Download MBBS Biochemistry PPT 68 Lipolysis And Fatty Acid Oxidation Lecture Notes

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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