FATTY ACID METABOLISMCHOLESTEROL BIOSYNTHESIS

Dr. Aga Syed SameerCSIR Lecturer

Department of Biochemistry,

Medical College,

Sher-I-Kashmir Institute of Medical Sciences,

Bemina, Srinagar, Kashmir, 190018. India.

The most prevalent steroid in animal cells is

cholesterol

Plants do not contain cholesterol, but they do

contain other steroids very similar to cholesterol

in structure

Cholesterol serves as a crucial component of cell

membranes and as a precursor to bile acids (e.g.,

cholate, glycocholate, taurocholate) and steroid

hormones (e.g., testosterone, estradiol,

progesterone)

Vitamin D3 is derived from 7-dehydrocholesterol,

the immediate precursor of cholesterol

Cholesterol

It is very Hydrophopic

Compound

Consists of four fused

Hydrocarbon rings (A, B,

C and D – Steriod

Nucleus)

In addition, it has 8

carbon, branched

hydrocarbon attached to

C17 of the D-ring

Ring A has OH- group at

C-3

Ring B has double bond

between C-5 and C-6

Cholesterol

Liver is the primary site of cholesterol

biosynthesis, in addition to Intestine, adrenal

Cortex and Reproductive Tissues

All Carbon atoms in cholesterol are provided by

acetate, and reducing equivalents are furnished

by NADPH

The pathway is driven by Hydrolysis of High

energy Thioester Bond of Acetyl CoA and ATPs

The enzymes involved are present in both Cytosol

and the membrane of ER

Synthesis

Synthesis of Cholesterol involves Four stages :

Mevalonate Synthesis

Squalene Synthesis

Lanosterol Synthesis

Conversion to Cholesterol

Synthesis

The third step in the pathway

is the rate-limiting step in

cholesterol biosynthesis

HMG-CoA undergoes two

NADPH-dependent reductions

to produce 3R-Mevalonate

The reaction is catalyzed by HMG-

CoA reductase, a 97-kD glycoprotein

that traverses the endoplasmic

reticulum membrane with its active

site facing the cytosol

As the rate-limiting step, HMG-CoA

reductase is the principal site of

regulation in cholesterol synthesis

Synthesis of Mevalonate

Three different regulatory mechanisms are

involved:

1. Phosphorylation by cAMP-dependent protein

kinases inactivates the reductase. This

inactivation can be reversed by two specific

phosphatases

2. Degradation of HMG-CoA reductase. This

enzyme has a half-life of only three hours, and the

half-life itself depends on cholesterol levels: high

[cholesterol] means a short half-life for HMG-CoA

reductase.

3. Gene expression—cholesterol levels control the

amount of mRNA. If [cholesterol] is high, levels of

mRNA coding for the reductase are reduced. If

[cholesterol] is low, more mRNA is made.

Regulation

The biosynthesis of squalene involves conversion

of mevalonate to two key 5-Carbon intermediates: Isopentenyl pyrophosphate (IPP)

Dimethylallyl pyrophosphate (DMP)

A series of four reactions

converts mevalonate to isopentenyl pyrophosphate and

then to dimethylallyl pyrophosphate

Synthesis of Squalene

The first three steps each

consume an ATP,

Two for the purpose of

forming a pyrophosphate at

the 5-position, and

Third to drive the

decarboxylation and double

bond formation in the third

step.

Synthesis of Squalene

Isomerization of the double

bond of IPP yields the

dimethylallyl pyrophosphate

Synthesis of Squalene

Condensation of IPP with

DMP produces Geranyl

pyrophosphate (10C)

Addition of another 5-carbon

isopentenyl group gives

farnesyl pyrophosphate (15C)

Both steps in the production

of farnesyl pyrophosphate

occur with release of

pyrophosphate, hydrolysis of

which drives these reactions

forward

Synthesis of Squalene

The next step—the joining

of two farnesyl

pyrophosphates to produce

squalene—is a ―tail-to-tail‖

condensation

It represents an important

exception to the general

rule

Synthesis of Squalene

Squalene monooxygenase, an

enzyme bound to the ER,

converts squalene to

squalene-2,3-epoxide

This reaction employs FAD

and NADPH as coenzymes

and requires O2 as well as a

cytosolic protein called

soluble protein activator

Second ER membrane

enzyme, 2,3-oxidosqualene

lanosterol cyclase, catalyzes

the second reaction

producing Lanosterol

Synthesis of Lanosterol

Although Lanosterol may appear similar to

cholesterol in structure, another 20 steps are

required to convert lanosterol to cholesterol

The enzymes responsible for this are all associated

with the endoplasmic reticulum

The primary pathway involves 7-dehydrocholesterol as

the penultimate intermediate

An alternative pathway, also composed of many steps,

produces the intermediate desmosterol

Reduction of the double bond at C-24 yields cholesterol

Synthesis of Cholesterol

Synthesis of Cholesterol

Questions?