Download MBBS Biochemistry PPT 70 Lipogenesis Lecture Notes

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Lipogenesis

? What is Lipogenesis ?

? Which forms of Lipids biosynthesized?

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? When Lipogenesis Occur?

? Where Lipogenesis takes place ?

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? Why Lipogenesis Occurs ?

? How Lipogenesis is made possible?

? Associated Disorders to Lipogenesis ?

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What Is Lipogenesis?

?Lipogenesis is

biosynthesis of various

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forms of Lipids in

human body.

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Which Forms Of Lipid

Biosynthesized In

Human Body Tissues?

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FORMS Of LIPID BIOSYNTHESIZED

1. Fatty acid Biosynthesis
2. Triacylglycerol Biosynthesis
3. Phospholipids Biosynthesis

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4. Glycolipids Biosynthesis
5. Cholesterol Biosynthesis
6. Eicosanoids Biosynthesis

When Lipogenesis Occurs?

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?Lipogenesis occurs in

well fed condition.

Conditions Favoring Lipogenesis

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vExcess of Free Glucose after

heavy Carbohydrate meals.

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v Insulin promotes Lipogenesis
Where Does Lipogenesis Occur?

Site Of Lipogenesis

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?Predominant site for

Lipogenesis

?Liver Cytoplasm

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?Other tissues for

Lipogenesis

?Intestine

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?Mammary glands

Lipoprotein VLDL

Mobilizes Out and Transport

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Endogenously Biosynthesized Lipids

From Liver To Extra hepatocytes

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? Endogenously biosynthesized

Lipids at Liver are

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? Gathered and mobilized out in a

form of Lipoprotein VLDL to

extrahepatic tissues.

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? VLDL carries endogenous

Lipids rich in TAG from Liver

to extra Hepatocytes.

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? TAG is stored as reserve

food material in Adipose

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tissue in an unlimited

amount.
Why Lipogenesis Takes Place?

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Excess Carbohydrates Are

Transformed To Triacylglycerol (Fat)
Reasons For Lipogenesis

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? Free excess Glucose cant be stored as

it is in body cells and tissues.

? Free excess Glucose is first converted

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and stored in the form of Glycogen

? Storage of Glycogen is limited

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? In a well fed condition after limited storage

of Glycogen

? When stil there remains Free excess

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Glucose

? This free excess Glucose is Oxidized to

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Pyruvate via Glycolysis

? Further Pyruvate to Acetyl-CoA via PDH

complex reaction

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? This Acetyl-CoA when excess is then

diverted for Lipogenesis.
? Thus Lipogenesis occur in a wel fed

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condition

? To transform free excess Glucose to

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Acetyl-CoA further into Fatty acids.

? Fatty acids are stored as TAG
? Storageable form of Lipid (TAG).
? TAG in Adiposecytes can be stored

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in unlimited amounts.

Hormonal Influences

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On Lipogenesis
? In a well fed condition

? Hormone Insulin stimulates

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Lipogenesis.

? Hormone Glucagon inhibits

Lipogenesis.

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Alterations Of Lipogenesis In Clinical

Conditions

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? Inhibition of lipogenesis occurs in

Type 1 (insulin-dependent)

Diabetes mel itus

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? Variations in Lipogenesis affect

nature and extent of obesity

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How Lipogenesis Occur?

? Complex Mechanism
? Tissue Specific
? Compartmentalized

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? Regulated

Precursors For Lipogenesis
Precursors For Lipogenesis

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? Acetyl-CoA serve as a precursor

for Fatty acids and Cholesterol

biosynthesis.

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? This Acetyl-CoA comes from

excess and free Glucose Oxidation

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in a wel fed condition.

?Phospholipid

biosynthesis needs

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Lipotropic factors.
De Novo Biosynthesis

Of Fatty Acids

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?Fatty acid biosynthesis is a

reductive biosynthetic

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mechanism.

?To form reduced molecules

of Fatty acid (Palmitate).

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? De novo biosynthesis of Fatty

acids is a new biosynthesis of

Fatty acids.

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? Using simple carbon units

Acetyl-CoA and reducing

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equivalents as NADPH+H+ to a

long chain fatty acids.

? Palmitic acid (16:0) can

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be further modified to

higher Fatty acids .
Site For Fatty Acid Biosynthesis

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Organs Involved For

Fatty Acid Synthesis

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? In humans, Fatty acids are

biosynthesized in Cytosol of:

?Liver (Predominantly)

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?Adipose tissue

?Intestine

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?Lungs

?Brain

?Renal Cortex

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?Mammary glands during lactation
Reductive Biosynthesis

Of Fatty acids

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Extra Mitochondrial/Cytosolic

Biosynthesis of Fatty acids

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? Biosynthetic pathway of Fatty acids

involves

? Use of reducing equivalents NADPH+H+

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in reduction steps.

? To form reduced molecule of fatty

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acids,

? Hence it is termed as reductive

Synthesis of Fatty acids.

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? Fatty acids biosynthesized are

later used up for biosynthesis

of :

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?Triacylglycerol

?Phospholipid

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?Glycolipid

?Cholesterol Ester

?Fatty acids are stored as

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Triacylglycerol, especially

in Adipose tissue.
Biosynthesis Of Palmitic Acid/Palmitate

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(C16)

Requirements Of

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De Novo Biosynthesis

Of Palmitate
Prerequisites for Fatty acid

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Biosynthesis

? Immediate Substrate/Hydrocarbon Units

? Enzyme Systems

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? Coenzymes and Cofactors

? Precursor for Palmitic acid

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biosynthesis are 8 molecules

of Acetyl-CoA
Source

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Of Acetyl-CoA for Fatty acid

Biosynthesis ?

? Free and Excess Glucose in a

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wel fed condition


? Is major source of

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carbon/Acetyl-CoA for De

novo fatty acid biosynthesis.
?Free and excess Glucose

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remained after limited

Glycogen storage

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?Is used for Acetyl-CoA

production and diverted for

Fatty acid biosynthesis.

