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Biochem > Cholesterol Biosynthesis > Flashcards

Cholesterol Biosynthesis Flashcards

1
Q

Properties of cholesterol (5)

A
  • steroid nucleus
  • very hydrophobic
  • OH group that can H bond with membrane phospholipids
  • precursor for steroid hormones, bile salts, vitamin D
  • component of membranes
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2
Q

major site of cholesterol biosynthesis

A

Liver

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3
Q

Requirements for cholesterol biosynthesis (3)

And why need each

A
  1. Acetyl CoA- hydrolysis of high energy thioester bonds
  2. ATP- for formation of activated isoprene units (activation step)
  3. NADPH
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4
Q

Where does the NADPH come from?

A

Pentose phosphate pathway

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5
Q

STEP 1

A

Joining 3 acetyl CoA molecules

Acetyl CoA + Acetyl CoA —> Acetoacetyl CoA (enzyme: thiolase)

Acetoacetyl CoA + Acetyl CoA —> HMG-CoA (enzyme: HMG-CoA synthase)

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6
Q

STEP 2

A

RATE LIMITING STEP

HMG-CoA + 2 NADPH + 2 H+—> Mevalonate + 2 NADP+ + CoA

Enzyme: HMG-CoA reductase

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7
Q

Step 4

A

Formation of Activated Isoprene Units

Mevalonate + 3 ATP —> 3-isopentenyl pyrophosphate + Pi + CO2

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8
Q

Isoprene units = _____ carbons

A

5

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9
Q

_____ ATP consumed to make 1 activated 5-C isoprene unit

A

3

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10
Q

What is the significance of forming the activated isoprene units?

A

Shortcut to making steroid nucleus

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11
Q

What contains isoprene units in the ETC?

A

CoQ

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12
Q

Drug ppl take to lower cholesterol

A

Statin drugs

Have to take CoQ supplement to combat muscle weakness

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13
Q

Statin mechanism

A

Competitive inhibitor of HMG-CoA reductase

Cannot make isoprene units therefore cannot make cholesterol

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14
Q

Step 4

A

3-isopentenyl pyrophosphate dimethylallyl pyrophosphate

*Both isomers are used in next step

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15
Q

Step 5

A

Condensation reactions:
- Start building the steroid nucleus by joining activated 5-C units —>

End product: 30-C squalene

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16
Q

What drives the condensation reactions?

A

Hydrolysis of PPi molecules

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17
Q

5-C units =

A

Dimethylallyl pyrophosphate

Isopentenyl pyrophosphate

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18
Q

10-C unit =

A

Geranyl pyrophosphate

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19
Q

15-C unit

A

Farnesyl pyrophosphate

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20
Q

Step 6

  • Where?
  • Requires?
  • Doing what?
A

Cyclization & Hydroxylation Reactions:

  • Occurs in smooth ER of liver
  • Requires O2 for OH group and NADPH
  • Completing the ring structure
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21
Q

Major regulated enzyme in cholesterol biosynthesis

A

HMG-CoA Reductase

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22
Q

__________ regulates the degradation and synthesis of HMG-CoA reductase

A

CHOLESTEROL

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23
Q

3 mechanisms of HMG-CoA regulation

A
  1. Hormonal
  2. Degradation
  3. Transcription and translation
24
Q

In fasted state, HMG-CoA reductase is ___________ and ____________

A

phosphorylated and INACTIVE

25
Q

In fasted state, glucagon and sterols activate ____________ which:

A

activate AMPK (also activated by AMP)

—> phosphorylates HMG-CoA reductase to inactivate it

26
Q

In fed state, HMG-CoA reductase is _________ and ________

A

Dephosphorylated and ACTIVE

27
Q

In fed state, insulin stimulates _____________ which:

A

A phosphatase

—> removes the phosphate and activates HMG-CoA reductase

28
Q

Degradation of HMG-CoA reductase depends on?

A

Cholesterol level

If high cholesterol level —> degrade HMG-CoA reductase

29
Q

Transcription and translation of HMG-CoA reductase is controlled by?

