Sterols

cholesterol function and structure

27 carbon atoms, 4 rings

• rigidity for cell membranes

• precursor for steroid hormones (sex hormones, aldosterone)

• raw material for bile salts and vit D

cholesterol synthesis- 3 stages

made from acetyl CoA

cytoplasm

1. formation of isopentenyl pyrophoshate

ER

2. condensation of 6 molecules of IP to form squalene

3. cyclisation

cholesterol synthesis- STAGE 1

formation of isopentenyl pyrophosphate from acetyl CoA

3 step process

• uses 2 NADPH

• 3 ATP

• happens in cytoplasm

1a) acetyl CoA → acetoacetyl CoA

1b) acetoacetyl CoA → HMG CoA

2) HMG CoA reduced → mevalonate

3) mevalonate → isopentenyl pyrophosphate

cholesterol synthesis- STAGE 1 (Step 1a)

1a) acetyl CoA + acetyl CoA → acetoacetyl CoA

cholesterol synthesis- STAGE 1 (Step 1b)

1b) acetoacetyl CoA + acetyl CoA → HMG-CoA

cholesterol synthesis- STAGE 1 (Step 2)

HMG CoA reduced → mevalonate

• use 2NADPH

cholesterol synthesis- STAGE 1 (Step 3)

mevalonate → isopentenyl pyrophosphate

• 3 phosphorylation steps (uses 3ATP)

• 1 decarboxylation step

cholesterol synthesis- STAGE 2

isomerisation of isopentenyl pyrophosphate to squalene

• 4 step process

• happens in ER

1) isomerisation of isopentenyl pyrophosphate → dimethylallyl pyrophosphate

2) dimethylallyl pyrophosphate → geranyl pyrophosphate (C10)

3) geranyl pyrophosphate → farnesyl pyrophosphate (C15)

4) x2 farnesyl pyrophosphate → squalene (C30)

cholesterol synthesis- STAGE 2 (Step 1)

isomerisation

isopentenyl pyrophosphate → dimethylallyl pyrophosphate

cholesterol synthesis- STAGE 2 (Step 2)

condensation

dimethylallyl pyrophosphate → geranyl pyrophosphate

cholesterol synthesis- STAGE 2 (Step 3)

condensation

geranyl pyrophosphate → farnesyl pyrophosphate (C15)

• same enzyme as Stage 2 Step 2

cholesterol synthesis- STAGE 2 (Step 4)

tail to tail reductive condensation

• uses NADPH

farnesyl pyrophosphate x2 → squalene (C30)

cholesterol synthesis- STAGE 3

cyclisation of squalene → cholesterol

• uses NADPH

• uses oxygen

• forms lanosterol intermediate

1) squalene + NADPH + O2 → squalene epoxide

2) squalene epoxide + proton → protosterol cation

3) protosterol cation → lanosterol

4) lanosterol → cholesterol

cholesterol synthesis- STAGE 3 (Step 1)

squalene → squalene epoxide (intermediate)

• uses NADPH

• uses oxygen

cholesterol synthesis- STAGE 3 (Step 2)

addition of H+ to oxygen triggers cyclisation

squalene epoxide → protosterol cation

cholesterol synthesis- STAGE 3 (Step 3)

protosterol cation → lanosterol

cholesterol synthesis- STAGE 3 (Step 4)

lanosterol → cholesterol

• 19 step process

• uses NADPH

cholesterol synthesis key intermediates

STAGE 1: isopentenyl pyrophosphate

STAGE 2: squalene

STAGE 3: lanosterol

regulation of cholesterol synthesis happens via

HMG CoA reductase (Stage 1 Step 2)

depends on level of cholesterol in cell

5 ways of cholesterol synthesis regulation

control of mRNA synthesis- SCAP and SREBP

controlled by:

• SREBP (sterol regulatory element binding protein) in ER

• SCAP (sterol cleavage activating protein) associated with SREBP

SCAP detects levels of cholesterol

control of mRNA synthesis- when cholesterol levels fall

• low cholesterol detected by SCAP in ER

• regulatory site of SREBP is cleaved by protease

• SCAP and SREBP migrate to Golgi apparatus

• SREBP further cleaved by metalloprotease

• SREBP DNA-binding domain migrates to nucleus

• binds to SRE (sterol regulatory element) upstream of HMG-CoA reductase gene

• switches HMG-CoA reductase gene on

• increases cholesterol synthesis

another protein involved in mRNA synthesis control is

Insig

further regulation

uses of isoprene

isoprene = isopentenyl pyrophosphate without pyrophosphate

statins

drugs to decrease cholesterol levels

• used to treat hypercholesterolaemia and atherosclerosis

• competitive inhibitor of HMG CoA reductase

• increases LDL-transporters

• side effects: muscle pain

examples of statins

lovastatin (first statin)

atorvastatin

How does increased saturated fats lead to increased cholesterol synthesis?

acetyl CoA comes from B-oxidation of fats so:

• increased saturated fats

• increases acetyl CoA synthesis

• increases cholesterol synthesis