Download MBBS Biochemistry PPT 70 Lipogenesis Lecture Notes

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Lipogenesis

Specific Learning Objectives

Lipogenesis

? What is Lipogenesis ?

? Which forms of Lipids biosynthesized?

? When Lipogenesis Occur?

? Where Lipogenesis takes place ?

? Why Lipogenesis Occurs ?

? How Lipogenesis is made possible?

? Associated Disorders to Lipogenesis ?
What Is Lipogenesis?

?Lipogenesis is

biosynthesis of various

forms of Lipids in

human body.

Which Forms Of Lipid

Biosynthesized In

Human Body Tissues?
FORMS Of LIPID BIOSYNTHESIZED

1. Fatty acid Biosynthesis
2. Triacylglycerol Biosynthesis
3. Phospholipids Biosynthesis
4. Glycolipids Biosynthesis
5. Cholesterol Biosynthesis
6. Eicosanoids Biosynthesis

When Lipogenesis Occurs?
?Lipogenesis occurs in

well fed condition.

Conditions Favoring Lipogenesis

vExcess of Free Glucose after

heavy Carbohydrate meals.

v Insulin promotes Lipogenesis
Where Does Lipogenesis Occur?

Site Of Lipogenesis

?Predominant site for

Lipogenesis

?Liver Cytoplasm
?Other tissues for

Lipogenesis

?Intestine
?Mammary glands

Lipoprotein VLDL

Mobilizes Out and Transport

Endogenously Biosynthesized Lipids

From Liver To Extra hepatocytes


? Endogenously biosynthesized

Lipids at Liver are

? Gathered and mobilized out in a

form of Lipoprotein VLDL to

extrahepatic tissues.
? VLDL carries endogenous

Lipids rich in TAG from Liver

to extra Hepatocytes.

? TAG is stored as reserve

food material in Adipose

tissue in an unlimited

amount.
Why Lipogenesis Takes Place?

Excess Carbohydrates Are

Transformed To Triacylglycerol (Fat)
Reasons For Lipogenesis

? Free excess Glucose cant be stored as

it is in body cells and tissues.

? Free excess Glucose is first converted

and stored in the form of Glycogen

? Storage of Glycogen is limited

? In a well fed condition after limited storage

of Glycogen

? When stil there remains Free excess

Glucose

? This free excess Glucose is Oxidized to

Pyruvate via Glycolysis

? Further Pyruvate to Acetyl-CoA via PDH

complex reaction

? This Acetyl-CoA when excess is then

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

condition

? To transform free excess Glucose to

Acetyl-CoA further into Fatty acids.

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

in unlimited amounts.

Hormonal Influences

On Lipogenesis
? In a well fed condition

? Hormone Insulin stimulates

Lipogenesis.

? Hormone Glucagon inhibits

Lipogenesis.

Alterations Of Lipogenesis In Clinical

Conditions

? Inhibition of lipogenesis occurs in

Type 1 (insulin-dependent)

Diabetes mel itus


? Variations in Lipogenesis affect

nature and extent of obesity
How Lipogenesis Occur?

? Complex Mechanism
? Tissue Specific
? Compartmentalized
? Regulated

Precursors For Lipogenesis
Precursors For Lipogenesis

? Acetyl-CoA serve as a precursor

for Fatty acids and Cholesterol

biosynthesis.

? This Acetyl-CoA comes from

excess and free Glucose Oxidation

in a wel fed condition.

?Phospholipid

biosynthesis needs

Lipotropic factors.
De Novo Biosynthesis

Of Fatty Acids

?Fatty acid biosynthesis is a

reductive biosynthetic

mechanism.

?To form reduced molecules

of Fatty acid (Palmitate).
? De novo biosynthesis of Fatty

acids is a new biosynthesis of

Fatty acids.

? Using simple carbon units

Acetyl-CoA and reducing

equivalents as NADPH+H+ to a

long chain fatty acids.