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?Glucose is oxidized to

Pyruvate via Glycolysis.
?Pyruvate(3C) is then oxidatively

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decarboxylated

?To a high energy compound

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Acetyl-CoA (2C)in Mitochondria

by PDH Complex.

? Excess of Acetyl CoA formed and

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present in Mitochondrial matrix


? Is diverted for Denovo

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Biosynthesis of Fatty acids.
? 8 molecules of Acetyl-CoA (C2)

are required

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? For biosynthesis of

1 molecule of even carbon

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Palmitate (C16).

? Enzymes Involved:

?Acetyl-CoA Carboxylase

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?Fatty Acyl Synthase (FAS)

Multi Enzyme Complex
Coenzymes and Cofactors for

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Fatty acid Biosynthesis

? Bicarbonate ions
? Biotin
? NADPH+ H+

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? ATP
? Mn +

? Requirement of HCO3-

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(Bicarbonate Ions) : Provides

CO2 for Acetyl-CoA

Carboxylation Reaction.

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Sources of Coenzyme Required

? Reducing Equivalent :

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?NADPH+H+

qMain source of NADPH+H+ is mainly by

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Pentose Phosphate Pathway.

qAnother source of NADPH+H+ Malic enzyme

activity converts Malate to Pyruvate which is

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Production of NADPH+ H+
?NADPH+H+ serves as an

electron donor in two

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reactions

?Involving substrate

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reduction in De Novo

Fatty acid biosynthesis.

Fatty Acyl Synthase (FAS)

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Multi Enzyme Complex

For De Novo Biosynthesis

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Of Fatty Acids


Acyl Carrier Protein

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Carrier of Intermediates in Fatty acid biosynthesis

? Discovered by P. Roy Vagelos.
Fatty Acyl Synthase (FAS) Complex

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? FAS is a Multi Enzyme Complex

Used in De Novo Biosynthesis of

Fatty acids.

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? Structurally FAS is a Homodimer

? Two alike monomeric subunits

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? Linked together in head to tail

fashion (Anti Paral el)
Structural Aspects Of FAS

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? FAS is Composed of 8

Components in one subunit.

? 7 Enzymes and 1 Protein

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Three Subunits/Domains

Of FAS Complex
1.Condensation Unit

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Has 3 Enzymes

? Acetyl Transacylase
? Malonyl Transacylase

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? Beta Keto Acyl Synthase

2. Reduction Unit

? ACP-(Acyl Carrier Protein)

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? Beta Keto Acyl Reductase
? Dehydratase
? Enoyl Reductase

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3. Cleavage /Releasing Unit

? Thioesterase (Deacylase)

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?In terms of

function, ACP is a

large CoA.

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Key Player:

Acyl Carrier

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Protein(ACP)

"Macro"

CoA, carries

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growing fatty

acid chain

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via Thioester


ACP Vs. Coenzyme A

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?Intermediates in synthesis are linked to -SH groups of

Acyl Carrier Proteins (as compared to -SH groups of CoA)

Acyl Carrier Protein

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Phosphopantetheine

H

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H HO CH3

O

HS-CH

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ACP

2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser-

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Cysteamine

O

O H H

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O

Acyl carrier protein

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10 kDa

H

H HO CH3

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O

O

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HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2

O

Adenine

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O

O H H

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O

O

O

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H

Coenzyme A

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O-P-O

OH

OH

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? ACP is a Conjugated Protein

component of FAS complex.

? ACP is a part of Reduction

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unit of FAS complex.

? 4- Phospho Pantethene serves as

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a prosthetic group of ACP.

? 4-Phospho Pantethene is a

derivative of Vitamin B 5-

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Pantothenic acid.

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? 4 Phosphopantetheine (Pant)

is covalently linked to Serine

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hydroxyl of Protein domain of

ACP via a phosphate ester

linkage .

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? ACP has ?SH group (Thiol) as

functional group.

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? -SH group of ACP is an acceptor of

Acetyl-CoA and Malonyl-CoA

during De novo biosynthesis of a

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Fatty acids.
Role of ACP In FAS Complex

? During De novo biosynthesis of

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fatty acids.

? Acyl Carrier Protein (ACP) of FAS

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complex is a carrier of growing

Acyl chain

? At end of Denovo Fatty acid

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biosynthesis

? Complete chain of Fatty

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acid is linked to ACP of FAS

complex.

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?Long flexible arm of

Phosphopantetheine

helps its Thiol

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?To move from one active

site to another within

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FAS complex.
FAS Complex Is Coded

By Single Gene

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Advantage Of Multi Enzyme Subunits

To Achieve

? An effect of compartmentalization of process

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? Good coordination and Communication

? Speed of reactions

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? Quality product
Location Of FAS Complex

?Cytosol

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?Extra mitochondrial

Hormones Regulating

FAS Complex

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? Insulin- Stimulates FAS Complex

? Glucagon-Inhibits FAS Complex
Functional Parts Of FAS Complex

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? FAS complex being dimer has two

functional Units.

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?-SH (Thiol) group of Cysteine of

condensation Enzyme Keto Acyl

Synthase.

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?-SH (Thiol) group of 4 Phospho

Pantethene of ACP.

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Thiol Cysteine residue

Thiol of Phosphopantetheine

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? As there are two functional units

? When FAS complex operates at a

time

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? There is biosynthesis of two Fatty

acids (Palmitate) molecule.
? Rate of Fatty acid

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biosynthesis is high in well-

fed state.

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X-Ray crystal ographic analysis at 3.2 ? resolution

shows the Dimeric Fatty Acid Synthase to have an

X-shape.

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Fatty Acid Synthase Complex

Fatty Acid Synthase Complex

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Stages And Steps

Of De Novo Biosynthesis

Of Fatty Acids

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Three Stages

Of

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De novo Biosynthesis

Of Fatty acid
I. Translocation of Acetyl-CoA from

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Mitochondria to Cytosol.

