Cholesterol Flashcards
How many carbon atoms are in cholesterol and what is its generic structure
27 - composed of cyclic rings with a hydrophobic tail . The steroid ring structure is planar and apart from the hydroxyl group at position 3, the molecule is very hydrophobic consisting o only carbon atoms and hydrogen atoms
Function of cholesterol
Vital components of cell membranes and it can increase and decrease membrane stiffness depending on temperature and the nature of the membrane.
Where is cholesterol synthesised
Dietary cholesterol is limited to around 500mg a day and so given the great need for cholesterol as a membrane component, all physiological requirements for cholesterol are supplied by the liver through de novo synthesis of cholesterol from acetyl coA
3 main parts of cholesterol synthesis
1) synthesis of isopentenyl pyrophsophate - cytoplasmic reaction
2) condensation of six molecules of isopentyl pyrophosphate to form squalene ( cytoplasmic reaction)
3) cyclisation and demethylation of squalene by monooxygenasss to give cholesterol
What happens during the formation of isopentynyl pyrophosphate
Two molecules of acetyl coA condense to form 4C acetoacyl CoA. Next another another molecule of acetyl-CoA condenses to form3-hydroxy-3-methyl glutaryl-CoA(HMG-CoA). HMG-CoA reductase reduces HMG-CoA to give the moleculemevalonate.
Mevalonate then undergoes sequential phosphorylation at the hydroxyl groups at position 3 and 5, followed by decarboxylation to form3-Isopentenyl pyrophosphate(isopentyl PP) which is 5 carbon .
Remember about end product inhibition/negative feedback of HMG-CoA reductase control by mevalonate and cholesterol and bile salts
What occurs during part 2 of cholesterol synthesis
Condensation of 6 molecules of isopentenyl pyrophosphate to form squalene - cytoplasm.
Step 1; isomerization reaction fo isopentenyl pyrophosphate to form dimethylallyl pyrophosphate
Step 2: two condesation reactions where 2 iso pp is added to dimethylallyl pyrophosphate and it grows to a 15 C species Farnesyl pyrophosphate
Step 3) Two molecules of farnesyl pyrophosphate form squalene plus two molecules of pyrophosphate
Part 3 of cholesterol synthesis
Cyclisation and demethylation of squalene by monooxygenases to give cholesterol
Step 1) Firstly, squalene is reduced in the presence of oxygen and NADPH to form squalene epoxide which has a different C=C bond distribution, priming the molecule for carbon ring fusion(Step 1).
Secondly, the enzyme squalene epoxide lanosterol-cyclasecatalyses the formation ofLanosterol (Step 2). A series of 1,2-methyl group and hydride shifts along the chain of the squalene molecule result in the formation of the four rings.
Step 3) Lanosterol is subsequently reduced and three methyl units removed (demethylated) to generate cholesterol.
What is cholesterol used to synthesise
Bile salts,
Steroid hormone
Vitamin D
Synthesis of bile salts from cholesterol
Major breakdown products of cholesterol. Cholesterol is converted to two main bile salts glycocholate and taurocholate
Steroid hormone synthesis from cholesterol
Precursor pregenolone is generated from cholesterol by the action of the enzyme demsmolase. All 5 classes of steroid hormones come from pregnenolone ; progestagens, glucocorticoids , mineralcorticoids , androgens and oestrogen
Vitamin D from cholesterol
Vitamin D is a collective term for a group of steroid which are vital for the intestinal absorption of important ions needed for bone development, namely calcium, phosphate and magnesium.
Calcitrol synthesis
Most active vitamin D metabolite and plays a key role in calcium metabolism. Functions as a steroid hormone binding to vitamin D response elements (VDREs) in the promoter of target genes and inducing key genes involved in glucose metabolism. Leads to rickets
Hypercholesterolaemia
FH is a mono genie dominant trait where cholesterol transportation is defective. Due to lack of functional LDLR which transports LDL
Heterozygous gave cholesterol levels approx 2-3 times higher in normal people and are susceptible to atherosclerosis in middle age.
Homozygotes are severely affected- serum cholesterol levels are 5 times higher than in healthy individuals and severe atherosclerosis and coronary infarction may be observed in adolescence. Orange-yellow xanthomas lying superficially over the knees wrists and hands arise from the scavenging of plasma LDL derived cholesterol by macrophages of the skin
How to control hypocholesteraemia
Inhibition of de novo cholesterol synthesis by liver or reduction of dietary cholesterol absorption by intestines. Achieved by HmG-CoA reductase inhibitors and resins
Resins/sequestrants
Cholestyramine prevents absorption by intestine . Lowers
LDL by binding or sequester bile acid cholesterol complexes