? Palmitic acid (16:0) can

be further modified to

higher Fatty acids .
Site For Fatty Acid Biosynthesis

Organs Involved For

Fatty Acid Synthesis

? In humans, Fatty acids are

biosynthesized in Cytosol of:

?Liver (Predominantly)

?Adipose tissue

?Intestine

?Lungs

?Brain

?Renal Cortex

?Mammary glands during lactation
Reductive Biosynthesis

Of Fatty acids

Extra Mitochondrial/Cytosolic

Biosynthesis of Fatty acids

? Biosynthetic pathway of Fatty acids

involves

? Use of reducing equivalents NADPH+H+

in reduction steps.

? To form reduced molecule of fatty

acids,

? Hence it is termed as reductive

Synthesis of Fatty acids.
? Fatty acids biosynthesized are

later used up for biosynthesis

of :

?Triacylglycerol

?Phospholipid

?Glycolipid

?Cholesterol Ester

?Fatty acids are stored as

Triacylglycerol, especially

in Adipose tissue.
Biosynthesis Of Palmitic Acid/Palmitate

(C16)

Requirements Of

De Novo Biosynthesis

Of Palmitate
Prerequisites for Fatty acid

Biosynthesis

? Immediate Substrate/Hydrocarbon Units

? Enzyme Systems

? Coenzymes and Cofactors

? Precursor for Palmitic acid

biosynthesis are 8 molecules

of Acetyl-CoA
Source

Of Acetyl-CoA for Fatty acid

Biosynthesis ?

? Free and Excess Glucose in a

wel fed condition


? Is major source of

carbon/Acetyl-CoA for De

novo fatty acid biosynthesis.
?Free and excess Glucose

remained after limited

Glycogen storage

?Is used for Acetyl-CoA

production and diverted for

Fatty acid biosynthesis.

?Glucose is oxidized to

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

decarboxylated

?To a high energy compound

Acetyl-CoA (2C)in Mitochondria

by PDH Complex.

? Excess of Acetyl CoA formed and

present in Mitochondrial matrix


? Is diverted for Denovo

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

are required

? For biosynthesis of

1 molecule of even carbon

Palmitate (C16).

? Enzymes Involved:

?Acetyl-CoA Carboxylase
?Fatty Acyl Synthase (FAS)

Multi Enzyme Complex
Coenzymes and Cofactors for

Fatty acid Biosynthesis

? Bicarbonate ions
? Biotin
? NADPH+ H+
? ATP
? Mn +

? Requirement of HCO3-

(Bicarbonate Ions) : Provides

CO2 for Acetyl-CoA

Carboxylation Reaction.


Sources of Coenzyme Required

? Reducing Equivalent :

?NADPH+H+

qMain source of NADPH+H+ is mainly by

Pentose Phosphate Pathway.

qAnother source of NADPH+H+ Malic enzyme

activity converts Malate to Pyruvate which is

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

electron donor in two

reactions

?Involving substrate

reduction in De Novo

Fatty acid biosynthesis.

Fatty Acyl Synthase (FAS)

Multi Enzyme Complex

For De Novo Biosynthesis

Of Fatty Acids


Acyl Carrier Protein

Carrier of Intermediates in Fatty acid biosynthesis

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

? FAS is a Multi Enzyme Complex

Used in De Novo Biosynthesis of

Fatty acids.

? Structurally FAS is a Homodimer

? Two alike monomeric subunits

? Linked together in head to tail

fashion (Anti Paral el)
Structural Aspects Of FAS

? FAS is Composed of 8

Components in one subunit.

? 7 Enzymes and 1 Protein

Three Subunits/Domains

Of FAS Complex
1.Condensation Unit

Has 3 Enzymes

? Acetyl Transacylase
? Malonyl Transacylase
? Beta Keto Acyl Synthase

2. Reduction Unit

? ACP-(Acyl Carrier Protein)
? Beta Keto Acyl Reductase
? Dehydratase
? Enoyl Reductase


3. Cleavage /Releasing Unit

? Thioesterase (Deacylase)


?In terms of

function, ACP is a

large CoA.

