Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 70 Lipogenesis Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
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