I . Carboxylation of Acetyl-CoA to

Malonyl-CoA

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I I. Reactions of FAS Complex

Stage I

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Translocation of Acetyl-CoA

from

Mitochondria to Cytosol

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Transport Of

Mitochondrial Acetyl-CoA

To Cytosol

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Since

Fatty Acid Synthesis

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Occurs in the Cytosol

Mitochondrial Acetyl-CoA

Is to be translocated In Cytosol

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Translocation Of Acetyl-CoA

Through

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Citrate Shuttle

Citrate Malate Pyruvate

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Transport System

Citrate transport

system

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? Mitochondrial Acetyl CoA is

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impermeable due to the

complex CoA .

? Impermeable Acetyl CoA is

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transformed to permeable

Citrate by Citrate Synthase.

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? Citrate is translocated out

in cytosol.

? Citrate in cytosol is cleaved

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by Citrate Lyase to liberate

Acetyl-CoA in cytosol.
Significance Of Citrate Malate Pyruvate

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Shuttle

?Citrate-Malate-Pyruvate shuttle

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during De novo Fatty acid

biosynthesis :

?Translocate Acetyl CoA to cytosol

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?Provides reducing equivalents

NADPH+H+

?Acetyl CoA from catabolism of

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Carbohydrates and Amino acids is

exported from Mitochondria via the

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Citrate transport system

?2 ATPs are required during work of

this system.

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?Impermeable Acetyl-CoA is

translocated out

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?From Mitochondrial Matrix

into Cytosol in the form of

permeable Citrate.

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?Acetyl-CoA(impermeable)

produced in the Mitochondria is

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condensed with Oxaloacetate to

form Citrate(permeable) by Citrate

Synthase.

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? Permeable Citrate is then

transported out into Cytosol

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? Citrate Lyase in Cytosol act

upon Citrate to regenerate

Acetyl-CoA and Oxaloacetate

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with consumption of ATP

?Most Acetyl-CoA used

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for FA synthesis comes

from Mitochondria.
Stage 2

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Carboxylation of

Acetyl-CoA to Malonyl-CoA

In Cytosol

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Fatty Acid Biosynthesis Initial Control ing Step

Carboxylation of

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Acetyl-CoA (2C)

to

Malonyl-CoA (3C)

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By

Acetyl CoA Carboxylase (ACC)
Acetyl-CoA(2C) Units

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Are Activated To

Malonyl-CoA(3C)

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For Transfer To Growing

Fatty Acid Chain

Malonyl-CoA (3C) Is a High Energy

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Compound

With a High Energy Bond In Its

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Structure
B. Carboxylation of Acetyl CoA

Enzyme: Acetyl CoA Carboxylase

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Prosthetic group - Biotin

?During biosynthesis of 16 C

saturated Palmitic acid

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?There requires total 8

molecules of Acetyl-CoA
?During FAS complex Fatty

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acid synthetic steps


?Only one molecule of Acetyl

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-CoA (C2) enters as it is in

first step of Third Stage of

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Fatty acid biosynthesis.

? Remaining 7 molecules of

Acetyl-CoA are entered in

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form of Malonyl-CoA (C3).
?Thus Seven Molecules of

Acetyl-CoA are

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?Transformed to Seven

molecules of Malonyl-

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CoA.

? Malonyl-CoA is obtained from

carboxylation reaction of Acetyl-

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CoA

? In presence of, enzyme Acetyl

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Carboxylase and coenzyme

Biotin and ATP.
vConversion of Acetyl-CoA to Malonyl

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CoA , is by catalytic activity of Acetyl

CoA Carboxylase , Biotin and ATP.
vThis is an Carboxylation reaction

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which provides energy input.
vTo form still more high energy

compound Malonyl-CoA(C3).

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? This carboxylation reaction

after use of high energy ATP

? Builds a high energy bond in

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a high energy compound

Malonyl-CoA.
? Input of Acetyl-CoA, into

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Fatty acid biosynthesis is by

its Carboxylation to Malonyl-

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CoA.
vLater this Malonyl CoA cleaves its high

energy bond and looses CO2 and energy

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vThis released energy is used for

condensation reaction during third stage

of Fatty acid biosynthesis for initiation and

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growing of Fatty acid.

?Thus spontaneous

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Decarboxylation of

Malonyl-CoA

?Drives condensation

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reaction of FAS complex.
HCO -

3 + ATP + Acetyl-CoA ADP + Pi + Malonyl-CoA

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Acetyl-CoA + HCO -3 + ATP Malonyl-CoA +ADP + Pi

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ACC-Biotin


Acetyl CoA Carboxylase (ACC)

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ACC

Formation of Malonyl-CoA

Acetyl-CoA Carboxylase

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has three activities:
?Biotin carrier Protein

?Biotin Carboxylase

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?Trans Carboxylase

Bicarbonate is

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Phosphorylated, then picked

up by Biotin

Biotin swinging arm

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transfers CO2 to acetyl-CoA
Significance Of

Formation of Malonyl-SCoA

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Significance Of

Formation of Malonyl-SCoA

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? This Carboxylation reaction is

considered as activation step.

? As the breaking of the CO2 bond of

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Malonyl-SCoA releases lot of energy

? That "drives" the reaction forward

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for condensation reaction of FAS

complex.
? High energy bond of Malonyl-

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CoA is hydrolyzed later

? To liberate energy which is

used up for Condensation

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reaction of FAS complex.

?Malonyl-CoA serves as

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activated donor of Acetyl

groups in FA synthesis.
? Fatty acid synthesis, from

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Acetyl-CoA and Malonyl-

CoA,

? Occurs by a series of

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reactions catalyzed by FAS

complex.

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Stage 3

Reactions Of FAS Complex

During

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De Novo Biosynthesis

Of a Fatty Acid-Palmitic Acid

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Step I-Step I I

Loading Of Precursors

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Acetyl CoA and Malonyl-CoA

On FAS Complex

By

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Acetyl and Malonyl Transacylases

Loading Of Precursor Acetyl CoA

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Step 1:

loading of

Acetyl-CoA

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onto Fatty

acid

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Synthase


Entry Of Malonyl-

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CoA

Step 2: loading

of Malonyl-

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CoA onto Fatty

acid Synthase

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? The Acetyl-CoA (2C) primer

molecule is first taken up by ?