Key Player:

Acyl Carrier

Protein(ACP)

"Macro"

CoA, carries

growing fatty

acid chain

via Thioester


ACP Vs. Coenzyme A

?Intermediates in synthesis are linked to -SH groups of

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

Acyl Carrier Protein

Phosphopantetheine

H

H HO CH3

O

HS-CH

ACP

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

Cysteamine

O

O H H

O

Acyl carrier protein

10 kDa

H

H HO CH3

O

O

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

O

Adenine

O

O H H

O

O

O

H

Coenzyme A

O-P-O

OH

OH
? ACP is a Conjugated Protein

component of FAS complex.

? ACP is a part of Reduction

unit of FAS complex.

? 4- Phospho Pantethene serves as

a prosthetic group of ACP.

? 4-Phospho Pantethene is a

derivative of Vitamin B 5-

Pantothenic acid.




? 4 Phosphopantetheine (Pant)

is covalently linked to Serine

hydroxyl of Protein domain of

ACP via a phosphate ester

linkage .

? ACP has ?SH group (Thiol) as

functional group.

? -SH group of ACP is an acceptor of

Acetyl-CoA and Malonyl-CoA

during De novo biosynthesis of a

Fatty acids.
Role of ACP In FAS Complex

? During De novo biosynthesis of

fatty acids.

? Acyl Carrier Protein (ACP) of FAS

complex is a carrier of growing

Acyl chain

? At end of Denovo Fatty acid

biosynthesis

? Complete chain of Fatty

acid is linked to ACP of FAS

complex.


?Long flexible arm of

Phosphopantetheine

helps its Thiol

?To move from one active

site to another within

FAS complex.
FAS Complex Is Coded

By Single Gene

Advantage Of Multi Enzyme Subunits

To Achieve

? An effect of compartmentalization of process

? Good coordination and Communication

? Speed of reactions

? Quality product
Location Of FAS Complex

?Cytosol

?Extra mitochondrial

Hormones Regulating

FAS Complex

? Insulin- Stimulates FAS Complex

? Glucagon-Inhibits FAS Complex
Functional Parts Of FAS Complex

? FAS complex being dimer has two

functional Units.

?-SH (Thiol) group of Cysteine of

condensation Enzyme Keto Acyl

Synthase.

?-SH (Thiol) group of 4 Phospho

Pantethene of ACP.


Thiol Cysteine residue

Thiol of Phosphopantetheine

? As there are two functional units

? When FAS complex operates at a

time

? There is biosynthesis of two Fatty

acids (Palmitate) molecule.
? Rate of Fatty acid

biosynthesis is high in well-

fed state.

X-Ray crystal ographic analysis at 3.2 ? resolution

shows the Dimeric Fatty Acid Synthase to have an

X-shape.


Fatty Acid Synthase Complex

Fatty Acid Synthase Complex
Stages And Steps

Of De Novo Biosynthesis

Of Fatty Acids

Three Stages

Of

De novo Biosynthesis

Of Fatty acid
I. Translocation of Acetyl-CoA from

Mitochondria to Cytosol.

I . Carboxylation of Acetyl-CoA to

Malonyl-CoA

I I. Reactions of FAS Complex

Stage I

Translocation of Acetyl-CoA

from

Mitochondria to Cytosol
Transport Of

Mitochondrial Acetyl-CoA

To Cytosol

Since

Fatty Acid Synthesis

Occurs in the Cytosol

Mitochondrial Acetyl-CoA

Is to be translocated In Cytosol


Translocation Of Acetyl-CoA

Through

Citrate Shuttle

Citrate Malate Pyruvate

Transport System

Citrate transport

system



? Mitochondrial Acetyl CoA is

impermeable due to the

complex CoA .

? Impermeable Acetyl CoA is

transformed to permeable

Citrate by Citrate Synthase.

? Citrate is translocated out

in cytosol.

? Citrate in cytosol is cleaved

by Citrate Lyase to liberate

Acetyl-CoA in cytosol.
Significance Of Citrate Malate Pyruvate

Shuttle

?Citrate-Malate-Pyruvate shuttle

during De novo Fatty acid

biosynthesis :

?Translocate Acetyl CoA to cytosol
?Provides reducing equivalents

NADPH+H+

?Acetyl CoA from catabolism of

Carbohydrates and Amino acids is

exported from Mitochondria via the

Citrate transport system

?2 ATPs are required during work of

this system.
?Impermeable Acetyl-CoA is

translocated out


?From Mitochondrial Matrix

into Cytosol in the form of

permeable Citrate.

