Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 68 Lipolysis And Fatty Acid Oxidation 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.
LIPID METABOLISM
Stages And Reaction Steps
Of Beta Oxidation Of Fatty Acids
Three Stages Of Beta Oxidation
For
Oxidation Fatty acid Palmitate
Stage I
Activation of
Long Chain Fatty acid (Acyl Chain)
To
Acyl-CoA In Cytosol
? Palmitate to Palmitoyl-CoA
In Cytosol
Stage II
Translocation of Activated Fatty acid
From Cytosol into Mitochondrial
Matrix
Through Role of Carnitine
(Carnitine Shuttle)
Stage I I
Steps of Beta Oxidation Proper
In Mitochondrial Matrix
?Oxidation Reaction
?Hydration Reaction
?Oxidation Reaction
?Cleavage Reaction
Stage I
Activation Of Fatty acid
In Cytosol
Is a Preparative Phase
Site Of Fatty acid Activation
? Fatty acid(Acyl Chain) is activated
in Cytosol to Acyl-CoA .
Requirements of FA Activation
?Enzyme:
?Thiokinase /Acyl CoA Synthetase
?Coenzymes/Cofactors:
? CoA-SH derived from Pantothenic acid
?ATP
?Magnesium ions (Mg++)
CoezymeA (CoA-SH)
Activates
Fatty Acids
for Beta Oxidation
CoA Helps in
Activation of Fatty Acid
? A long chain Fatty acid is termed as
Acyl chain.
? Every Fatty acid which undergoes
Oxidation of Fatty acid is first
activated to Acyl-CoA.
? Activation of a
Fatty acid means:
? Linking of Acyl Chain to
Coenzyme A to form Acyl-CoA
with a high energy bond.
? During Activation of
Fatty acid (Acyl Chain)
? `H' of CoA-SH (Coenzyme A) is
substituted by Acyl chain
? To form CoA-S Acyl, i.e. Acyl-CoA an
activated Fatty acid.
?Thus CoenzymeA is a
carrier of Acyl chain in
an activated fatty acid.
Steps Of Fatty Acid Activation
Activation Of a Fatty Acid
Is ATP Dependent
Converts ATP to AMP
Hence Requirement is
equivalent to 2 ATPs
Acyl-CoA Synthetase/
Fatty Acid Thiokinase
condenses Fatty acids with CoA,
with simultaneous hydrolysis of
ATP to AMP and PPi
?An Acyl-CoA is an
activated energetic
compound having high
energy bond in it.
? Thus formation of Acyl?CoA is
an expensive energetical y
Fatty acid Activation
? Activation of Fatty acids is esterification
of Fatty acid with Coenzyme A
? In presence of Acyl-CoA Synthetase
(Thiokinase) forming an activated Fatty
acid as Acyl-CoA.
? This process is ATP-dependent, & occurs
in 2 steps.
? During the activation of Fatty acid
ATP is converted to AMP and ppi.
? Two high energy bonds of ATP are
cleaved and utilized in this activation
which is equivalent to 2 ATPs.
? Subsequent hydrolysis of PPi from
ATP drives the reaction strongly
forward.
? Note the Acyl- Adenylate is an
intermediate in the mechanism.
? There are different Acyl-CoA
Synthetase for fatty acids of
different chain lengths.
Activated Fatty Acid (Acyl-CoA)
is a High Energy Compound
Which Facilitates
Second Stage
Of
Beta Oxidation Of Fatty Acid
Stage I
Translocation Of Acyl-CoA
From Cytosol
Into Mitochondrial Matrix
With The Help Of Carnitine
?-oxidation proper
occurs in Mitochondrial
matrix.
? CoA is a complex structure.
? CoA part of Palmitoyl-CoA is
impermeable to inner membrane
of Mitochondria
? Long-chain Fatty acids more than 12
Carbon atoms cannot be directly
translocated into the Mitochondrial
matrix.
? However short chain Fatty acids are
directly translocated into the
Mitochondrial matrix
? To translocate an activated long chain
Fatty acid (Acyl-CoA) from cytosol to
mitochondrial matrix
? Across mitochondrial membrane
operates a specialized Carnitine Carrier
System.
What Is Carnitine?
? Carnitine is a functional, Non
Protein Nitrogenous (NPN)
substance.
? Carnitine is biosynthesized in the
body by amino acids Lysine and
Methionine.
?
? Long chain Acyl CoA traverses
an inner mitochondrial
membrane with a special
transport mechanism called
Carnitine Shuttle.
Significance Of Acyl-CoA Formation
? High energy bond of Acyl-CoA
releases high energy which
helps in condensation of Acyl
with Carnitine for further
translocation.
Mechanism Of Carnitine
In Transport Of
Fatty Acyl CoA
From Cytosol To Mitochondrial Matrix
? Acyl-CoA a high energy
compound cleave its high energy
bond in second stage.
? Bond energy released is used up
for linking Carnitine to Acyl chain
to form Acyl-Carnitine.
