Step 6 - Where? - Requires? - Doing what?

Cyclization & Hydroxylation Reactions: - Occurs in smooth ER of liver - Requires O2 for OH group and NADPH - Completing the ring structure

Cholesterol Biosynthesis Flashcards by Lindsay Roethke

Properties of cholesterol (5)

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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major site of cholesterol biosynthesis

Liver

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Requirements for cholesterol biosynthesis (3)

And why need each

Acetyl CoA- hydrolysis of high energy thioester bonds
ATP- for formation of activated isoprene units (activation step)
NADPH

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Where does the NADPH come from?

Pentose phosphate pathway

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STEP 1

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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STEP 2

RATE LIMITING STEP

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

Enzyme: HMG-CoA reductase

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Step 4

Formation of Activated Isoprene Units

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

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Isoprene units = _____ carbons

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

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What is the significance of forming the activated isoprene units?

Shortcut to making steroid nucleus

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What contains isoprene units in the ETC?

CoQ

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Drug ppl take to lower cholesterol

Statin drugs

Have to take CoQ supplement to combat muscle weakness

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Statin mechanism

Competitive inhibitor of HMG-CoA reductase

Cannot make isoprene units therefore cannot make cholesterol

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Step 4

3-isopentenyl pyrophosphate dimethylallyl pyrophosphate

*Both isomers are used in next step

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Step 5

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

End product: 30-C squalene

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What drives the condensation reactions?

Hydrolysis of PPi molecules

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5-C units =

Dimethylallyl pyrophosphate

Isopentenyl pyrophosphate

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10-C unit =

Geranyl pyrophosphate

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15-C unit

Farnesyl pyrophosphate

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Step 6

Where?
Requires?
Doing what?

Cyclization & Hydroxylation Reactions:

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

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Major regulated enzyme in cholesterol biosynthesis

HMG-CoA Reductase

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__________ regulates the degradation and synthesis of HMG-CoA reductase

CHOLESTEROL

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3 mechanisms of HMG-CoA regulation

Study These Flashcards

Hormonal
Degradation
Transcription and translation

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

Study These Flashcards

phosphorylated and INACTIVE

In fasted state, glucagon and sterols activate ____________ which:

activate AMPK (also activated by AMP) —> phosphorylates HMG-CoA reductase to inactivate it

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

Dephosphorylated and ACTIVE

In fed state, insulin stimulates _____________ which:

A phosphatase —> removes the phosphate and activates HMG-CoA reductase

Degradation of HMG-CoA reductase depends on?

Cholesterol level If high cholesterol level —> degrade HMG-CoA reductase

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

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

Within the ER there are ?

2 integral membrane proteins SCAP SREBP

SCAP

Senses levels of cholesterol in liver

2 domains of SREBP

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

If cholesterol levels fall —>

Entire SCAP + SREBP complex migrates to Golgi

2 proteolytic enzymes in the Golgi

1. Serine protease | 2. Metalloprotease

Serine protease

Cuts loop on SREBP the spans into the lumen —> separates regulatory and DNA binding domain

Metalloprotease

- 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

What happens in the nucleus?

DNA binding domain binds to SRE (sterol response element) —> increases transcription of HMG-CoA reductase gene

Lovastatin (mevinolin)

- 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

How is cholesterol transported to tissues in the body?

LDL

LDL is from?

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

HDL function?

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

Triglyceride and protein content of carrier molecules

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

With age, total cholesterol _____ and HDL levels _______

- Cholesterol rises | - HDL levels may fall

Regular exercise is known to

Raise HDL levels

Low fat diet

Reduces serum cholesterol levels

Trans-fat

Raises LDL and lowers HDL

Saturated fat

Raises LDL and does not affect HDL

2 ways that cholesterol regulates it own biosynthesis

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

More cholesterol in circulation —> _____________ _____ receptor synthesis

Increase LDL receptor synthesis

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

1. LDL receptor And/or 2. regulation of HMG-CoA reductase

LDL receptor structure

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

Homozygous individuals = Result?

No LDL receptors —> high levels of LDL —> familial hypercholesterolemia

Heterozygous individuals =

1/2 levels of LDL receptors

What happens when there are mutations in the LDL receptor?

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...

How does LDL receptor work?

Receptor-mediated endocytosis * feedback control *

Process of receptor mediated endocytosis

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

When LDL is brought into liver cell:

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

Cholesterol Biosynthesis Flashcards

(57 cards)