Introduction
Occurance Structure Function Biosynthesis & Regulation.
hence so named (cholesterol literally means solid alcohol from bile).cholesterol is an important component of some cell membranes & of plasma proteins besides this its also the precursor of many other biologically important steriods,such as bile acids.
occurence
Cholesterol is found exclusively in animals,hence its
often known as animal sterol.The total body content of cholesterol in adult man weighing 70 kg is about 140 g i.e., around 2g/kg body weight.its found abundantly in nerve tissues & in gallstones. It occurs either free or as fatty esters in all animal cells. Its main sources are fish liver oil & the brain & spinal cord of cattle.
structure
The parent hydrocarbon of cholesterol is cholestane,
C2H28. The structure of cholesterol was determined by the German chemist Adolph windaus(LT,1879-1959) who received the Nobel Prize in chemistry. Its molecular formula isC27H45OH In addition to an OH group at C3, there is a double bond at C5. The hydroxyl group constitutes its polar head,the rest of the molecule is hyhrophobic. Its white crystalline solid with a melting point of 149 degree calcius.
Functions of Cholesterol
Cholesterol is essential to life as it performs a number of functions: Its structural component of cell membrane. Its the precursor for the synthesis of all other steriods in the body.These include steroid hormones,vitamin D & bile acids. Fatty acids are transported to liver as cholesteryl esters for oxidation.
Cholesterol biosynthesis
About 1g of cholesterol is synthesized per day in
adults. Almost all the tissues of the body participate in its biosynthesis but the largest contribution is made by the Liver (50%),intestine(15%),skin,adrenal cortex,repropductive tissues etc. The enzymes involved in cholesterol synthesis are found in the cytosol & microsomal fractions of the cell.Acetate of acetyl coA provides all the carbon atoms in cholesterol.
(Hydroxymethylglutaryl-coenzyme A )
Formation of mevalonate(6c) Production of isoprenoid units(5c)
Synthesis of squalene(30c)
Conversion of squalene to cholesterol(27c)
O C SCoA
hydroxymethylglutaryl-CoA
Hydroxymethylglutaryl-coenzyme A (HMGCoA) is the precursor for cholesterol synthesis. HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-CoA. HMG-CoA destined for cholesterol synthesis is made by equivalent, but different, enzymes in the cytosol.
O CH2 C SCoA
acetyl-CoA
H3 C
hydroxymethylglutaryl-CoA
catalyzed by HMG-CoA Synthase. HMG-CoA Reductase catalyzes production of mevalonate from HMGCoA.
The carboxyl of HMG that is in ester linkage to the CoA thiol is reduced to an aldehyde, and then to an alcohol.
HO C H2C
C O
C O
mevalonate
The HMG-CoA Reductase reaction, in which mevalonate is formed from HMG-CoA, is ratelimiting for cholesterol synthesis.
HO
Mevalonate is phosphorylated by 2 sequential Pi transfers from ATP, yielding the pyrophosphate derivative. ATP-dependent decarboxylation, with dehydration, yields isopentenyl pyrophosphate.
C H2C
C O
mevalonate
2 ATP (2 steps) 2 ADP O O P O ATP ADP + Pi O CH2 CH2 O P O O O P O O O O P O O
HO C H2C C O O
5-pyrophosphomevalonate
CO2
CH3 C H2C
isopentenyl pyrophosphate
isopentenyl pyrophosphate
dimethylallyl pyrophosphate
Isopentenyl Pyrophosphate Isomerase inter-converts isopentenyl pyrophosphate & dimethylallyl pyrophosphate. Mechanism: protonation followed by deprotonation.
Condensation Reactions
Prenyl Transferase catalyzes head-to-tail condensations:
Dimethylallyl pyrophosphate & isopentenyl pyrophosphate
O P O O
dimethylallyl pyrophosphate
isopentenyl pyrophosphate
O O O P O O CH2 CH2 O P O O O P O O O P O CH3
CH3 C CH CH2 O
geranyl pyrophosphate
H2C PPi CH3 H3C C CH CH2 CH2 CH3 C CH CH2
isopentenyl pyrophosphate
CH3 O CH CH2 O P O O O P O O
CH2 C
farnesyl pyrophosphate
Each condensation involves a carbocation formed as PPi is eliminated.
CH3
O P O O
O P O O
2 H3C
2 farnesyl pyrophosphate
NADP+ NADPH
H+
O2
H2O
HO
squalene
2,3-oxidosqualene
lanosterol
Squalene Synthase: Head-to-head condensation of 2 farnesyl pyrophosphate, with reduction by NADPH, yields squalene.
NADP+ NADPH
H+
O2
H2O
HO
squalene
2,3-oxidosqualene
lanosterol
Squaline epoxidase catalyzes conversion of squalene to 2,3-oxidosqualene. This mixed function oxidation requires NADPH as reductant & O2 as oxidant. One O atom is incorporated into substrate (as the epoxide) & the other O is reduced to water.
Squalene Oxidocyclase catalyzes a series of electron shifts, initiated by protonation of the epoxide, resulting in cyclization.
.
H+
HO
2,3-oxidosqualene
lanosterol
19 steps
HO HO
lanosterol
cholesterol
Regulations:
Cholesterol biosynthesis is controlled by the rate limiting
HMG CoA reductase is found in association with Endoplasmic reticulum,& is subjected to different metabolic controls. controls its own synthesis by a feedback mechanism.Increase in the cellular concentration of cholesterol reduces the synthesis of the enzyme HMG CoA reductase.
3.
lovastatin(mevinolin) are fungal products. These are used to decrease the serum cholesterol level in patients with hypercholesterolemia.These are competitive inhibitors of the enzyme HMG CoA reductase & therefore reduce cholesterol synthesis.