? Long-chain FA are converted to
Acyl Carnitine and are then
transported
? Acyl-CoA are reformed inside an
inner membrane of
mitochondrial matrix.
q Acyl groups from Acyl-COA is
transferred to Carnitine to form Acyl-
Carnitine catalyzed by Carnitine Acyl
Transferase I (CAT I)
q CAT I is present associated to outer
mitochondrial membrane
.
q Acylcarnitine is then shuttled across an
inner mitochondrial membrane by a
Translocase enzyme.
q Acyl group is linked to CoA of
Mitochondrial pool in mitochondrial
matrix by Carnitine Acyl Transferase I
(CAT I ) to regenerate Acyl-CoA in
mitochondrial matrix.
q Finally, Carnitine is returned to cytosolic
side by Protein Translocase, in exchange
for an incoming Acyl Carnitine.
Points To Remember
? Cell maintains two separate pools of
Coenzyme-A:
?Cytosolic pool of CoA
?Mitochondrial pool of CoA
?CoA is complex structure cannot
transport across Mitochondrial
membrane
?CoA linked to Fatty acid in
Mitochondria is different from
that CoA used for Fatty acid
activation.
Translocation of Palmitoyl-CoA
Across
Mitochondrial Membrane
ATP + CoA
AMP + PPi
palmitate
palmitoyl-CoA
Cytoplasm
OUTER
ACS
MITOCHONDRIAL
CPT-I
[1]
[2]
MEMBRANE
CoA
palmitoyl-CoA
Intermembrane
palmitoyl-carnitine
Space
carnitine
Activation of Palmitate to Palmitoyl CoA and conversion to Palmitoyl
Carnitine
CPT-I
palmitoyl-CoA
CoA
Intermembrane Space
Palmitoyl-Carnitine
Carnitine
INNER
CAT
[3]
MITOCHONDRIAL
MEMBRANE
Matrix
CPT-II
Carnitine
palmitoyl-carnitine
[4]
palmitoyl-CoA
CoA
Mitochondrial uptake via of Palmitoyl-Carnitine via the Carnitine-
Acylcarnitine Translocase (CAT)
ATP + CoA AMP + PPi
Cytoplasm
palmitate
palmitoyl-CoA
OUTER
MITOCHONDRIAL
ACS
CPT-I
MEMBRANE
[1]
[2]
CoA
Intermembrane
palmitoyl-CoA
Space
palmitoyl-carnitine
Carnitine
INNER
CAT
[3]
MITOCHONDRIAL
MEMBRANE
CPT-II
Matrix
carnitine
palmitoyl-carnitine
[4]
palmitoyl-CoA
CoA
Carnitine-mediated transfer of the fattyAcyl moiety into the
mitochondrial matrix is a 3-step process:
1. Carnitine Palmitoyl Transferase I, an enzyme on the
cytosolic surface of the outer mitochondrial membrane,
transfers a fatty acid from CoA to the OH on Carnitine.
2. An Translocase/Antiporter in the inner mitochondrial
membrane mediates exchange of Carnitine for Acylcarnitine.
3. Carnitine Palmitoyl Transferase I , an enzyme within the
matrix, transfers the fatty acid from Carnitine to CoA.
(Carnitine exits the matrix in step 2.)
The fatty acid is now esterified to CoA in the mitochondrial
matrix.
Stage I I
Steps of Beta Oxidation Proper/Cycle
In Mitochondrial Matrix
?Oxidation Reaction
?Hydration Reaction
?Oxidation Reaction
?Cleavage Reaction
Site/Occurrence Of
? Oxidation Proper
? In Mitochondrial Matrix of
Cel s.
? After translocation of Acyl-
CoA in Mitochondrial matrix.
Mechanism Of Reactions
Of
Beta Oxidation Proper
of
Palmitoyl-CoA
Step I: Oxidation by
FAD linked Acyl CoA Dehydrogenase
Step I : Hydration by Enoyl CoA Hydratase
Step I I: Oxidation by NAD linked
eta Hydroxy Acyl CoA Dehydrogenase
Step IV: Thiolytic Cleavage by Keto
Thiolase
Palmitoylcarnitine
inner mitochondrial
Carnitine
membrane
respiratory chain
translocase
Palmitoylcarnitine
matrix side
1.5 ATP2.5 ATP
Palmitoyl-CoA
FAD
oxidation
FADH2
hydration
H2O
-Oxidation of
recycle
NAD+
Palmitoyl CoA
oxidation
6 times
NADH
cleavage
CoA
CH3-(CH)12-C-S-CoA + Acetyl CoA
Citric
O
acid
cycle
2 CO2
? Strategy of First 3 reactions of Beta
Oxidation proper is to
? Create a Carbonyl group (C=O) on
-Carbon atom (CH2) of a Fatty
acid.
? This weakens bond between and
Carbon atoms of Fatty acid.
? Fourth reaction cleaves "-
Keto ester" in a reverse
Claisen condensation reaction.
? Products of Each turn/cycle of
beta oxidation proper are :
?Acetyl-CoA
?Acyl-CoA with two carbons
shorter
Step 1
Role Of
Acyl-CoA Dehydrogenase
To Bring
Oxidation of the C-C bond
of Fatty acid
Acyl CoA Dehydrogenase is a
FAD linked Enzyme
(Flavoprotein)
? Acyl CoA Dehydrogenase catalyzes
Oxidation reaction
? Where there is a removal of
Hydrogen from alpha and beta
carbon atoms of Acyl-CoA.