?Acetyl-CoA(impermeable)

produced in the Mitochondria is

condensed with Oxaloacetate to

form Citrate(permeable) by Citrate

Synthase.
? Permeable Citrate is then

transported out into Cytosol


? Citrate Lyase in Cytosol act

upon Citrate to regenerate

Acetyl-CoA and Oxaloacetate

with consumption of ATP

?Most Acetyl-CoA used

for FA synthesis comes

from Mitochondria.
Stage 2

Carboxylation of

Acetyl-CoA to Malonyl-CoA

In Cytosol

Fatty Acid Biosynthesis Initial Control ing Step

Carboxylation of

Acetyl-CoA (2C)

to

Malonyl-CoA (3C)

By

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

Are Activated To

Malonyl-CoA(3C)

For Transfer To Growing

Fatty Acid Chain

Malonyl-CoA (3C) Is a High Energy

Compound

With a High Energy Bond In Its

Structure
B. Carboxylation of Acetyl CoA

Enzyme: Acetyl CoA Carboxylase

Prosthetic group - Biotin

?During biosynthesis of 16 C

saturated Palmitic acid

?There requires total 8

molecules of Acetyl-CoA
?During FAS complex Fatty

acid synthetic steps


?Only one molecule of Acetyl

-CoA (C2) enters as it is in

first step of Third Stage of

Fatty acid biosynthesis.

? Remaining 7 molecules of

Acetyl-CoA are entered in

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

Acetyl-CoA are

?Transformed to Seven

molecules of Malonyl-

CoA.

? Malonyl-CoA is obtained from

carboxylation reaction of Acetyl-

CoA

? In presence of, enzyme Acetyl

Carboxylase and coenzyme

Biotin and ATP.
vConversion of Acetyl-CoA to Malonyl

CoA , is by catalytic activity of Acetyl

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

which provides energy input.
vTo form still more high energy

compound Malonyl-CoA(C3).

? This carboxylation reaction

after use of high energy ATP

? Builds a high energy bond in

a high energy compound

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

Fatty acid biosynthesis is by

its Carboxylation to Malonyl-

CoA.
vLater this Malonyl CoA cleaves its high

energy bond and looses CO2 and energy

vThis released energy is used for

condensation reaction during third stage

of Fatty acid biosynthesis for initiation and

growing of Fatty acid.

?Thus spontaneous

Decarboxylation of

Malonyl-CoA

?Drives condensation

reaction of FAS complex.
HCO -

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

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



ACC-Biotin


Acetyl CoA Carboxylase (ACC)

ACC

Formation of Malonyl-CoA

Acetyl-CoA Carboxylase

has three activities:
?Biotin carrier Protein

?Biotin Carboxylase

?Trans Carboxylase

Bicarbonate is

Phosphorylated, then picked

up by Biotin

Biotin swinging arm

transfers CO2 to acetyl-CoA
Significance Of

Formation of Malonyl-SCoA

Significance Of

Formation of Malonyl-SCoA

? This Carboxylation reaction is

considered as activation step.

? As the breaking of the CO2 bond of

Malonyl-SCoA releases lot of energy

? That "drives" the reaction forward

for condensation reaction of FAS

complex.
? High energy bond of Malonyl-

CoA is hydrolyzed later

? To liberate energy which is

used up for Condensation

reaction of FAS complex.

?Malonyl-CoA serves as

activated donor of Acetyl

groups in FA synthesis.
? Fatty acid synthesis, from

Acetyl-CoA and Malonyl-

CoA,

? Occurs by a series of

reactions catalyzed by FAS

complex.

Stage 3

Reactions Of FAS Complex

During

De Novo Biosynthesis

Of a Fatty Acid-Palmitic Acid


Step I-Step I I

Loading Of Precursors

Acetyl CoA and Malonyl-CoA

On FAS Complex

By

Acetyl and Malonyl Transacylases

Loading Of Precursor Acetyl CoA

Step 1:

loading of

Acetyl-CoA

onto Fatty

acid

Synthase


Entry Of Malonyl-

CoA

Step 2: loading

of Malonyl-

CoA onto Fatty

acid Synthase

? The Acetyl-CoA (2C) primer

molecule is first taken up by ?

