cholesterol synthesis.pptx

Metabolism of Cholesterol
Biosynthesis of Cholesterol
Ass.prof.Dr. Sukayna Hussain
Rashed
Mosul university / College of Science / Chemistry Department
Email :sukaynarashed@uomosul.edu.iq
2022-2023
April 23 Ass.prof.Dr. Sukayna Hussain

Structure of cholesterol:
• The structure of cholesterol consists of four fused rings (The rings in
steroids are denoted by the letters A, B, C, and D.), with the carbons
numbered in the sequence, and an eight numbered, and branched
hydrocarbon chain attached to the D ring. Cholesterol contains two
angular methyl groups: the C-19 methyl group is attached to C-10, and the
C-18 methyl group is attached to C-13.The C-18 and C-19 methyl groups of
cholesterol lie above the plane containing the four rings.

Cholesterol Forms
Free Cholesterol And Esterified Cholesterol
R C O
O
Cholesteryl Ester

Free Cholesterol is a derived Lipid (30%)
Cholesterol Ester is a simple Lipid and a body Wax. (70%)
Cholesteryl Ester is a storage and excretory form of Cholesterol
which is found in most tissues.

• Functions of cholesterol
1-It is a major constituent of the plasma membrane and of plasma lipoproteins.
2-It is a precursor of bile salts.
3-It is a precursor of steroid hormones that include adrenocortical hormones,
sex hormones, placental hormones.
4- Also a precursor of vitamin D3.
5- It is required for the nerve transmission. Cholesterol is widely distributed in all
cells of the body but particularly abundant in nervous tissue.

Sources of cholesterol
Cholesterol is derived from:
1- Diet (exogenous cholesterol).
2- Endogenous cholesterol, the liver and intestine account
approximately 10% each of total synthesis in humans.
(about 2 g/day), and the remainder is provided by the average diet.

Endogenous And Exogenous
Sources Of Body Cholesterol
About 1 g/day originates by biosynthesis
About 0.3 g/day extracted from food
80% Endogenously produced by Liver (0.8 gram/day)
20% Exogenously comes from digestive tract (0.3 gm/day)
Assume 400 mg is an intake of dietary Cholesterol per day
It absorb about 50% Cholesterol
200 mg is absorbed from GIT
800 mg of Cholesterol is from de novo synthesis

Exogenous Sources Of Cholesterol
(Animal Sterol)

Cholesterol Biosynthesis
Is To Provide
Endogenous Source of Body Cholesterol

Amount Of Cholesterol Biosynthesis
Endogenously about 1 gm/day of Cholesterol is
biosynthesized.
Ingestion of excess of Carbohydrates elevates
Cholesterol biosynthesis.

Conditions Favoring For Cholesterol Biosynthesis
Biosynthesis of Cholesterol takes place:
1- In well fed condition.
2- When excess of free cellular Glucose.
3- On stimulation of Insulin.
Amount of Cholesterol biosynthesis depends upon
Availability of Acetyl-CoA obtained from Glucose metabolism
in a well fed state.

Cholesterol Synthesis
All 27 carbon units of Cholesterol Structure are biosynthesized using
2 carbon moiety Acetyl-CoA units ,obtained from Glucose
metabolism.
Site of Cholesterol Biosynthesis
Organs Involved For Cholesterol Biosynthesis:
Liver (80% ); Intestine (10%); Skin (5%); Adrenal Cortex
Ovaries , Testes , Placenta; Arterial walls (some extent).
Cholesterol Synthesizing Enzymes are partly located in:
Cytoplasm
Endoplasmic Reticulum

Requirements For Cholesterol Biosynthesis
1. Metabolic Precursor- Acetyl CoA (Obtained from
excess Glucose metabolism)
2. Enzymes ,Coenzymes and Cofactors
3. 16 NADPH +H+ (Through HMP Shunt)
4. 36 ATPs
Stages Of Cholesterol Biosynthesis
Biosynthesis of Cholesterol is a very complex process
To understand divided in 5 Stages
Requires more than 25 steps.

Stage 1.
Acetyl-CoA forms HMG-CoA and Mevalonate.
Stage 2.
Mevalonate forms Active Isoprenoid units(C5)
Stage 3.
6 Isoprenoid units form Squalene (C30)
Stage 4.
Squalene is converted to Lanosterol
Stage 5.
Lanosterol is converted to Cholesterol(C27)

Overview/Outline of Cholesterol Synthesis

• Detail steps of cholesterol
Acetyl-CoA acts as a precursor of cholesterol. All 27 carbon atoms of
cholesterol are derived from acetyl CoA in three stages:
• Stage one: Initially two molecules of acetyl-CoA condense to form Acetoacetyl-
CoA catalyzed by cytosolic thiolase. Acetoacetyl-CoA condenses with a further
molecule of acetyl-CoA catalyzed by HMG-CoA synthase to form HMG-CoA,
that is reduced to mevalonate by NADPH catalyzed HMG-CoA reductase.

Steps of
mevalonate
synthesis .

• Stage two: synthesis of Isoprenoid pyrophosphate, an activated isoprene unit
that is the key building unit of cholesterol.
• Mevalonate in three subsequent steps is
• Phosphorylated with ATPs
• Dehydrated and
• Decarboxylated
• To form Isoprenoid unit(C5)- Isopentenyl pyrophosphate(IPP).

Stage 3,4, and 5:
Condensation of six molecules of Isoprenoid pyrophosphate
to form Squalene. So the squalene cyclizes by oxidosqualene
lanosterol cyclase reaction to produce tetracyclic product
(Lanosterol C30) is subsequently converted into cholesterol
C27.

Demethylation, desaturation and saturation steps convert Lanosterol to
Cholesterol

Regulation Of Cholesterol Biosynthesis
HMG-CoA Reductase
Is regulatory/ key enzyme of Cholesterol Biosynthesis.
This enzyme is stimulated and inhibited as per requirement of bodies
need.
• Enzyme HMG-CoA reductase has half-life of 3 hrs.
• Degradation of HMG-CoA reductase depends on Cholesterol levels.
Modes Of Cholesterol Regulation
Hormonal Influence
Covalent Modification
Feedback Inhibition

Hormonal Regulation
Insulin
In well fed state:
Stimulates and increases HMG CoA Reductase
Increases Cholesterol Biosynthesis
Glucagon and Glucocorticoids in emergency states:
Inhibits HMG CoA Reductase.
Decreases Cholesterol Biosynthesis.

• Degradation of cholesterol
• Synthesis of bile acids.
• Synthesis of steroid hormones.
• Synthesis of Vitamin D.
• By conversion into bile acids and bile salts-excreted in the feces. Secretion of
cholesterol in bile–transported to intestine, for elimination cholesterol is
converted into 7-hydroxycholesterol by 7alpha-hydroxylase. Most of 7-
hydroxycholesterol is converted to cholic acid. Cholic acid can combine with:
* glycine to form glycholic acid
* taurine to form taurocholic acid
• Some 7-hydroxycholesterol is converted into chenodeoxycholic acid. This can
form glychenodeoxycholic acid and taurochenodeoxycholic acid.

• All these compounds are known as primary bile acids, and their sodium
and potassium salts are known as bile salts (Bile salts are formed in liver,
and are excreted through bile into intestine. Most of the bile salts
entering the intestine are re-absorbed into portal blood, brought to
liver, and are re-excreted into the intestine by the liver (enterohepatic
circulation of bile salts). Finally bile salts are converted into secondary
bile acids (deoxycholic acid and lithocholic acid), most of the lithocholic
acid is excreted in the feces.

Detail steps of
cholesterol
degradation

cholesterol synthesis.pptx

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