? There forms a double bond
between C -C / C2 and C3 of
Fatty Acid.
? The product of this oxidation
reaction is - Unsaturated Acyl
CoA /Trans Enoyl CoA.
? Coenzyme FAD is the temporary
hydrogen acceptor in this oxidation
reaction .
? The reduced FADH2 is generated by
oxidation reaction of Acyl CoA
Dehydrogenase.
? FADH2 is then reoxidized, after its enter
into Electron Transport Chain
? Mechanism of Acyl CoA
Dehydrogenase involves :
?Proton Abstraction/Removes
Hydrogen
?Double bond formation
?Hydride removal by FAD
?Generation of reduced FADH2
? FADH2 is oxidized by entering into
ETC.
? Electrons from FADH2 are passed to
Electron transport chain
components,
? Coupled with phosphorylation to
generate 1.5 ATP
(By Oxidative Phosphorylation).
Acyl-CoA Dehydrogenase
? There are different Acyl-CoA
Dehydrogenases :
?Short Chain Fatty acids (4-6 C),
?Medium Chain Fatty Acids (6-10 C),
?Long (12-18 C) and very long (22 and
more)chain Fatty acids.
Inhibitor Of
Acyl CoA Dehydrogenase
?Acyl CoA Dehydrogenase is
inhibited by a Hypoglycin
(from Akee fruit)
Step 2
Role Of
Enoyl CoA Hydratase
To add water across the double bond
C = C of Trans-Enoyl-CoA
Saturate the double bond of Enoyl-CoA
Generate Hydroxyl group at beta carbon
?Enoyl-CoA Hydratase catalyzes
stereospecific hydration of the trans
double bond
?It adds water across the double bond
at C2 and C3 of Trans Enoyl CoA
?This hydration reaction generates
Hydroxyl (OH) group at beta
carbon atom of FA
?Converts Trans-Enoyl-CoA to
L -Hydroxyacyl-CoA
Step 3
Role Of
Hydroxyacyl-CoA Dehydrogenase
To Oxidizes the -Hydroxyl Group of
-Hydroxyacyl-CoA
And
Transform it into
-Ketoacyl-CoA
? -Hydroxyacyl-CoA Dehydrogenase is
NAD+ dependent
? It catalyzes specific oxidation of the
Hydroxyl group in the b position (C3) to
form a ketone group.
? NAD+ is the temporary electron acceptor
for this step which generates reduced
form NADH+H+
? The oxidation of
-Hydroxyacyl CoA produces a
product - Ketoacyl-CoA.
Step 4
Role Of b- Ketothiolase
/Thiolase
Catalyzes Thiolytic cleavage of the
two carbon fragment
by splitting the
bond between and carbons
? An enzyme -Keto Thiolase attacks
the -carbonyl group of -Ketoacyl-
CoA.
? This results in the cleavage of the
C-C bond.
? Releases Acetyl-CoA(2C) and an Acyl-
CoA (-2carbons shorter ).
Repetitions Of 4 Steps Of
Beta Oxidation Proper
? The b-oxidation proper pathway
is cyclic.
? 4 Steps of Beta Oxidation proper
are repeated
? Til whole chain of Fatty acid is
oxidized completely.
? Product, 2 carbons shorter
Acyl -CoA,
? Is input to another
round/turn of the beta
oxidation proper pathway.
? Acyl CoA molecule released at end of
Beta Oxidation
? Is the substrate for the next round of
oxidation starting with Acyl CoA
Dehydrogenase.
? Repetition continues until all the carbon
atoms of the original Fatty acyl CoA are
converted to Acetyl CoA.
The shortened Acyl
CoA then undergoes
another cycle of beta
oxidation
The number of beta
oxidation cycles:
n/2-1, where n ? the
number of carbon atoms
Products Of Each Turn
Of
Beta Oxidation Proper
? Each turn/cycle of oxidation proper
generates one molecule each of:
?FADH2
?NADH+H+
?Acetyl CoA
?Fatty Acyl CoA ( with 2 carbons shorter each round)
Steps Of
-Oxidation Proper
of Fatty Acids Continues
With
A Repeated Sequence
of 4 Reactions
Til
A Long Fatty Acyl Chain Is
Completely Oxidized
?For an oxidation of Palmitic
acid through beta oxidation
? 7 turns/cycles of beta
oxidation proper steps occur.
Beta Oxidation
Fates of the products
of
-oxidation of Fatty Acid
? NADH+H+ and FADH2 - are
reoxidized in ETC to generate ATP
? Acetyl CoA - Enters the Citric acid
cycle(TCA cycle) for its complete
oxidation.
? Acyl CoA ? Undergoes the next
turn/cycle of oxidation proper.
Complete Oxidation Of Fatty Acids
Fatty Acid
Oxidation
Acetyl CoA +ATP
TCA Cycle
CO2 +H2O and ATP
? Fatty acid is activated and oxidized via
Beta Oxidation in specific number of
cycles depending upon chain length.