SH group of ACP of FAS

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complex

? To form Acetyl-S-ACP catalyzed

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by Acetyl Transacylase.
? Acetyl group from ACP is shifted

to Cysteine-SH of enzyme Keto

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Acyl Synthase of FAS complex.


? To form Acetyl-S-Enzyme Keto

--- Content provided by‌ FirstRanker.com ---

Acyl Synthase in presence of

Acetyl Transacylase.

? Malonyl-CoA (3Carbon unit)

--- Content provided by⁠ FirstRanker.com ---

enters and is taken up by

-SH of ACP of FAS complex

--- Content provided by‍ FirstRanker.com ---

? To form Malonyl-S ACP catalyzed

by Malonyl Transacylase.

--- Content provided by FirstRanker.com ---

Step IV

Condensation Reaction

Catalyzed By

--- Content provided by‍ FirstRanker.com ---

Beta Keto Acyl Synthase

To Generate

--- Content provided by⁠ FirstRanker.com ---

Keto group

At Beta Carbon Atom

Step 2: Condensation

--- Content provided by​ FirstRanker.com ---

v Reaction of Malonyl

group with Acetyl

--- Content provided by‌ FirstRanker.com ---

group to form

Acetoacetyl- ACP

v Loss of CO2 and energy

--- Content provided by​ FirstRanker.com ---

from decarboxylation

of Malonyl-CoA.
? Malonyl Group is

--- Content provided by FirstRanker.com ---

decarboxylated releasing

CO2 and high energy

--- Content provided by FirstRanker.com ---

? Which is used for bond

building and condensation

reaction.

--- Content provided by FirstRanker.com ---

? During condensation reaction there

is linking of 2C units of Acetyl and

--- Content provided by​ FirstRanker.com ---

2C units of decarboxylated Malonyl

carbon units

? To form a 4 C Beta Keto Butyryl

--- Content provided by⁠ FirstRanker.com ---

ACP/ Keto Acyl ACP.


Step V

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Reduction Reaction

By

--- Content provided by‍ FirstRanker.com ---

Keto Acyl Reductase

To

Generate Beta Hydroxyl group

--- Content provided by⁠ FirstRanker.com ---

Step 3: Reduction of beta Keto

group to form beta Hydroxyl group
Reduction Of Keto Acyl- ACP

--- Content provided by‌ FirstRanker.com ---

? Keto Acyl- ACP is reduced to

Hydroxy Acyl- ACP

--- Content provided by‍ FirstRanker.com ---

? In presence of reducing

equivalents NADPH+H+ and

Enzyme Keto Acyl Reductase.

--- Content provided by‌ FirstRanker.com ---

Step VI

Dehydration Reaction

--- Content provided by⁠ FirstRanker.com ---

By

Dehydratase

To

--- Content provided by⁠ FirstRanker.com ---

Develop Double Bond


Step 4: Dehydration Reaction

--- Content provided by‌ FirstRanker.com ---

? Hydroxy Acyl- ACP is

dehydrated to Enoyl CoA/

--- Content provided by⁠ FirstRanker.com ---

? Unsaturated Acyl ACP

by the catalytic action of

Dehydratase.

--- Content provided by‌ FirstRanker.com ---

Step VI

Reduction Reaction

--- Content provided by‍ FirstRanker.com ---

By

Enoyl-CoA Reductase

--- Content provided by​ FirstRanker.com ---

To Generate

Saturated Bond

Step 5: Reduction of double bond to Single

--- Content provided by‌ FirstRanker.com ---

bond


? ? Unsaturated Acyl ACP is

--- Content provided by​ FirstRanker.com ---

reduced to Butyryl ?S-ACP

? By NADPH+ H+ and enzyme

--- Content provided by‍ FirstRanker.com ---

Enoyl Reductase.

Overview of

Assembly Stage

--- Content provided by‍ FirstRanker.com ---

4 steps:

Condensation

--- Content provided by⁠ FirstRanker.com ---

Reduction


Overview of

--- Content provided by​ FirstRanker.com ---

Assembly Stage

Dehydration

Reduction

--- Content provided by​ FirstRanker.com ---

Step VI I

Translocation Of Butyryl-S CoA to

--- Content provided by‍ FirstRanker.com ---

SH group of Condensing Enzyme

Beta Keto Acyl Synthase

--- Content provided by​ FirstRanker.com ---

Transfer of Butyryl Chain to SH group

of Beta Keto Acyl Synthase

Elongation and Growing

--- Content provided by​ FirstRanker.com ---

Of Fatty Acid Chain


To Elongate the Fatty Acid Chain

--- Content provided by‌ FirstRanker.com ---

To 16 Carbon Palmitate

There Should Be Entry

--- Content provided by​ FirstRanker.com ---

Of

6 More Molecules of

Malonyl CoA

--- Content provided by‍ FirstRanker.com ---

By Six Time Repetitions of

Steps I I-VI I

--- Content provided by‌ FirstRanker.com ---

1 Malonyl-CoA entry each

Time

Next cycle begins

--- Content provided by‌ FirstRanker.com ---

?Another

Malonyl group is

--- Content provided by‌ FirstRanker.com ---

linked to ACP


Repetitions Of

--- Content provided by⁠ FirstRanker.com ---

6 More Cycles

With 5 Steps

Fatty Acyl Synthase

--- Content provided by FirstRanker.com ---

The Steps in the De Novo biosynthesis of fatty acid

? Initiation To Form An Acyl Chain

--- Content provided by​ FirstRanker.com ---

I.

Loading of Precursor ?Acetyl-CoA at SH-ACP

--- Content provided by⁠ FirstRanker.com ---

I .