SH group of ACP of FAS

complex

? To form Acetyl-S-ACP catalyzed

by Acetyl Transacylase.
? Acetyl group from ACP is shifted

to Cysteine-SH of enzyme Keto

Acyl Synthase of FAS complex.


? To form Acetyl-S-Enzyme Keto

Acyl Synthase in presence of

Acetyl Transacylase.

? Malonyl-CoA (3Carbon unit)

enters and is taken up by

-SH of ACP of FAS complex

? To form Malonyl-S ACP catalyzed

by Malonyl Transacylase.


Step IV

Condensation Reaction

Catalyzed By

Beta Keto Acyl Synthase

To Generate

Keto group

At Beta Carbon Atom

Step 2: Condensation

v Reaction of Malonyl

group with Acetyl

group to form

Acetoacetyl- ACP

v Loss of CO2 and energy

from decarboxylation

of Malonyl-CoA.
? Malonyl Group is

decarboxylated releasing

CO2 and high energy

? Which is used for bond

building and condensation

reaction.

? During condensation reaction there

is linking of 2C units of Acetyl and

2C units of decarboxylated Malonyl

carbon units

? To form a 4 C Beta Keto Butyryl

ACP/ Keto Acyl ACP.


Step V

Reduction Reaction

By

Keto Acyl Reductase

To

Generate Beta Hydroxyl group

Step 3: Reduction of beta Keto

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

? Keto Acyl- ACP is reduced to

Hydroxy Acyl- ACP

? In presence of reducing

equivalents NADPH+H+ and

Enzyme Keto Acyl Reductase.

Step VI

Dehydration Reaction

By

Dehydratase

To

Develop Double Bond


Step 4: Dehydration Reaction

? Hydroxy Acyl- ACP is

dehydrated to Enoyl CoA/

? Unsaturated Acyl ACP

by the catalytic action of

Dehydratase.


Step VI

Reduction Reaction

By

Enoyl-CoA Reductase

To Generate

Saturated Bond

Step 5: Reduction of double bond to Single

bond


? ? Unsaturated Acyl ACP is

reduced to Butyryl ?S-ACP

? By NADPH+ H+ and enzyme

Enoyl Reductase.

Overview of

Assembly Stage

4 steps:

Condensation

Reduction


Overview of

Assembly Stage

Dehydration

Reduction

Step VI I

Translocation Of Butyryl-S CoA to

SH group of Condensing Enzyme

Beta Keto Acyl Synthase


Transfer of Butyryl Chain to SH group

of Beta Keto Acyl Synthase

Elongation and Growing

Of Fatty Acid Chain


To Elongate the Fatty Acid Chain

To 16 Carbon Palmitate

There Should Be Entry

Of

6 More Molecules of

Malonyl CoA

By Six Time Repetitions of

Steps I I-VI I

1 Malonyl-CoA entry each

Time

Next cycle begins

?Another

Malonyl group is

linked to ACP


Repetitions Of

6 More Cycles

With 5 Steps

Fatty Acyl Synthase


The Steps in the De Novo biosynthesis of fatty acid

? Initiation To Form An Acyl Chain

I.

Loading of Precursor ?Acetyl-CoA at SH-ACP

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
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

?Elongation and Growing of Acyl Chain

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

?Cleavage of Fatty acid/ Palmitate

?By Thioesterase activity to release Palmitate and FAS
? Following transfer of growing

fatty acid from

Phosphopantetheine to the

Condensing Enzyme's Cysteine

sulfhydryl.

? Cycle begins again, with another

Malonyl-CoA.

? Elongation of Fatty Acyl

chain occurs by addition of

Malonyl-CoA after every

cycle.

? Every time a new Malonyl ?

CoA enters and taken up by

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

Malonyl-CoA and

? Elongate the Fatty Acid Chain to

16 Carbon Palmitate.

Remember

? At Each turn one Molecule of Malonyl

CoA enters

? Accepted by ACP-SH to form Malonyl ?