? Acetyl CoA an end product of Beta
oxidation of Fatty acid
? Is further completely oxidized via
TCA cycle.
1
Palmitoylcarnitine
inner mitochondrial
Carnitine
membrane
respiratory chain
translocase
Palmitoylcarnitine
matrix side
1.5 ATP2.5 ATP
Palmitoyl-CoA
FAD
oxidation
FADH2
Figure 4.
hydration
H2O
Processing and
NAD+
-oxidation of
recycle
oxidation
Palmitoyl CoA
6 times
NADH
cleavage
CoA
CH3-(CH)12-C-S-CoA + Acetyl CoA
Citric
O
acid
cycle
2 CO2
-Oxidation
Overal Flow
CAPILLARY
Lipoproteins
(Chylomicrons
L [2]
FABP
MITOCHONDRION
P
or VLDL)
FA
L
acetyl-CoA
TCA
A
[7]
[3]
cycle
[4] C
FA
FA
-oxidation
S
[6]
FA
FA
albumin
acyl-CoA
acyl-CoA
FABP
FABP
FA
[5]
carnitine
CYTOPLASM
transporter
[1]
from
fat
cel membrane
cel
FA = fatty acid
LPL = lipoprotein lipase
FABP = fatty acid binding protein
ACS = acyl CoA synthetase
Figure 2. Overview of fatty acid degradation
Energetics Of Beta oxidation
Of Palmitate
? Oxidation of Palmitic Acid C16
Number of turns of fatty acid
spiral = 8-1 = 7 Cycles of beta
oxidation proper.
? Generates 8 Acetyl CoA
During Electron Transport and
Oxidative Phosphorylation
Each FADH2 yield 1.5 ATP
and NADH 2.5 ATP
Energetics of Fatty Acid Beta Oxidation
e.g. Palmitic (16C):
1.-oxidation of Palmitic acid will be repeated in 7
cycles producing 8 molecules of Acetyl COA.
2.In each cycle 1 FADH2 and 1 NADH+H+ is produced
and will be transported to the respiratory chain/ETC.
? FADH2 1.5 ATP
? NADH + H+ 2.5 ATP
? Thus Each cycle of -oxidation 04 ATP
? So 7 cycles of -oxidation 4 x 7 = 28 ATP
1 Acetyl CoA
Yields 10 ATPs
via
TCA Cycle
? Review ATP Generation ?TCA/ Citric Acid
Cycle which start with Acetyl CoA
? Step
ATP produced
? Step 4 (NADH+H to ETC)
2.5 ATP
? Step 6 (NADH+H to E.T.C.) 2.5 ATP
? Step 10 (NADH+H to ETC) 2.5 ATP
? Step 8 (FADH2 to E.T.C.)
1.5 ATP
? 1 GTP
01 ATP
? NET per turn of TCA Cycle 10 ATP
1 ATP converted to AMP
during activation of
Palmitic acid to Palmitoyl-CoA
is equivalent to 2ATPs utilized
3. Each Acetyl COA which is oxidized
completely in citric cycle/TCA cycle gives 10
ATP
4. Hence 8 Acetyl CoA via TCA cycle (8 x 10 =
80 ATP)
5. 2 ATP are utilized in the activation of Fatty
acid
6. Energy gain = Energy produced - Energy
utilized
7. 28 ATP + 80 ATP - 2 ATP = 106 ATP
Thus On Complete Oxidation of
One molecule of Palmitate
106 molecules of ATP
are generated
ATP Generation from Palmitate Oxidation
Net yield of ATP per one oxidized Palmitate
Palmitate (C15H31COOH) - 7 cycles ? n/2-1
Palmitoyl CoA + 7 HS-CoA + 7 FAD+ + 7 NAD+ + 7 H2O
8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+
ATP generated
8 Acetyl CoA(TCA)
10x8=80
7 FADH2
7x1.5=10.5
7 NADH
7x2.5=17.5
108 ATP
ATP expended to activate Palmitate -2 ATP
Net yield of ATPs with Palmitate Oxidation: 106 ATP
Total End Products
Of
Beta Oxidation
Of
1 molecule of a Palmitic Acid
Palmitic acid
With 7 Turns of
Beta Oxidation Proper
Generates
8 Molecules Of Acetyl-CoA
7 FADH2+7 NADH+H+
Summary of one round/turn/cycle of the
b-oxidation pathway:
Fatty Acyl-CoA + FAD + NAD+ + HS-CoA
+Acetyl-CoA
Fatty Acyl-CoA (2 C less) + FADH2 + NADH + H+
Stoichiometry for
Palmitic Acid Oxidation
-Oxidation Proper of Acyl-CoA
b F
-O at
xi ty
da acyl
tion CoA
of
Saturated fatty acids
Regulation Of Beta Oxidation
Of Fatty Acids
?Lipolysis and
Oxidation of Fatty acids
are well regulated under
Hormonal influence.
Insulin secretion is
In Wel Fed Condition
? Insulin inhibits Lipolysis of Adipose
Fat (TAG) and mobilization of Free
Fatty acids.
? Insulin decreases Oxidation of
Fatty acids.
Glucagon In Emergency Condition
? When Cellular or Blood Glucose
lowers down there is secretion of
Glucagon.