Translocation of Acetyl ?S-ACP to SH-Condensing Enzyme (SH-CE)

I I. Entry of Malonyl-CoA and Loading of Malonyl to SH-ACP

--- Content provided by‍ FirstRanker.com ---

IV. Condensation of the Acetyl and Malonyl with decarboxylation
V. Reduction Reaction to transform beta Keto group to Hydroxyl
VI. Dehydration Reaction to transform Hydroxyl group to Enoyl
VII. Reduction Reaction to transform Enoyl
VII . Translocation of Butyryl From S-ACP to SH-CE

--- Content provided by FirstRanker.com ---

?Elongation and Growing of Acyl Chain

?By Six Time Repetitions of Steps I I-VII
?Entry Of 6 Malonyl-CoA's at SH-ACP

--- Content provided by‍ FirstRanker.com ---

?1 Malonyl-CoA in each cycle to ACP-SH

?Cleavage of Fatty acid/ Palmitate

?By Thioesterase activity to release Palmitate and FAS

--- Content provided by‍ FirstRanker.com ---

? Following transfer of growing

fatty acid from

Phosphopantetheine to the

--- Content provided by FirstRanker.com ---

Condensing Enzyme's Cysteine

sulfhydryl.

--- Content provided by FirstRanker.com ---

? Cycle begins again, with another

Malonyl-CoA.

? Elongation of Fatty Acyl

--- Content provided by FirstRanker.com ---

chain occurs by addition of

Malonyl-CoA after every

--- Content provided by‍ FirstRanker.com ---

cycle.

? Every time a new Malonyl ?

CoA enters and taken up by

--- Content provided by FirstRanker.com ---

SH-ACP.
? There are total 7 cycles to utilize
? 1 Acetyl-CoA and 7 molecules of

--- Content provided by‍ FirstRanker.com ---

Malonyl-CoA and

? Elongate the Fatty Acid Chain to

16 Carbon Palmitate.

--- Content provided by⁠ FirstRanker.com ---

Remember

? At Each turn one Molecule of Malonyl

--- Content provided by‌ FirstRanker.com ---

CoA enters

? Accepted by ACP-SH to form Malonyl ?

SACP.

--- Content provided by FirstRanker.com ---

? Then repetitions of Condensation

,Reduction , Dehydration and

--- Content provided by‌ FirstRanker.com ---

Reduction Reactions takes place.
? Decarboxylation of Malonyl-

CoA and

--- Content provided by FirstRanker.com ---

? Reducing power of

NADPH+H+ drive fatty chain

growth.

--- Content provided by​ FirstRanker.com ---

? Butyryl group (C4) is shifted to

SH of Cysteine of Keto Acyl

--- Content provided by‍ FirstRanker.com ---

Synthase.

? SH of ACP is free for accepting

second molecule of Malonyl

--- Content provided by‍ FirstRanker.com ---

CoA to form Malonyl-S-ACP.
? Steps of Condensation ,Reduction,

Dehydration and Reduction

--- Content provided by​ FirstRanker.com ---

repeats.

? Aim of these steps is to convert a

--- Content provided by‍ FirstRanker.com ---

C=O group to CH2 group at

carbon of growing Acyl chain.

?After completion of total 7

--- Content provided by⁠ FirstRanker.com ---

cycles

?There is Palmitate

--- Content provided by‌ FirstRanker.com ---

synthesized and is carried

by S-ACP of FAS

complex(Palmitoyl-S-ACP)

--- Content provided by FirstRanker.com ---

Cleavage Of Completely

Biosynthesized Palmitate

From ACP of FAS Complex

--- Content provided by‌ FirstRanker.com ---

By Catalytic Activity Of Thioesterase

To Release

--- Content provided by FirstRanker.com ---

Free Palmitate and FAS Complex

? Cleavage enzyme Thioesterase

cleaves Thioester linkage and

--- Content provided by FirstRanker.com ---

? Releases free Palmitic acid

carried by S-ACP of FAS complex.
? Since FAS complex is a dimeric unit

--- Content provided by‌ FirstRanker.com ---

having two functional units.


? During its operation at a time two

--- Content provided by‍ FirstRanker.com ---

molecules of Palmitic acid are

biosynthesized and released.

--- Content provided by⁠ FirstRanker.com ---

Step 1: Loading Reactions


Step 2: Condensation Rxn

--- Content provided by‌ FirstRanker.com ---

Condensation reaction


Step 3: Reduction

--- Content provided by​ FirstRanker.com ---

Reduction Reaction


Step 4: Dehydration

--- Content provided by FirstRanker.com ---

Dehydration


Step 5: Reduction

--- Content provided by‌ FirstRanker.com ---

Reduction
Step 6: Next condensation

Repetitions Of 7

--- Content provided by⁠ FirstRanker.com ---

Cycles


Termination of

--- Content provided by​ FirstRanker.com ---

Fatty Acid

Acyl-CoA

Synthesis

--- Content provided by‌ FirstRanker.com ---

synthetase

Final reaction of FA synthesis is Cleavage

--- Content provided by⁠ FirstRanker.com ---

? Palmitoyl-ACP is hydrolyzed by a Thioesterase


Overal Reaction of Palmitate Synthesis from Acetyl

--- Content provided by⁠ FirstRanker.com ---

CoA and Malonyl CoA

Acetyl CoA + 7 Malonyl CoA + 14 NADPH + 14 H+

Palmitate + 7 CO2 + 14 NADP+ + 8 HS-CoA + 6 H2O

--- Content provided by‍ FirstRanker.com ---

Summary based on Malonate as an input:
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH

Palmitate + 7 CO2 + 14 NADP+ + 8 CoA

--- Content provided by​ FirstRanker.com ---

Fatty acid synthesis occurs in cytosol. Acetyl-

CoA generated in mitochondria is transported

to cytosol via a shuttle mechanism involving

--- Content provided by‌ FirstRanker.com ---

Citrate.

Stoichiometry for Palmitic Acid Synthesis

--- Content provided by‌ FirstRanker.com ---

Diagrammatic View of

Fatty Acid Biosynthesis

--- Content provided by FirstRanker.com ---

Energetics Of De Novo Synthesis

Of Fatty Acids
?De Novo Fatty acid

--- Content provided by‌ FirstRanker.com ---

biosynthesis is an

Anabolic process

involving use of ATPs.