SACP.

? Then repetitions of Condensation

,Reduction , Dehydration and

Reduction Reactions takes place.
? Decarboxylation of Malonyl-

CoA and

? Reducing power of

NADPH+H+ drive fatty chain

growth.

? Butyryl group (C4) is shifted to

SH of Cysteine of Keto Acyl

Synthase.

? SH of ACP is free for accepting

second molecule of Malonyl

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

Dehydration and Reduction

repeats.

? Aim of these steps is to convert a

C=O group to CH2 group at

carbon of growing Acyl chain.

?After completion of total 7

cycles

?There is Palmitate

synthesized and is carried

by S-ACP of FAS

complex(Palmitoyl-S-ACP)
Cleavage Of Completely

Biosynthesized Palmitate

From ACP of FAS Complex

By Catalytic Activity Of Thioesterase

To Release

Free Palmitate and FAS Complex

? Cleavage enzyme Thioesterase

cleaves Thioester linkage and

? Releases free Palmitic acid

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

having two functional units.


? During its operation at a time two

molecules of Palmitic acid are

biosynthesized and released.

Step 1: Loading Reactions


Step 2: Condensation Rxn

Condensation reaction


Step 3: Reduction

Reduction Reaction


Step 4: Dehydration

Dehydration


Step 5: Reduction

Reduction
Step 6: Next condensation

Repetitions Of 7

Cycles


Termination of

Fatty Acid

Acyl-CoA

Synthesis

synthetase

Final reaction of FA synthesis is Cleavage

? Palmitoyl-ACP is hydrolyzed by a Thioesterase


Overal Reaction of Palmitate Synthesis from Acetyl

CoA and Malonyl CoA

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

Palmitate + 7 CO2 + 14 NADP+ + 8 HS-CoA + 6 H2O
Summary based on Malonate as an input:
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH

Palmitate + 7 CO2 + 14 NADP+ + 8 CoA

Fatty acid synthesis occurs in cytosol. Acetyl-

CoA generated in mitochondria is transported

to cytosol via a shuttle mechanism involving

Citrate.

Stoichiometry for Palmitic Acid Synthesis


Diagrammatic View of

Fatty Acid Biosynthesis

Energetics Of De Novo Synthesis

Of Fatty Acids
?De Novo Fatty acid

biosynthesis is an

Anabolic process

involving use of ATPs.

? Total 23 ATPs are utilized

during biosynthesis of one

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

through Citrate transport system

? For 8 Acetyl CoA translocation uses 16 ATPs

?1 ATP each is used for Acetyl CoA Carboxylation

to Malonyl CoA.

? To form 7 Malonyl CoAs 7 ATPs are utilized.

? 16+7 =23 ATPs Net utilized

Regulation Of Fatty Acid Biosynthesis
Nutritional Status Regulates

Lipogenesis

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

Enzyme Acetyl-CoA Carboxylase

Is a

Regulatory ,Key Enzyme

Of

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

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

?Carboxylation of Acetyl-CoA

to form Malonyl-CoA

?Is an Irreversible, committed

step in Fatty acid biosynthesis
Modes Of Regulation

Of Acetyl CoA Carboxylase

of FA Biosynthesis

Acetyl-CoA Carboxylase is regulated

by 3 modes:

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

? ACC is an Inducible Enzyme:

?Induced by Insulin

?Insulin activates ACC

?Repressed by Glucagon

?Glucagon inhibits ACC
2. Al osteric Modifiers



?Citrate Activates Acetyl-CoA

Carboxylase (Feed Forward)

?Fatty Acyl-CoAs inhibit Acetyl-

CoA Carboxylase

Al osteric modification of

Acetyl-Co A Carboxylase

?Activated by: Citrate
?Inhibited by: Long Chain

Fatty Acid
? Body with high levels of cel ular

Citrate

? Stimulate De novo biosynthesis of

Fatty acids.

? Body on a high fat diet experience

little if any de novo fatty acid

synthesis.