? Glucagon and Epinephrine
stimulates Lipolysis in emergency
condition.
? Glucagon stimulates the Enzyme
Hormone sensitive Lipase and
hydrolyzes depot Fat(TAG).
? Glucagon mobilizes Free fatty
acids out into blood circulation
? Increases Oxidation of Fatty
acids.
Regulation Of
Beta Oxidation Of Fatty Acid
At Two Levels
? Carnitine Shuttle
? Beta Oxidation Proper
Transport of Fatty Acyl CoA
from Cytosol
into Via Carnitine Shuttle
Mitochondrial Matrix
Is a Rate-limiting step
Malonyl-CoA
Regulates Beta Oxidation
At Carnitine Transport
Level
Malonyl-CoA an intermediate of
Lipogenesis Is an Inhibitor of Carnitine
Acyl Transferase I
Malonyl-CoA is produced from Acetyl-CoA by the enzyme
Acetyl-CoA Carboxylase during Fatty acid biosynthesis.
Malonyl-CoA (which is a precursor for fatty acid synthesis)
inhibits Carnitine Palmitoyl Transferase I.
This Control of Fatty acid oxidation is exerted mainly at the
step of Fatty acid entry into mitochondria.
Acyl-CoA Dehydrogenase is
Regulatory or Key Enzyme
of
Beta Oxidation Of Fatty Acids
Significance Of Beta oxidation
of a Fatty acid
?Beta oxidation cycles
helps in cleaving and
shortening of a long
chain Fatty acid
? Oxidation of Beta carbon
atom of a Fatty acid
transforms stronger bond
between alpha and beta
carbon atom to a weaker
bond.
? Transformation to a weaker bond
helps in easy cleavage between
alpha and beta carbon
? During oxidation there is
dehydrogenation of beta carbon
atom (CH2 to C=O)
? Hydrogen atoms removed during beta
oxidation are
? Temporarily accepted by the oxidized
coenzymes (FAD and NAD+) to form
reduced coenzymes
? Reduced coenzymes then final y enter
ETC and get reoxidized
? The byproduct of ETC is ATP
? Thus Beta oxidation of
Fatty acid
? Metabolizes a long chain
fatty acid with liberation of
chemical form of energy
ATP for cel ular activities.
Summary of -Oxidation
Repetition of the -Oxidation Cycle yields a succession of
Acetate units
? Palmitic acid yields eight Acetyl-CoAs
? Complete -oxidation of one Palmitic acid yields
106 molecules of ATP
? Large energy yield is consequence of the highly
reduced state of the carbon in fatty acids
? This makes fatty acid the fuel of choice for
migratory birds and many other animals
Disorders OF Beta Oxidation
Of Fatty Acids
Deficiencies of Carnitine
OR
Carnitine Transferase
OR
Translocase Activity
Are
Related to Disease State
Biochemical Consequences of
Carnitine Shuttle Defect
? Defect in Carnitine shuttle system
? No Beta Oxidation of Fatty acids
? No ATP generation
? All ATP dependent processes will be
ceased
? Cell deaths
? Organ failures
Carnitine Shuttle Defects
?Affects normal
function of Muscles,
Kidney, and Heart.
? Symptoms include Muscle
cramping, during exercise, severe
weakness and death.
? Muscle weakness occurs since
they are related with Fatty acid
oxidation for long term energy
source.
Management Of Individuals with
Carnitine Shuttle Defects
? Note people with the Carnitine
Transporter Defect
?Should be supplemented with a diet
with medium chain fatty acids
?Since MCFAs do not require Carnitine
shuttle to enter Mitochondria.
Sudden Infant Death Syndrome
(SIDS)
SIDS
? SIDS is a congenital rare disorder with
an incidence of 1 in 10,000 births.
? Biochemical Defect: Due to congenital
defect of Enzyme Acyl-CoA
Dehydrogenase a regulatory enzyme
of Oxidation of Fatty acid.
? Biochemical Consequences Of SIDS
? Deficiency of Acyl-CoA Dehydrogenase
? Blocks Oxidation of Fatty acid.
? Stops liberation and supply of energy in
form of ATPs in fasting condition
? Leads to unexpected death of an infant.
Symptoms in defective Beta Oxidation of Fatty
acids include:
wHypoglycemia
wLow Ketone body production during
fasting
wFatty Liver
wHeart and/or Skeletal muscle defects
wComplications of pregnancy
wSudden infant death (SID).
? Hereditary deficiency of Medium
Chain Acyl-CoA Dehydrogenase
(MCAD)
? Most common genetic disease
relating to fatty acid catabolism,
has been linked to SIDS.
Jamaican Vomiting Sickness
? Jamaican Vomiting Syndrome
is due to ingestion of unripe
Ackee fruit by people in
Jamaica
(Jamaica-Country of Caribbean)
Ackee Fruit
? Ackee fruit is rich in Hypoglycin ?A
? Hypoglycin is an inhibitor of
regulatory Enzyme Oxidation
Proper Acyl-CoA Dehydrogenase.
