BIOC 503 - Cholesterol Biosynthesis

cholesterol

precursor for generation of bile acids, steroids hormones & vitamin D

acetyl-CoA

cholesterol is synthesized from ___ aka activated acetate

4 steps of cholesterol synthesis

1- 3 acetate condenses to form mevalonate

2- mevalonate converts to phosphorylated 5C isoprene

3- 6 isoprene molecules polymerize to form 30C squalene

4- squalene cyclizes to form the 4 rings which are modified to form cholesterol

step 1 formation of mevalonate from acetyl-CoA

1- 2 acetyl-CoA used by thiolase to form acetoacetyl-CoA

2- acetoacetyl-CoA + acetyl-CoA + HMG-CoA synthase = CoA + HMG-CoA

3-HMG-CoA + HMG-CoA reductase + 2 NADPH = 2 NADP + CoA + mevalonate`

step 2 formation of activated isoprene from mevalonate

mevalonate + 3 ATP = 3 ADP + CO2 + activated isoprene

HMG-reductase

rate limiting enzyme of cholesterol synthesis

activated isoprene molecules

• D³-isopentyl pyrophosphate

• dimethylallylpyrophosphate

step 3 activated isoprene condenses to squalene

1- 2 activated isoprene molecules join head to head to form geranyl phosphate

2- geranyl-phosphate + activated isoprene = farnesyl phosphate

3 2 farnesyl phosphates + NADPH = NADP + squalene

step 4 from squalene to 4 rings sterol nucleus

1- squalene + NADPH +O2 = squalene-2,3-epoxide + NADP

2- squalen-2,3-epoxide + enzyme = lanosterol which gets transformed to cholesterol

3

for formation of each isoprene molecule, __ ATP used

18

number of ATP used to form cholesterol

14

number of NADPH molecules required for the biosynthesis of cholesterol

glucagon, epinephrine, LOW ATP, oxysterol

inhibitors of cholesterol synthesis

insulin

activator of cholesterol synthesis

dephosphorylated, phosphorylated

HMG-CoA reductase is the regulation point of cholesterol synthesis; it is active when ___ and inactive when ____

proteolytic degradation

Another way to regulate HMG-CoA reductase is ___ which is done by an ER protein

transcriptional regulaiton

__ of HMG-CoA in cholesterol synthesis happens on the LONG term and involve enhancement by TF SREBP

insulin, glucagon, epinephrine

__ dephosphorylate/increases HMG-CoA reductase, while __ and __ phosphorylate/decrease its activity

AMP-dependent protein kinase

aka AMPK

decreases activity/downregulate HMG-CoA reductase

statins

drugs acting as inhibitors of HMG-CoA reductase

bile acids, bile salts

__ and __ are synthesized from cholesterol and emulsify fats by increasing the surface area to facilitate hydrolysis 

steroids

___ are made from cholesterol by modifying or cleaving the side chain on C17

• mixed functions oxidase

• NADPH

adreanl glands

mineralocorticoids and glucocorticoids are made in ___ and control electrolytes balance

vitamin D

__ synthesized from 7-dehydrocholesterol

• sunlight makes it into __3

• liver hydroxylates position 25

• kidney hydroxylates position 1

isoprenoids

synthesis of ___ stems off of activated isoprene D³-isopentyl pyrophosphate