A

Cholesterol levels

If high cholesterol levels —> complex does not move to Golgi

30
Q

Within the ER there are ?

A

2 integral membrane proteins

SCAP
SREBP

31
Q

SCAP

A

Senses levels of cholesterol in liver

32
Q

2 domains of SREBP

A
  1. Regulatory - normally interacts with SCAP
  2. DNA binding - binds to DNA
    * functions as transcription factor
33
Q

If cholesterol levels fall —>

A

Entire SCAP + SREBP complex migrates to Golgi

34
Q

2 proteolytic enzymes in the Golgi

A
  1. Serine protease

2. Metalloprotease

35
Q

Serine protease

A

Cuts loop on SREBP the spans into the lumen

—> separates regulatory and DNA binding domain

36
Q

Metalloprotease

A
  • requires zinc

Cuts at intersection of alpha-helix and loop that connects the DNA binding domain

—> frees up DNA binding domain to travel to the nucleus

37
Q

What happens in the nucleus?

A

DNA binding domain binds to SRE (sterol response element)

—> increases transcription of HMG-CoA reductase gene

38
Q

Lovastatin (mevinolin)

A
  • Blocks HMG-CoA reductase and prevent cholesterol synthesis
  • Is an (inactive) lactone
  • In body, lactone is hydrolyzed to mevinolinic acid which is a competitive inhibitor of HMG-CoA reductase because it looks very similar to Mevalonate
39
Q

How is cholesterol transported to tissues in the body?

A

LDL

40
Q

LDL is from?

A

VLDL

When newly synthesized TG are unloaded —> VLDL becomes a little heavier —> VLDL becomes IDL —> eventually LDL

41
Q

HDL function?

A

Reverse cholesterol transport

- removes excess/damaged cholesterol from cells and returns to liver

42
Q

Triglyceride and protein content of carrier molecules

A

(MOST TG) Chylomicron —> VLDL —> IDL —> LDL —> HDL (LEAST TG)

Reverse for protein

43
Q

With age, total cholesterol _____ and HDL levels _______

A
  • Cholesterol rises

- HDL levels may fall

44
Q

Regular exercise is known to

A

Raise HDL levels

45
Q

Low fat diet

A

Reduces serum cholesterol levels

46
Q

Trans-fat

A

Raises LDL and lowers HDL

47
Q

Saturated fat

A

Raises LDL and does not affect HDL

48
Q

2 ways that cholesterol regulates it own biosynthesis

A
  1. Concentration of LDL receptors determined by need for cholesterol
  2. Regulates HMG-CoA reductase synthesis/degradation
49
Q

More cholesterol in circulation —> _____________ _____ receptor synthesis

A

Increase LDL receptor synthesis

50
Q

Usually ppl who have trouble regulating cholesterol have an issue with (2)

A
  1. LDL receptor

And/or

  1. regulation of HMG-CoA reductase
51
Q

LDL receptor structure

A
  • Single transmembrane protein
  • Majority faces outside
  • LDL binding domain is on N-terminus
  • Has a cytosolic domain
52
Q

Homozygous individuals =

Result?

A

No LDL receptors

—> high levels of LDL
—> familial hypercholesterolemia

53
Q

Heterozygous individuals =

A

1/2 levels of LDL receptors

54
Q

What happens when there are mutations in the LDL receptor?

A

Cholesterol is not getting into cells and there is no feedback to stop its biosynthesis —> liver thinks there is not enough cholesterol so it makes it…

55
Q

How does LDL receptor work?

A

Receptor-mediated endocytosis

  • feedback control *
56
Q

Process of receptor mediated endocytosis

A

Receptors cluster in region called coated pits that have high conc of protein clathrin —> LDL binds to receptor —> membrane invaginates to form a vesicle —> vesicle fused with endosomal compartment with a slightly lower pH —> drop in pH separates the LDL receptor and LDL particle —> cholesterol unloaded

57
Q

When LDL is brought into liver cell:

A
  1. Decrease cholesterol synthesis
  2. HMG-CoA reductase activity and synthesis decreases
  3. Increase degradation of HMG-CoA reductase

Biochem (15 decks)

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