? Jamaican Vomiting Disease leads to
complications characterized by :
?Severe Vomiting (throwing out)
?Hypoglycemia
?Water Electrolyte Imbalance
?Convulsions
?Coma
?Death
Beta Oxidation
Of
Odd Chain Saturated Fatty Acids
?Ingestion of Odd chain
carbon Fatty acids are less
common in human body.
?Odd chain Fatty acids are
formed by some bacteria in
the stomachs of ruminants
and the human colon.
? -oxidation of odd chain Saturated Fatty
acid occurs same as even chain Fatty
acid oxidation
? Releasing Acetyl CoA (2C) in every turn.
? Until the final Thiolase cleavage
? Which results in a 3 Carbon Acyl-CoA
/Propionyl-CoA in last cycle and last
step of beta oxidation.
End Products Of
Odd Chain Fatty Acid Oxidation
? End products of b-oxidation of
an odd-number Fatty acid is :
?Acetyl-CoA(C2)
?Propionyl-CoA(C3)
Fate Of Acetyl-CoA
? Acetyl CoA released from beta
oxidation of odd chain fatty
acid
? Enter in TCA cycle and get
completely oxidized.
Fate Of Propionyl-CoA
OR
Metabolism Of Propionyl CoA
Propionyl CoA (3C)
An End Product Of Odd Chain
Fatty Acid
Is Converted into
Succinyl CoA (4C)
A TCA intermediate
Metabolism Of Propionyl-CoA
? Metabolism of Propionyl-CoA
? The Propionyl-CoA is converted to
Succinyl-CoA.
? Which is an intermediate of
TCA/Citric acid cycle
? Propionyl CoA metabolism is
dependent on Two Vitamin B
complex members:
?Biotin
?Vitamin B12
? Special set of 3 Enzymes are
required to further metabolize
Propionyl-CoA to Succinyl -CoA.
? Final Product Succinyl-CoA enters
TCA cycle and get metabolized.
? Three Enzymes convert Propionyl-
CoA to Succinyl-CoA:
1. Carboxylase
2. Epimerase
3. Mutase
Step1
? Propionyl CoA is Carboxylated to yield
D Methylmalonyl CoA.
? Enzyme: Propionyl CoA Carboxylase
? Coenzyme: Cyto Biotin
? An ATP is required
Step2
? The D Methylmalonyl CoA
is racemized to the
L Methylmalonyl CoA.
? Enzyme: Methylmalonyl-CoA
Racemase/ Epimerase
Step 3
? L Methylmalonyl CoA is converted
into Succinyl CoA by an
intramolecular rearrangement
? Enzyme: Methylmalonyl CoA
Mutase
? Coenzyme of Vitamin B12 :Deoxy
Adenosyl Cobalamin
Fates Of Succinyl CoA
? Succinyl CoA
? Enters TCA cycle and get metabolized
? Serve as Glucogenic precursor for Glucose
biosynthesis in emergency condition
? Used as a precursor for Heme biosynthesis
? Involves in Thiophorase reaction of
Ketolysis.
Oxidation of Odd-chain Fatty Acids
Conversion of Propionyl-CoA to Succinyl-CoA
Defects In Propionyl CoA Metabolism
? Deficiency of Enzyme Propionyl-CoA
Carboxylase will block the
metabolism of Propionyl-CoA.
? Accumulates Propionyl-CoA in blood
leading to Propionicacidemia.
? Deficiency of Vitamin B Complex
members affects Propionyl CoA
metabolism to Succinyl ?CoA.
? Vitamin B12 deficiency blocks the
Mutase reaction
? Accumulates L-Methyl Malonyl-
CoA leading to Methyl
Malonylaciduria.
Alpha Oxidation Of Fatty Acid
OR
Oxidation Of
Branched-Chain Fatty Acid
OR
Phytanic Acid Oxidation
3,7,11,15-tetramethyl
Hexadecanoic acid
? Source of Phytanic acid in
human body is through
ingestion of animal Foods.
? Phytanic acid is a breakdown
product of Phytol component
of plant chlorophyl .
Why Phytanic Acid
Does Not Initiate With
Beta Oxidation Process?
? Phytanic acid is a 16 Carbon
Branched chain Fatty Acid.
? Has Four Methyl branches at odd-
number carbons 3,7,11 and 15.
? Which is not good substrates for -
oxidation.
? Branched chain Phytanic acid
contains Methyl (CH3) group at
Carbon atom.
? Hence it cannot get oxidized
initial y via oxidation
pathway
?Thus initially Phytanic acid
fol ows Oxidation
?Modify Phytanic acid to
Pristanic acid and
?Further present it for
Beta Oxidation process.
Occurrence Of Alpha
Oxidation Of Phytanic Acid
Predominantly Alpha Oxidation
Of Phytanic Acid
Takes Place in
Endoplasmic Reticulum
of Brain Cel s
Also In Peroxisomes
Mechanism Of Alpha
Oxidation Of Phytanic Acid
? Phytanic acid 3,7,11,15-
Tetramethyl Hexadecanoic
acid
? Alpha oxidation removes
Methyl groups at beta carbon.
? Later making Fatty acid ready
for beta oxidation process.