--- Content provided by​ FirstRanker.com ---

? Total 23 ATPs are utilized

during biosynthesis of one

--- Content provided by​ FirstRanker.com ---

molecule of Palmitate.
?2 ATPs are used for 1 Acetyl-CoA translocation

through Citrate transport system

--- Content provided by⁠ FirstRanker.com ---

? For 8 Acetyl CoA translocation uses 16 ATPs

?1 ATP each is used for Acetyl CoA Carboxylation

to Malonyl CoA.

--- Content provided by FirstRanker.com ---

? To form 7 Malonyl CoAs 7 ATPs are utilized.

? 16+7 =23 ATPs Net utilized

--- Content provided by​ FirstRanker.com ---

Regulation Of Fatty Acid Biosynthesis
Nutritional Status Regulates

Lipogenesis

--- Content provided by FirstRanker.com ---

? High Carbohydrate
? High Lipid Diet
? Acyl-CoA Inhibits Pyruvate Dehydrogenase

Enzyme Acetyl-CoA Carboxylase

--- Content provided by​ FirstRanker.com ---

Is a

Regulatory ,Key Enzyme

--- Content provided by⁠ FirstRanker.com ---

Of

De Novo Fatty acid Synthesis.
? Committed Step of Fatty Acid Synthesis

--- Content provided by‍ FirstRanker.com ---

? Carboxylation of Acetyl CoA to Malonyl CoA
? By Acetyl CoA Carboxylase - Biotin

?Carboxylation of Acetyl-CoA

--- Content provided by FirstRanker.com ---

to form Malonyl-CoA

?Is an Irreversible, committed

step in Fatty acid biosynthesis

--- Content provided by‌ FirstRanker.com ---

Modes Of Regulation

Of Acetyl CoA Carboxylase

of FA Biosynthesis

--- Content provided by FirstRanker.com ---

Acetyl-CoA Carboxylase is regulated

by 3 modes:

--- Content provided by‌ FirstRanker.com ---

1. Hormonal Influence
2. Al osteric Control
3. Covalent Modification
1. Hormonal Influence

--- Content provided by FirstRanker.com ---

? ACC is an Inducible Enzyme:

?Induced by Insulin

?Insulin activates ACC

--- Content provided by‍ FirstRanker.com ---

?Repressed by Glucagon

?Glucagon inhibits ACC
2. Al osteric Modifiers

--- Content provided by‌ FirstRanker.com ---

?Citrate Activates Acetyl-CoA

--- Content provided by‌ FirstRanker.com ---

Carboxylase (Feed Forward)

?Fatty Acyl-CoAs inhibit Acetyl-

CoA Carboxylase

--- Content provided by⁠ FirstRanker.com ---

Al osteric modification of

Acetyl-Co A Carboxylase

--- Content provided by‌ FirstRanker.com ---

?Activated by: Citrate
?Inhibited by: Long Chain

Fatty Acid
? Body with high levels of cel ular

--- Content provided by​ FirstRanker.com ---

Citrate

? Stimulate De novo biosynthesis of

--- Content provided by​ FirstRanker.com ---

Fatty acids.

? Body on a high fat diet experience

little if any de novo fatty acid

--- Content provided by FirstRanker.com ---

synthesis.

3. Covalent Modification Of

--- Content provided by⁠ FirstRanker.com ---

Acetyl-CoA Carboxylase(ACC)

? ACC is Activated by :

Dephosphorylation

--- Content provided by​ FirstRanker.com ---

? ACC is Inhibited by:

Phosphorylation

--- Content provided by‍ FirstRanker.com ---

Covalent Modification Of ACC

Covalent Regulation OF

--- Content provided by FirstRanker.com ---

Acetyl CoA Carboxylase


? Activation of ACC

--- Content provided by​ FirstRanker.com ---

? In a wel Fed state

?Insulin induces Protein Phosphatase

?Activates ACC by De phosphorylation

--- Content provided by FirstRanker.com ---

? Inactivation of ACC

? In a Starved state

--- Content provided by⁠ FirstRanker.com ---

?Glucagon increases cAMP

?Activates Protein kinase A

--- Content provided by FirstRanker.com ---

?Inactivates ACC by Phosphorylation

Acetyl-CoA Carboxylase

--- Content provided by FirstRanker.com ---

Control of Fatty Acid Synthesis

Remember

Lipogenesis Is Inhibited

--- Content provided by​ FirstRanker.com ---

In

Type I Diabetes Mel itus And

--- Content provided by‍ FirstRanker.com ---

Obesity
Biosynthesis and Degradation

of

--- Content provided by⁠ FirstRanker.com ---

Fatty Acid

are

Reciprocal y Regulated

--- Content provided by​ FirstRanker.com ---

Very Wel Coordination And Regulation

Of Lipolysis And Lipogenesis

--- Content provided by‌ FirstRanker.com ---

Is A Healthy Lipid Metabolism
Both Lipogenesis And Lipolysis Should Be

Kept In Dynamism For Good Health

--- Content provided by FirstRanker.com ---

Wel Regulated Lipolysis And

Lipogenesis Prevent From Lipid

Associated Disorders

--- Content provided by‍ FirstRanker.com ---

?During Starvation

?Epinephrine & Glucagon Stimulate

Lipolysis

--- Content provided by⁠ FirstRanker.com ---

?Brings degradation of FA


?Wel Fed state

--- Content provided by⁠ FirstRanker.com ---

v Insulin inhibits Lipolysis

vInsulin Stimulates Fatty acid

--- Content provided by‍ FirstRanker.com ---

biosynthesis.

? ACC also influences degradation of Fatty

acids.

--- Content provided by⁠ FirstRanker.com ---

?Malonyl CoA inhibits Carnitine

Acyltransferase I activity.

--- Content provided by‍ FirstRanker.com ---

?This limits Beta oxidation of Fatty acids

in Mitochondrial Matrix.