3. Covalent Modification Of

Acetyl-CoA Carboxylase(ACC)

? ACC is Activated by :

Dephosphorylation

? ACC is Inhibited by:

Phosphorylation


Covalent Modification Of ACC

Covalent Regulation OF

Acetyl CoA Carboxylase


? Activation of ACC

? In a wel Fed state

?Insulin induces Protein Phosphatase

?Activates ACC by De phosphorylation


? Inactivation of ACC

? In a Starved state

?Glucagon increases cAMP

?Activates Protein kinase A

?Inactivates ACC by Phosphorylation

Acetyl-CoA Carboxylase


Control of Fatty Acid Synthesis

Remember

Lipogenesis Is Inhibited

In

Type I Diabetes Mel itus And

Obesity
Biosynthesis and Degradation

of

Fatty Acid

are

Reciprocal y Regulated

Very Wel Coordination And Regulation

Of Lipolysis And Lipogenesis

Is A Healthy Lipid Metabolism
Both Lipogenesis And Lipolysis Should Be

Kept In Dynamism For Good Health

Wel Regulated Lipolysis And

Lipogenesis Prevent From Lipid

Associated Disorders
?During Starvation

?Epinephrine & Glucagon Stimulate

Lipolysis

?Brings degradation of FA


?Wel Fed state

v Insulin inhibits Lipolysis

vInsulin Stimulates Fatty acid

biosynthesis.

? ACC also influences degradation of Fatty

acids.

?Malonyl CoA inhibits Carnitine

Acyltransferase I activity.

?This limits Beta oxidation of Fatty acids

in Mitochondrial Matrix.


Reciprocal Control


Overview of Fatty Acid Metabolism:

Insulin Effects

? Liver

? Increased fatty acid

synthesis

? Glycolysis, PDH, FA

synthesis

? Increased TAG synthesis

and transport as VLDL

? Adipose

? Increased VLDL

metabolism

? lipoprotein lipase

? Increased storage of

lipid

? Glycolysis

Overview of Fatty Acid Metabolism:

Glucagon/Epinephrine Effects

? Adipose
? Hormone-sensitive

lipase Increased

? Increased TAG

mobilization

? Increased FA

oxidation

? All tissues Except

CNS and RBC


Post-Synthesis Modifications

Of

Biosynthesized Fatty Acids

? C16 Saturated fatty acid (Palmitate) is

product which may undergo:

?Elongation

?Unsaturation

?Incorporation to form

Triacylglycerols

?Incorporation into Acylglycerol

phosphates to form

Phospholipids
Chain Elongation Of Fatty Acids

Occurs In

Mitochondria

And

Smooth Endoplasmic Reticulum

Elongation Of Fatty Acids

In Microsomes /Mitochondria

To

Synthesize Long Chain Fatty Acids
? Palmitate biosynthesized by De

Novo Biosynthesis in Cytosol by

the activity of FAS Complex

? Is further elongated to more higher

Fatty acid either in Mitochondria

/Endoplasmic reticulum.

Mitochondrial Chain Elongation

? Here Acetyl-CoA is successively

added to Fatty acid chain lengthened

? In presence of reducing equivalents

NADPH+ H+

? Steps are almost reversal of Beta

Oxidation of Fatty acids.


Microsomal/ER Chain Elongation Of

Fatty Acid

? This is more predominant way of

Fatty acid Chain Elongation.

? It involves successive addition of

Malonyl-CoA with the

participation of NADPH+ H+ and

enzyme Elongases.

Elongation of Chain (Two Systems)

R-CH2CH2CH2C~SCoA

Malonyl-CoA*

O

(cytosol)

HS-CoA

OOC-CH2C~SCoA

CH3C~SCoA

O

CO

O

2

Acetyl-CoA

R-CH

(mitochondria)

2CH2CH2CCH2C~SCoA

O

O

1 NADPH

NADH

Elongation systems are

2 - H

found in smooth ER and

2O

mitochondria

3 NADPH

R-CH2CH2CH2CH2CH2C~SCoA

O
Synthesis Of Unsaturated

Fatty Acids

Mammals can Biosynthesize

Long Chain And

Monounsaturated

Fatty acids

Using Elongation And

Desaturation


Desaturation of Fatty Acid Chain In

Microsomes

? Enzyme Fatty Acyl-CoA Desaturase

which is a Flavoprotein

? Helps in creating double bonds and

forming Mono Unsaturated Fatty

acids.