? During Oxidation there occurs:
? Hydroxylation at Carbon in
presence of Enzyme Hydroxylase or
Monoxygenase .
? This reaction is Vitamin C dependent
forming Hydroxy Acyl-CoA.
? Hydroxy Acyl-CoA is then
oxidized to Keto Acyl-CoA.
? Ketonic group at Carbon atom is
decarboxylated
? Yielding CO2 molecule and a Fatty
acid with one Carbon atom less.
? Phytanic acid on alpha oxidation is
converted to Pristanic acid
? Which is further metabolized via
beta oxidation process to
generate Propionyl-CoA.
Products of Phytanic Acid Oxidation
? Alpha oxidation of Phytanic acid
Generates
?Acetyl-CoA
?Propionyl-CoA
?Isobutryl-CoA
Disorders Associated
With
Defective Oxidation
Of Phytanic Acid
Refsums Disease
?Refsums disease is a rare
but severe neurological
disorder.
?Caused due to defect in
Oxidation of Phytanic
acid
The Enzyme Defects
? Deficiency of Enzyme Phytanic
acid Oxidase/ Phytanol-CoA
Dioxygenase leads to Refsum's
disease.
? Autosomal Recessive
? Biochemical Consequence Of Refsums
disease Is:
? No Oxidation of Phytanic acid
? Accumulation of Phytanic acid in
Brain cel s and Other Tissues
? Dysfunction of Brain
? Manifesting Neurological disorder
? Management Of Refsums
disease is :
? Avoid eating diet containing
Phytol /Phytanic acid.
Omega Oxidation Of Fatty Acids
?Omega Oxidation of Fatty
acid is:
?Oxidation of Omega Carbon
atom (CH3) of a Fatty acid.
When Does Omega Oxidation
Of Fatty Acid Occurs?
? Omega Oxidation takes
place when there is defect
in Oxidation of fatty acid.
?During Oxidation of
Fatty acid
? Carbon atom (CH3)
of a Fatty acid is
transformed to -COOH
? Omega oxidation forms
Dicarboxylic acid
? Which further undergo oxidation
? Form more short Dicarboxylic
acids Adipic acid and Succinic acid
? Which are more polar excreted
out in Urine.
-Oxidation of Fatty acids
Occur in
Endoplasmic Reticulum
of Liver Cells
Mechanism Of Oxidation
? Oxidation of Fatty
acid is a minor
alternative oxidative
Pathway.
? Omega Oxidation of a Fatty
acid takes place with:
?Hydroxylation Reaction
?Oxidation Reaction
=Omega,last
letterinGreek
alphabet
? In Oxidation of Fatty acid there occurs
Hydroxylation at Carbon atom
? Converting into Primary terminal Alcohol
(-CH2OH) group.
? This reaction is catalyzed by NADPH+H+
dependent Cytochrome P450 system
? Next primary terminal Alcohol group is
oxidized to form -COOH group .
? Further Dicarboxylic acid
generated through Omega
Oxidation undergoes beta
oxidation
? To produce short chain
Dicarboxylic acids as Adipic acid
and Succinic acid
? Which are polar and excreted
out through Urine.
Significance Of Omega Oxidation
? Omega Oxidation transforms a
non polar Fatty acid to polar
Dicarboxylic fatty acid.
? Omega Oxidation of fatty acid
facilitates excretion of
accumulated fatty acids due to
defective normal Oxidation in
cel s.
Peroxisomal Oxidation Of
Fatty Acids
OXIDATION OF FATTY ACIDS IN PEROXISOMES
? Peroxisomes ? Cell organelles
containing Enzymes Peroxidase and
Catalase
? These Enzymes catalyzes
dismutation of Hydrogen peroxide
into water and molecular oxygen
When ? Why? How?
Does
Peroxisomal Oxidation
OF
Fatty Acid Occurs?
vb-Oxidation of very long-chain
fatty acids(>C22) occurs within
Peroxisomes initial y
v Later undergoes
Mitochondrial Oxidation .
? Carnitine is involved in transfer
of Very long Chain Fatty acids
(VLCFAS >C22) into and out of
Peroxisomes.
? Peroxisomal Fatty acid oxidation
is induced by a high Fat diet with
VLCFAs.
? To shortens VLCFAs into LCFAs
? Which are further degraded by
Beta oxidation process.
Peroxisomal -Oxidation
? Similar to Mitochondrial -
oxidation,
? Initial double bond formation
is catalyzed by Flavoprotein
Acyl-CoA Oxidase
Acyl CoA Oxidase?FAD transfers electrons to
O2 to yield H2O2.
? Coenzyme FAD is e- acceptor for
Peroxisomal Acyl-CoA Oxidase,
which catalyzes 1st oxidative step
of pathway.
? FADH2 generated at this step
instead of transferring high-
energy electrons to ETC, as
occurs in Mitochondrial beta-
oxidation.
? Electrons of FADH2 directly go
to O2 at reaction level to
generate H2O2 in Peroxisomes.
? Thus FADH2 generated in
Peroxisomes by Fatty acid oxidation
do not enter ETC to liberate ATPs.
? Instead peroxisome, FADH2
generated by fatty acid oxidation by
Acyl CoA Oxidase is reoxidized
producing Hydrogen peroxide.