--- Content provided by⁠ FirstRanker.com ---

Reciprocal Control


Overview of Fatty Acid Metabolism:

--- Content provided by FirstRanker.com ---

Insulin Effects

? Liver

? Increased fatty acid

--- Content provided by‍ FirstRanker.com ---

synthesis

? Glycolysis, PDH, FA

--- Content provided by‌ FirstRanker.com ---

synthesis

? Increased TAG synthesis

and transport as VLDL

--- Content provided by‌ FirstRanker.com ---

? Adipose

? Increased VLDL

--- Content provided by‌ FirstRanker.com ---

metabolism

? lipoprotein lipase

? Increased storage of

--- Content provided by‌ FirstRanker.com ---

lipid

? Glycolysis

--- Content provided by​ FirstRanker.com ---

Overview of Fatty Acid Metabolism:

Glucagon/Epinephrine Effects

? Adipose

--- Content provided by⁠ FirstRanker.com ---

? Hormone-sensitive

lipase Increased

? Increased TAG

--- Content provided by‌ FirstRanker.com ---

mobilization

? Increased FA

--- Content provided by FirstRanker.com ---

oxidation

? All tissues Except

CNS and RBC

--- Content provided by⁠ FirstRanker.com ---

Post-Synthesis Modifications

Of

--- Content provided by‌ FirstRanker.com ---

Biosynthesized Fatty Acids

? C16 Saturated fatty acid (Palmitate) is

--- Content provided by​ FirstRanker.com ---

product which may undergo:

?Elongation

?Unsaturation

--- Content provided by‌ FirstRanker.com ---

?Incorporation to form

Triacylglycerols

--- Content provided by​ FirstRanker.com ---

?Incorporation into Acylglycerol

phosphates to form

Phospholipids

--- Content provided by‌ FirstRanker.com ---

Chain Elongation Of Fatty Acids

Occurs In

Mitochondria

--- Content provided by​ FirstRanker.com ---

And

Smooth Endoplasmic Reticulum

--- Content provided by‍ FirstRanker.com ---

Elongation Of Fatty Acids

In Microsomes /Mitochondria

To

--- Content provided by​ FirstRanker.com ---

Synthesize Long Chain Fatty Acids
? Palmitate biosynthesized by De

Novo Biosynthesis in Cytosol by

--- Content provided by​ FirstRanker.com ---

the activity of FAS Complex

? Is further elongated to more higher

--- Content provided by‌ FirstRanker.com ---

Fatty acid either in Mitochondria

/Endoplasmic reticulum.

Mitochondrial Chain Elongation

--- Content provided by​ FirstRanker.com ---

? Here Acetyl-CoA is successively

added to Fatty acid chain lengthened

--- Content provided by FirstRanker.com ---

? In presence of reducing equivalents

NADPH+ H+

? Steps are almost reversal of Beta

--- Content provided by‌ FirstRanker.com ---

Oxidation of Fatty acids.


Microsomal/ER Chain Elongation Of

--- Content provided by​ FirstRanker.com ---

Fatty Acid

? This is more predominant way of

--- Content provided by⁠ FirstRanker.com ---

Fatty acid Chain Elongation.

? It involves successive addition of

Malonyl-CoA with the

--- Content provided by FirstRanker.com ---

participation of NADPH+ H+ and

enzyme Elongases.

--- Content provided by FirstRanker.com ---

Elongation of Chain (Two Systems)

R-CH2CH2CH2C~SCoA

Malonyl-CoA*

--- Content provided by‌ FirstRanker.com ---

O

(cytosol)

--- Content provided by​ FirstRanker.com ---

HS-CoA

OOC-CH2C~SCoA

CH3C~SCoA

--- Content provided by FirstRanker.com ---

O

CO

--- Content provided by​ FirstRanker.com ---

O

2

Acetyl-CoA

--- Content provided by FirstRanker.com ---

R-CH

(mitochondria)

--- Content provided by FirstRanker.com ---

2CH2CH2CCH2C~SCoA

O

O

--- Content provided by⁠ FirstRanker.com ---

1 NADPH

NADH

--- Content provided by⁠ FirstRanker.com ---

Elongation systems are

2 - H

found in smooth ER and

--- Content provided by‌ FirstRanker.com ---

2O

mitochondria

--- Content provided by‌ FirstRanker.com ---

3 NADPH

R-CH2CH2CH2CH2CH2C~SCoA

O

--- Content provided by‌ FirstRanker.com ---

Synthesis Of Unsaturated

Fatty Acids

Mammals can Biosynthesize

--- Content provided by‌ FirstRanker.com ---

Long Chain And

Monounsaturated

--- Content provided by⁠ FirstRanker.com ---

Fatty acids

Using Elongation And

Desaturation

--- Content provided by FirstRanker.com ---

Desaturation of Fatty Acid Chain In

Microsomes

--- Content provided by‍ FirstRanker.com ---

? Enzyme Fatty Acyl-CoA Desaturase

which is a Flavoprotein

--- Content provided by FirstRanker.com ---

? Helps in creating double bonds and

forming Mono Unsaturated Fatty

acids.

--- Content provided by​ FirstRanker.com ---

Palmitic acid

modifications

--- Content provided by‌ FirstRanker.com ---

Cell makes a pool of

palmitic acid that it can

elongate and/or

--- Content provided by‌ FirstRanker.com ---

desaturate in the ER.

Elongation system is

--- Content provided by​ FirstRanker.com ---

very similar to synthesis:

2C units added from

malonyl-CoA.

--- Content provided by​ FirstRanker.com ---

? Palmitic acid and Stearic acid

on Desaturation

? Forms corresponding MUFAS

--- Content provided by​ FirstRanker.com ---

Palmitoleic and Oleic acid

respectively.

--- Content provided by‍ FirstRanker.com ---

? Human body lack ability to introduce

double bonds beyond carbon 9 and

10 of Fatty acids.

--- Content provided by FirstRanker.com ---

? Hence body cannot biosynthesize

Linoleic and Linolenic acid and

--- Content provided by FirstRanker.com ---

become dietary essential Fatty acids.
? However Linoleic Acid by

Chain Elongation and

--- Content provided by⁠ FirstRanker.com ---

Desaturation


? Forms Arachidonic acid in

--- Content provided by‍ FirstRanker.com ---

Human body.

