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contents:

Introduction
Occurance Structure Function Biosynthesis & Regulation.

(chole=bile) it was first isolated in 1784,from human gallstones &

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.

The reducing equivalents are supplied by NADH while

ATP provides energy.


For the production of 1 mole of cholesterol,18 moles of

acetyl COA,36 moles of ATP & 16 moles of NADPH are required.

The synthesis of cholesterol may occur in five stages:


Synthesis of HMG-COA

(Hydroxymethylglutaryl-coenzyme A )
Formation of mevalonate(6c) Production of isoprenoid units(5c)

Synthesis of squalene(30c)
Conversion of squalene to cholesterol(27c)

OH CH2 C CH3 CH2

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 H2O O H3C SCoA HSCoA O

O CH2 C SCoA

acetoacetyl-CoA HMG-CoA Synthase


OH CH2 C CH3 CH2 O C SCoA

acetyl-CoA

H3 C

hydroxymethylglutaryl-CoA

HMG-CoA is formed by condensation of acetyl-CoA & acetoacetyl-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

CH3 CH2 C O SCoA

C O

NADPH serves as reductant in the 2-step reaction.


Mevaldehyde is thought to be an active site intermediate, following the first reduction and release of CoA.

HMG-CoA HMG-CoA Reductase


CH3 CH2 H2 C OH

2NADPH 2NADP+ + HSCoA HO C H2C

C O

mevalonate

HMG-CoA Reductase is an integral protein of endoplasmic reticulum membranes

The HMG-CoA Reductase reaction, in which mevalonate is formed from HMG-CoA, is ratelimiting for cholesterol synthesis.

This enzyme is highly regulated and the target of pharmaceutical intervention.

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

CH3 CH2 CH2 OH

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

CH3 CH2 CH2

5-pyrophosphomevalonate
CO2

CH3 C H2C

isopentenyl pyrophosphate

CH3 C H2C CH2 CH2 O O P O O O P O O

isopentenyl pyrophosphate

CH3 C H3C CH CH2 O O P O O O P O O

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

react to form geranyl pyrophosphate.


Condensation with another isopentenyl pyrophosphate

yields farnesyl pyrophosphate.


Each condensation reaction is thought to involve a reactive

carbocation formed as PPi is eliminated.

CH3 H3C C CH CH2 O

O P O O

O P O H2C PPi O CH3 C CH2 CH2 O O P O O 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 H3C C CH CH2 CH2

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

CH3 CH CH2 CH2 C CH CH2

CH3 CH2 C CH CH2 O

O P O O

O P O O

2 H3C

NADPH NADP+ + 2 PPi

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

The product is the sterol lanosterol.

19 steps
HO HO

lanosterol

cholesterol

Conversion of lanosterol to cholesterol involves 19 reactions, catalyzed by enzymes in ER membranes.


Additional modifications yield the various steroid hormones or vitamin D.

Regulations:
Cholesterol biosynthesis is controlled by the rate limiting

enzyme HMG CoA reductase,beginning of pathway.

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.

1. Feed back control: the end product cholestrol

2.Hormonal regulation: The enzyme HMG CoA


reductase exists in two interconvertible forms. The dephosphorylated form. Phosphorylated form The dephosphorylated form of HMG CoA is more active than phosphorylated form. The hormones glucagon & glucocorticoids favor the formation of inactive HMG CoA reductase (phosphorylated form) & thus,decreses cholesterol synthesis. Insulin & thyroxine increase cholesterol production by enhancing the formation of active HMG CoA reductase(dephosphorylated form).

3.

Inhibition by drugs:the drugs compactin and

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.