Cholesterol Biosynthesis Flashcards
Cholesterol
- vital component of cell membrane, precursor of steroid hormones and bile salts
- Deposition in arteries associated with CV disease and stroke.
- All carbon atoms for biosynthesis come from acetate in 3 stage process
3 stages of cholesterol synthesis - summarised
- Stage 1: acetate is converted to C5 units – isoprene
- Stage 2: 6 Isoprene units fused to form a linear molecule – Squalene
- Stage 3: Linear molecule is circularised to produce cholesterol
STAGE 1: Formation of Isoprene from acetyl-Co-A (first step)
- production of HMG-CoA, precursor for isoprene units
- Reaction is identical to that of ketone body formation
- Enzymes for cholesterol biosynthesis are cytosolic
STAGE 1: Formation of Isoprene from acetyl-Co-A (second step)
- conversion of HMG-CoA to mevalonate
- Rate-limiting/controlling step of cholesterol biosynthesis
- Requires 2 molecules of NADPH – 4 electron reduction
- Hydroxal functional group required for next step
STAGE 1: Formation of Isoprene from acetyl-Co-A (third step)
- phosphorylation of mevalonate
- ATP hydrolysis required
- Enzyme is Mevalonate-5-phosphotransferase
STAGE 1: Formation of Isoprene from acetyl-Co-A (fourth step)
- Isoprenoid units are pyrophosphate molecules
- Need to convert phosphomevalonate to a pyrophosphate
- Requires hydrolysis of second ATP molecule
STAGE 1: Formation of Isoprene from acetyl-Co-A (fifth step)
- 5-pyrophosphomevalonate – precursor for isopentenyl-PP
- Reaction is a decarboxylation requiring ATP hydrolysis
- Isopentenyl-PP acts as precursor for the second isoprenoid - dimethylallyl-PP
STAGE 1: Formation of Isoprene from acetyl-Co-A (sixth step)
- Isopentenyl-PP converted to dimethylallyl-PP by Isopentenyl-PP isomerase
- Movement of C=C bond from C1 to C2
- Occurs by a protonation/deprotonation reaction (i.e. addition/removal of H+)
STAGE 1: Formation of Isoprene from acetyl-Co-A (seventh step)
- Two different isoprenoids required for cholesterol
- Biosynthesis requires 2 dimethylallyl-PP and 4 isopentenyl-PP
STAGE 2: Formation of Squalene (first step)
- Isoprenoid units are condensed together by Prenyltransferase in two reactions to form Farnesyl-PP.
- Reactions:
1. Isopentenyl-PP to dimethylallyl-PP
2. Isopentenyl-PP to geranyl-PP
STAGE 2: Formation of Squalene (second step)
- Condensation of 2 X farnesyl-PP = Squalene
- Requires NADPH as reducing equivalent
- Enzyme is Squalene synthase
- Linear form of cholesterol
STAGE 3: Circularisation of Squalene to Cholesterol (first step)
- First step epoxidation of squalene
- Requires molecular O2 and NADPH
- Formation of cyclic 3 atom ring
STAGE 3: Circularisation of Squalene to Cholesterol (second step)
- conversion of epoxide group to a hydroxal group and linking of rings
- Enzyme – oxidosqualene cyclase
- Intermediate molecule – protosterol cation
- Conversion to lanosterol: 1) Removal of H+, formation of C=C bond, 2) Rearrangement of H atoms at tail
STAGE 3: Circularisation of Squalene to Cholesterol (third step)
- Lanosterol converted to cholesterol – 19 steps
- Includes removal of 3 methyl groups, reduction of a double bond and migration of the other double bond
- Requires NADPH and O2 molecule
5 classes of cholesterol
- Progestins
- Androgens
- Glucocorticoids
- Mineral glucocorticoids
- Oestrogens
Functions of cholesterol
- Control metabolism
- Inflammation
- Immune function
- Sexual development
- Salt and water balance
Cholesterol as bile acid precursor
- Modifications: reduce C5-C6 bond, hydroxylation C7/C12, conversion of C24 to COOH, epimerisation 3b-OH and conjugation
- First run C7 hydroxylation – rate limiting
- Enzyme is cholesterol 7a-hydroxylase (CYP7A1)
- Dietary fat absorption, cholesterol excretion
How is cholesterol transported?
- in bloodstream as lipoprotein complex (cholesterol, TAGs, apolipoprotein).
What enzyme converts cholesterol to cholesteryl ester for packaging?
- Acyl-CoA : cholesterol acyltransferase (ACAT)
How is cholesterol packaged by liver?
- VLDLs (very low density lipoproteins)
Cholesterol when released into bloodstream
- to be stored or utilised by adipocytes and muscle
Cholesterol transport/utilisation
- Release of TAGs from VLDL via lipases on capillary surfaces results in IDL (intermediate-density lipoproteins) which are rich in cholesteryl esters
- IDLs then converted to LDLs (low-density lipoproteins) by the removal for further TAGs
- Peripheral tissues take up cholesterol from LDL.
- LDL/IDL return cholesterol to liver
- HDL ‘picks up’ and transports cholesterol from tissues/plasma from dying cells to liver
LDL uptake by receptor-mediated endocytosis
- receptor functions to internalize LDL
- LDL is delivered to lysosomes where its degraded and its cholesterol is released for use in the synthesis of membranes, steroid hormones and bile acids
When things go wrong with cholesterol
- Elevated blood cholesterol levels arise from genetic defects or high dietary intake
- Dietary cholesterol enters bloodstream as chylomicrons
- TAGS removed by peripheral tissue – remnants absorbed by liver
What can we fix?
- Ingestion of anion exchange resins – bind bile salt and ↑ cholesterol excretion e.g. cholestyramine (Questran)
- Cholesterol reducing drugs (statins) – inhibitors of HMG-CoA reductase