FADH2 + O2 FAD + H2O2
Peroxisomal enzyme Catalase degrades
H2O2:
2 H2O2 2 H2O + O2
These reactions produce No ATP.
? Once Very Long Chain Fatty acids
are reduced in length within the
Peroxisomes
? They may shift to Mitochondrial
beta oxidation for further
catabolism of fatty acids.
?No ATPs result from
steps of Peroxisomal
oxidation of VLCFAs.
?Steps of Peroxisomal
Oxidation of Fatty acid
does not generate ATPs
?Instead energy dissipated
in form of heat.
? Many drugs commercially available
in market for reducing obesity
? Stimulate Peroxisomal beta
oxidation
? Where Fatty acids are oxidized
without much liberation of calories
(ATPs).
? Peroxisomal Oxidation of Fatty
acid efficiently takes place in:
?Obese persons
?Persons taking Hypolipidemic
drugs(Clofibrate).
Zel wegers Syndrome
OR
Cerebrohepatorenal Syndrome
Peroxisomal Disorder
? Zellweger
Syndrome
? Cerebro-Hepato-
Renal Syndrome
Biochemical Causes
?Rare genetic autosomal
recessive disorder.
?Characterized by
absence of functional
Peroxisomes.
?Gene mutations in
PEX Genes leads to
Zel wegers Syndrome.
Biochemical Alterations
? No oxidation of very long
chain Fatty acids and
branched chain fatty acids
in Peroxisomes
?Accumulation of large
abnormal amounts of VLCFAs
in Peroxisomes of tissues.
?No normal function of
Peroxisomes.
? Progressive degeneration of
Brain/Liver/Kidney, with
death ~6 month after onset.
Signs and Symptoms
? Defect in normal function of multiple organ
system.
? Impaired neuronal migration, positioning and
brain development.
? Hypomyelination affecting nerve impulse
transmission.
? Hepatomegaly
? Renal Cysts
? Typical Dysmorphic facies.
Diagnosis
?Detection of Increased
levels of Serum Very
Long Chain Fatty Acids-
VLCFAs
Oxidation Of Unsaturated
Fatty Acids
? PUFAs having double bonds in their
structure are unstable.
? Double bonds are hydrolyzed and
metabolized faster than saturated
bonds.
? Thus dietary intake of PUFA get
readily metabolized
? Which reduces risk of
Atherosclerosis.
? PUFAs are less reduced than
SFAs
? Hence PUFAs are less
energetic than SFAs
Mechanism Of Oxidation
Of Unsaturated Fatty
Acids
? Initial and later Oxidation of
PUFAs is by
? Similar steps of Oxidation
in parts, of saturated bonds.
? Double bonds of UFAs are cleaved by
action of Extra Enzymes:
? Isomerase (Enoyl CoA Isomerase)
(For odd numbered double bonds MUFAs)
?Reductase (2,4 Dienoyl CoA Reductase)
(For even numbered double bonds PUFAS)
?Epimerase
(Converts D-Isomer to L-Isomer)
? Enoyl CoA Isomerase handles
odd numbered double bonds
in MUFAs.
? 2,4 Dienoyl CoA Reductase
handles even numbered
double bonds in PUFAs.
? Usually natural unsaturated fatty
acids have cis double bonds.
? Which is transformed to trans
double bonds by the action of an
Isomerase .
? As next enzyme to act is Enoyl
Hydratase ,which acts only on
trans double bonds.
? Enoyl-CoA Isomerase converts
Cis unsaturated Fatty acids to
Trans- 2 Enoyl-CoA
? Now -oxidation can continue
with hydration of trans- 2-
Enoyl-CoA by Enoyl CoA
Hydratase
Oxidation Of
Monounsaturated Fatty Acids
? Oleic acid, Palmitoleic acid
? Normal -oxidation for three cycles
? Cis-3 Acyl-CoA cannot be utilized by
Acyl-CoA dehydrogenase
? Enoyl-CoA Isomerase converts this to
trans- 2 Acyl CoA
? -oxidation continues from this point
Oxidation Of
Polyunsaturated Fatty Acids
Slightly more complicated
? Same as for Oleic acid, but only up to a point:
? 3 cycles of -oxidation
? Enoyl-CoA Isomerase
? 1 more round of -oxidation
? Trans- 2, cis- 4 structure is a problem.
? 2,4-Dienoyl-CoA Reductase transform it to odd numbered.
? NADPH dependent 2,4-Dienoyl- Co A
Reductase reduces and merges two
double bonds to form one Trans at C3
? That is then isomerized by Enoyl CoA
Isomerase to C2- Trans double bond.
Oxidation of Unsaturated Fatty Acids (Remember they are cis!)
b-oxidation of fatty acids with even
numbered double bonds
? The Oxidation of PUFAs provide less
energy than saturated Fatty acids as
they are less reduced compounds.
? At double bonds the Isomerase act
and convert it into Trans ?Enoyl
CoA.
? This bypasses the Acyl-CoA
Dehydrogenase ?FAD linked beta
oxidation reaction.
? 1.5 ATP less per double bond.
This post was last modified on 05 April 2022