Palmitate

Desaturase

--- Content provided by⁠ FirstRanker.com ---

16:0 Elongase

Palmitoleate

--- Content provided by‍ FirstRanker.com ---

Stearate

16:1(9)

18:0 Desaturase Permitted

--- Content provided by‌ FirstRanker.com ---

Oleate

transitions

--- Content provided by⁠ FirstRanker.com ---

18:1(9)

in mammals

Essential

--- Content provided by​ FirstRanker.com ---

fatty acid

Desaturase

--- Content provided by‍ FirstRanker.com ---

Linoleate

Desaturase

18:2(9,12)

--- Content provided by⁠ FirstRanker.com ---

-Linolenate

-Linolenate

--- Content provided by⁠ FirstRanker.com ---

Desaturase

18:3(6,9,12)

18:3(9,12,15)

--- Content provided by‍ FirstRanker.com ---

ElongaseEicosatrienoate

Other lipids

--- Content provided by⁠ FirstRanker.com ---

Desaturase20:3(8,11,14)

Arachidonate

20:4(5,8,11,14)

--- Content provided by⁠ FirstRanker.com ---

Differences Between

Beta Oxidation Of Fatty Acid

--- Content provided by​ FirstRanker.com ---

And

De Novo Biosynthesis Of Fatty Acids
Biosynthesis and Degradation

--- Content provided by⁠ FirstRanker.com ---

Pathways are Different

?Major differences

--- Content provided by FirstRanker.com ---

between Fatty acid

breakdown and

biosynthesis are as:

--- Content provided by​ FirstRanker.com ---

Beta Oxidation

De Novo Biosynthesis

--- Content provided by​ FirstRanker.com ---

Palmitic acid Pathway Palmitic acid Pathway
Catabolic /Oxidative

Anabolic /Reductive

--- Content provided by⁠ FirstRanker.com ---

Occurs In Mitochondria Occurs In Cytosol
Acetyl CoA is an end

Acetyl CoA is a precursor

--- Content provided by‍ FirstRanker.com ---

product
Beta Carbon CH2 is

Beta Carbon C=O is

--- Content provided by‌ FirstRanker.com ---

transformed to C=O

converted to CH2

Generates 106 ATPs

--- Content provided by​ FirstRanker.com ---

Utilizes 23 ATPs

Coenzymes FAD and

--- Content provided by​ FirstRanker.com ---

Coenzymes NADPH +H+ is

NAD+ are involved

involved

--- Content provided by FirstRanker.com ---

CoA is an Acyl Carrier ACP is an Acyl Carrier
Fatty Acid Synthesis

Fatty Acid Beta Oxidation

--- Content provided by​ FirstRanker.com ---

? C=O -CH2

--- Content provided by FirstRanker.com ---

? CH2 C=O
Triacylglycerol (TAG) Biosynthesis

Site For TAG Biosynthesis
? TAG biosynthesis predominantly

--- Content provided by⁠ FirstRanker.com ---

occurs in Liver and Adipocytes

TAG Biosynthesis

--- Content provided by​ FirstRanker.com ---

Takes Place In

Smooth Endoplasmic Reticulum

--- Content provided by‍ FirstRanker.com ---

? TAG biosynthesis takes place after De

Novo Biosynthesis of Fatty acids.

? Fatty acids and Glycerol are activated

--- Content provided by‌ FirstRanker.com ---

before TAG biosynthesis.

? Fatty acids are activated to Acyl CoA by

--- Content provided by‍ FirstRanker.com ---

Thiokinase

? Glycerol is activated to Glycerol-3-

Phosphate by Glycerol Kinase.

--- Content provided by​ FirstRanker.com ---

Phospholipids are Common Intermediates of

TAG ,Phospholipids and Glycolipid Biosynthesis
? An Acyl chain is transferred to

--- Content provided by⁠ FirstRanker.com ---

Glycerol by Acyl Transferase

producing Lysophosphatidic

--- Content provided by‌ FirstRanker.com ---

acid.

? Lysophosphatidic acid is

transformed to Phosphatidic

--- Content provided by‍ FirstRanker.com ---

acid on addition of one more

Acyl chain.

--- Content provided by‌ FirstRanker.com ---

? Phosphate group is removed

from Phosphatidic acid to

generate Diacylglycerol.

--- Content provided by⁠ FirstRanker.com ---

? The addition of third Acyl chain

to Diacylglycerol finally results

--- Content provided by‍ FirstRanker.com ---

in Triacylglycerol.

? Usually a mixed type of TAG is

synthesized in the body.

--- Content provided by​ FirstRanker.com ---

Triacylglycerol Synthesis

Phospholipid Biosynthesis

--- Content provided by​ FirstRanker.com ---

Glycerophospholipid Synthesis

? Glycerophospholipids are

biosynthesized from

--- Content provided by​ FirstRanker.com ---

Phosphatidic acid and

Diacylglycerol.

--- Content provided by FirstRanker.com ---

? These are also intermediates of

TAG biosynthesis.
Synthesis OF Lecithin and Cephalin

--- Content provided by⁠ FirstRanker.com ---

? Nitrogenous bases Choline and Ethanolamine

are activated by CTP

--- Content provided by‌ FirstRanker.com ---

? To form CDP-Choline and CDP-Ethanolamine.

? These then added to Phosphatidic acid to

form Lecithin and Cephalin respectively.

--- Content provided by‌ FirstRanker.com ---

? Addition of Serine /Inositol to

Phosphatidic acid forms

--- Content provided by FirstRanker.com ---

Phosphatidyl Serine and

Phosphatidyl Inositol

--- Content provided by⁠ FirstRanker.com ---

Degradation Of Phospholipids

By Phospholipases

OR

--- Content provided by‍ FirstRanker.com ---

Different Types Of Phospholipases


Phospholipases are Rich In Poisonous

--- Content provided by⁠ FirstRanker.com ---

Snake Venoms
How and Why Snake Venom Is Toxin?