosterone (→ 11-dehydrocorticosterone) using NAD+

BUT: doesn’t affect aldosterone

  • on the ER’s cytosolic surface
  • present in mineralocorticoid target cells
37
Q

What is the condition which results from deficiency of 11βOH Steroid Dehydrogenase 2?

A

Apparent Mineralocorticoid Excess

  • hypertension + hypokalemia, BUT…

low aldosterone levels + high cortisol/cortisone in urine

38
Q

What enzyme opposes the “prereceptor specificity” effects of the enzyme protecting mineralocorticoid receptors from excess stimulation?

What is its purpose?

A

11βOH Steroid Dehydrogenase 1 (on the ER lumen surface)

  • reduces inactive cortisone to active cortisol within cortisol target cells
  • uses NADPH and H+
39
Q

What 3 factors contribute to aldosterone production and secretion?

A
  1. Stress - via ACh + ACTH (Ca2+ + cAMP increases)
  2. Hypovolemia - angiotensin II —> Ca2+ increase
  3. [K+]EC Increase - Ca2+ influx
40
Q

What are some effects of cortisol?

On carbohydrate metabolism?

Lipid metabolism?

Protein metabolism?

Other effects?

A

Carbs:

  • glucose oxidation decrease
  • gluconeogenesis increase (via PEPCK)
  • liver glycogen increase

Lipids:

  • plasma FFA increase

Proteins:

  • proteolysis increase

Other:

  • immunosuppresion
  • osteoporosis (negative Ca2+ balance)

​

41
Q

What is the condition of excess cortisol called?

Symptoms?

A

Cushing Syndrome

  • symptoms basically relate to cortisol effects
  • impaired glucose tolerance
  • visceral obesity
  • muscle atrophy
  • osteoporosis
  • infections (due to immunosuppression)
42
Q

What is the condition of deficiency of cortisol called?

Symptoms?

A

Adrenal Cortex Insufficiency

  • Low BP
  • Dehydration
  • K+ increase
  • Na+ decrease
  • Exhaustion
  • Impaired hair growth
43
Q

What two main factors stimulate cortisol production?

Via what hormone?

And what 2nd messenger?

A
  1. Stress
  2. CRH from hypothalamus
  • Both release ACTH
  • ACTH increases z. fascicularis cAMP
44
Q

What 3 mechanisms promote tissue-specific action of glucocorticoids?

A
  1. Pre-receptor Specificity - via 11β-HSD1/2
  2. Different Receptor Isoforms - of glucocorticoid receptor
  3. Co-activators/Repressors - modify effects of hormone in different tissues
45
Q

What is the condition resulting from a hereditary defect in cortisol synthesis?

A

Congenital Adrenal Hyperplasia

  • most commonly… deficiencies of 21-OHase or 11-β Hydroxylase
  • no cortisol to suppress ACTH secretion leads to adrenal hyperplasia

Biochemistry II (16 decks)

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