Palmitic acid

modifications

Cell makes a pool of

palmitic acid that it can

elongate and/or

desaturate in the ER.

Elongation system is

very similar to synthesis:

2C units added from

malonyl-CoA.
? Palmitic acid and Stearic acid

on Desaturation

? Forms corresponding MUFAS

Palmitoleic and Oleic acid

respectively.

? Human body lack ability to introduce

double bonds beyond carbon 9 and

10 of Fatty acids.

? Hence body cannot biosynthesize

Linoleic and Linolenic acid and

become dietary essential Fatty acids.
? However Linoleic Acid by

Chain Elongation and

Desaturation


? Forms Arachidonic acid in

Human body.

Palmitate

Desaturase

16:0 Elongase

Palmitoleate

Stearate

16:1(9)

18:0 Desaturase Permitted

Oleate

transitions

18:1(9)

in mammals

Essential

fatty acid

Desaturase

Linoleate

Desaturase

18:2(9,12)

-Linolenate

-Linolenate

Desaturase

18:3(6,9,12)

18:3(9,12,15)

ElongaseEicosatrienoate

Other lipids

Desaturase20:3(8,11,14)

Arachidonate

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


Differences Between

Beta Oxidation Of Fatty Acid

And

De Novo Biosynthesis Of Fatty Acids
Biosynthesis and Degradation

Pathways are Different

?Major differences

between Fatty acid

breakdown and

biosynthesis are as:

Beta Oxidation

De Novo Biosynthesis

Palmitic acid Pathway Palmitic acid Pathway
Catabolic /Oxidative

Anabolic /Reductive

Occurs In Mitochondria Occurs In Cytosol
Acetyl CoA is an end

Acetyl CoA is a precursor

product
Beta Carbon CH2 is

Beta Carbon C=O is

transformed to C=O

converted to CH2

Generates 106 ATPs

Utilizes 23 ATPs

Coenzymes FAD and

Coenzymes NADPH +H+ is

NAD+ are involved

involved

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

Fatty Acid Beta Oxidation



? C=O -CH2

? CH2 C=O
Triacylglycerol (TAG) Biosynthesis

Site For TAG Biosynthesis
? TAG biosynthesis predominantly

occurs in Liver and Adipocytes

TAG Biosynthesis

Takes Place In

Smooth Endoplasmic Reticulum


? TAG biosynthesis takes place after De

Novo Biosynthesis of Fatty acids.

? Fatty acids and Glycerol are activated

before TAG biosynthesis.

? Fatty acids are activated to Acyl CoA by

Thiokinase

? Glycerol is activated to Glycerol-3-

Phosphate by Glycerol Kinase.

Phospholipids are Common Intermediates of

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

Glycerol by Acyl Transferase

producing Lysophosphatidic

acid.

? Lysophosphatidic acid is

transformed to Phosphatidic

acid on addition of one more

Acyl chain.

? Phosphate group is removed

from Phosphatidic acid to

generate Diacylglycerol.

? The addition of third Acyl chain

to Diacylglycerol finally results

in Triacylglycerol.

? Usually a mixed type of TAG is

synthesized in the body.
Triacylglycerol Synthesis

Phospholipid Biosynthesis


Glycerophospholipid Synthesis

? Glycerophospholipids are

biosynthesized from

Phosphatidic acid and

Diacylglycerol.

? These are also intermediates of

TAG biosynthesis.
Synthesis OF Lecithin and Cephalin

? Nitrogenous bases Choline and Ethanolamine

are activated by CTP


? To form CDP-Choline and CDP-Ethanolamine.

? These then added to Phosphatidic acid to

form Lecithin and Cephalin respectively.

? Addition of Serine /Inositol to

Phosphatidic acid forms

Phosphatidyl Serine and

Phosphatidyl Inositol


Degradation Of Phospholipids

By Phospholipases

OR

Different Types Of Phospholipases


Phospholipases are Rich In Poisonous

Snake Venoms
How and Why Snake Venom Is Toxin?

This post was last modified on 05 April 2022