Cholesterol Flashcards
What is in cholesterol synthesis?
- Synthesis of isopentenyl pyrophosphate an activated isoprene unit which reverses as a key building block (cytoplasm)
- Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasmic reactions)
- Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER reactions)
What are the first three steps in cholesterols synthesis 1?
- 2 molecules of acetyl CoA condense to form Acetoacyl CoA
- Acetyl CoA condenses and forms 3-hydroxy-3 methyl glutaryl-CoA (HMG-CoA)
- HMG-CoA reductase reduces HMG-CoA to give molecule mevalonate (NADPH used as source of reducing power for biosynthetic reactions)
What are the final three steps of cholesterol synthesis 1?
- HMG-CoA reductase negative feedback control by cholesterol (end product of pathway) and reaction product mevalonate and bile salts (generated from cholesterol molecules)
- The mevalonate, sequential phosphorylation hydroxyl groups at position 3 and 5
- Then decarboxylation to form 3-isopentenyl pyrophosphate (isopentyl PP)
What are the three steps in cholesterol synthesis 2?
- Isomerisation reaction: dimethylallyl pyrophosphate produced from isopentyl PP
- Two contestation reactions which isopentyl PP is sequentially added to the Dimdthylallyl pyrophosphate grows the chain to the 15 carbon species Farnesyl pyrophosphate
- Two farnesyl-PP molecules then condense to from the 30 carbon molecule squalene plus 2 molecules of pyrophosphate
What are the four steps in cholesterol synthesis 3?
- Squalene reduced in presence of oxygen and NADPH to form squalene epoxide
- Enzyme squalene epoxide lanosterol-cyclase catalyses the formation of Lanosterol (A series of 1,2-methyl group and hydride shifts along the chin of the squalene molecule result in formation of the four rings)
- Lanosterol subsequently reduced and three methyl units removed (demethylated) to generate cholesterol
- This pathways consumed ATP (phosphorylation of mevalonate) and used NADPH as reducing power
What are the steps of bile synthesis from cholesterol?
- Bile salts emulsify dietary fats due to hydrophobic and hydrophilic faces
- Bile salts major breakdown products of cholesterol and amount for half of 800mg of cholesterol made each day by liver
- Cholesterol converted into glycocholate (primary bile salt) and taurolate
- Polar groups attached to cholesterol core unit which form hydrophilic face of the bile salts
What are the steps of steroid synthesis from cholesterol?
- Precursor pregnenolone generated from cholesterol by enzyme desmolase
- All five classes of steroid hormones come from pregnenolone: Prostestagens, glucocorticoids, mineralocorticoids, androgens, oestrogen
What are the steps for vitamin D synthesis from cholesterol?
- General term for group of steroids for intestinal absorption of important ions needed for bone development e.g, calcium, phosphate and magnesium
- Main source activity of UV light upon 7-dehydrocholesterol in epidermis of the skin (as western died low in Vit D)
- Calcitriol most active vitamin D metabolite and in calcium metabolism: functions as steroid hormone binding to VDREs in promoter of target genes e.g. genes involved in bone metabolism
- Deficient of Vit D3 in childhood leads to rickets, defect of bone development in children
What is hypercholesterolaemia and its control?
-Familial hypercholesterolaemia (FH) monogenic dominant trait where cholesterol transportation is defective
Heterozygotes levels of cholesterol 2-3 times high than normal peoeprl and are susceptible to atherosclerosis (hardening of arteries) in middle age
Homozygotes severly affected cholesterol serum level five times higher and sever atherosclerosis and coronary infraction in adolescence
Homozygous: orange yellow xanthomas lying superficially over knees wrist and hands from scavenging of plasmas LDL derived cholesterol by macrophages of the skin
Deposition of LDL-derived cholesterol in the coronary arteries, can lead to their occlusion and myocardial infarction (B is cholesterol rich plaque almost totally blocking artery)
How do you control hypercholesterolaemia?
- Inhibition of de novo cholesterol synthesis by the liver
- Reduction of dietary cholesterol absorption by intestines: achieved by HMG-CoA reductase inhibitors and resins respectively
What are resins or sequestrants?
e.g Cholestyramine (Questran and prevalite)
These bind or sequester bile acid-cholesterol complexes preventing they reabsorption by the intestine and they can lower LDL (“bad”m cholesterol) by 15-30% and raise HDL (“good” cholesterol) by 3-5%
What are HMG-CoA-Reducatse inhibitors?
Statins e.g. Lipitor (pfixer), Cresteor (astra Zeneca).. The mechanism of action of lovastatin is competitive inhibitor of HMG-CoA reductase
