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

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Of Beta Oxidation Of Fatty Acids
Three Stages Of Beta Oxidation

For

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Oxidation Fatty acid Palmitate

Stage I

Activation of

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Long Chain Fatty acid (Acyl Chain)

To

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Acyl-CoA In Cytosol

? Palmitate to Palmitoyl-CoA

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In Cytosol
Stage II

Translocation of Activated Fatty acid

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From Cytosol into Mitochondrial

Matrix

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Through Role of Carnitine

(Carnitine Shuttle)

Stage I I

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Steps of Beta Oxidation Proper

In Mitochondrial Matrix

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?Oxidation Reaction

?Hydration Reaction

?Oxidation Reaction

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?Cleavage Reaction
Stage I

Activation Of Fatty acid

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In Cytosol

Is a Preparative Phase

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Site Of Fatty acid Activation

? Fatty acid(Acyl Chain) is activated

in Cytosol to Acyl-CoA .

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Requirements of FA Activation

?Enzyme:

?Thiokinase /Acyl CoA Synthetase

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?Coenzymes/Cofactors:

? CoA-SH derived from Pantothenic acid
?ATP

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?Magnesium ions (Mg++)

CoezymeA (CoA-SH)

Activates

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Fatty Acids

for Beta Oxidation

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CoA Helps in

Activation of Fatty Acid

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? A long chain Fatty acid is termed as

Acyl chain.

? Every Fatty acid which undergoes

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Oxidation of Fatty acid is first

activated to Acyl-CoA.
? Activation of a

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Fatty acid means:

? Linking of Acyl Chain to

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Coenzyme A to form Acyl-CoA

with a high energy bond.

? During Activation of

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Fatty acid (Acyl Chain)

? `H' of CoA-SH (Coenzyme A) is

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substituted by Acyl chain

? To form CoA-S Acyl, i.e. Acyl-CoA an

activated Fatty acid.

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?Thus CoenzymeA is a

carrier of Acyl chain in

an activated fatty acid.

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Steps Of Fatty Acid Activation


Activation Of a Fatty Acid

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Is ATP Dependent

Converts ATP to AMP

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Hence Requirement is

equivalent to 2 ATPs

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Acyl-CoA Synthetase/

Fatty Acid Thiokinase

condenses Fatty acids with CoA,

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with simultaneous hydrolysis of

ATP to AMP and PPi
?An Acyl-CoA is an

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activated energetic

compound having high

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energy bond in it.

? Thus formation of Acyl?CoA is

an expensive energetical y

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Fatty acid Activation

? Activation of Fatty acids is esterification

of Fatty acid with Coenzyme A

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? In presence of Acyl-CoA Synthetase

(Thiokinase) forming an activated Fatty

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acid as Acyl-CoA.

? This process is ATP-dependent, & occurs

in 2 steps.

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? During the activation of Fatty acid

ATP is converted to AMP and ppi.

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? Two high energy bonds of ATP are

cleaved and utilized in this activation

which is equivalent to 2 ATPs.

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? Subsequent hydrolysis of PPi from

ATP drives the reaction strongly

forward.

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? Note the Acyl- Adenylate is an

intermediate in the mechanism.

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? There are different Acyl-CoA

Synthetase for fatty acids of

different chain lengths.

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Activated Fatty Acid (Acyl-CoA)

is a High Energy Compound

Which Facilitates

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Second Stage

Of

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Beta Oxidation Of Fatty Acid

Stage I

Translocation Of Acyl-CoA

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From Cytosol

Into Mitochondrial Matrix

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With The Help Of Carnitine


?-oxidation proper

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occurs in Mitochondrial

matrix.

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? CoA is a complex structure.
? CoA part of Palmitoyl-CoA is

impermeable to inner membrane

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of Mitochondria
? Long-chain Fatty acids more than 12

Carbon atoms cannot be directly

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translocated into the Mitochondrial

matrix.

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? However short chain Fatty acids are

directly translocated into the

Mitochondrial matrix

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? To translocate an activated long chain

Fatty acid (Acyl-CoA) from cytosol to

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mitochondrial matrix

? Across mitochondrial membrane

operates a specialized Carnitine Carrier

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System.


What Is Carnitine?

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? Carnitine is a functional, Non

Protein Nitrogenous (NPN)

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substance.

? Carnitine is biosynthesized in the

body by amino acids Lysine and

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Methionine.

?

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? Long chain Acyl CoA traverses

an inner mitochondrial

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membrane with a special

transport mechanism called

Carnitine Shuttle.

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Significance Of Acyl-CoA Formation

? High energy bond of Acyl-CoA

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releases high energy which

helps in condensation of Acyl

with Carnitine for further

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translocation.
Mechanism Of Carnitine

In Transport Of

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Fatty Acyl CoA

From Cytosol To Mitochondrial Matrix

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? Acyl-CoA a high energy

compound cleave its high energy

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bond in second stage.

? Bond energy released is used up

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for linking Carnitine to Acyl chain

to form Acyl-Carnitine.
? Long-chain FA are converted to

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Acyl Carnitine and are then

transported

? Acyl-CoA are reformed inside an

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inner membrane of

mitochondrial matrix.

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q Acyl groups from Acyl-COA is

transferred to Carnitine to form Acyl-

Carnitine catalyzed by Carnitine Acyl

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Transferase I (CAT I)

q CAT I is present associated to outer

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mitochondrial membrane

.
q Acylcarnitine is then shuttled across an

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inner mitochondrial membrane by a

Translocase enzyme.

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q Acyl group is linked to CoA of

Mitochondrial pool in mitochondrial

matrix by Carnitine Acyl Transferase I

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(CAT I ) to regenerate Acyl-CoA in

mitochondrial matrix.

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q Finally, Carnitine is returned to cytosolic

side by Protein Translocase, in exchange

for an incoming Acyl Carnitine.

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Points To Remember

? Cell maintains two separate pools of

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Coenzyme-A:

?Cytosolic pool of CoA
?Mitochondrial pool of CoA
?CoA is complex structure cannot

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transport across Mitochondrial

membrane

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?CoA linked to Fatty acid in

Mitochondria is different from

that CoA used for Fatty acid

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activation.

Translocation of Palmitoyl-CoA

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Across

Mitochondrial Membrane
ATP + CoA

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AMP + PPi

palmitate

palmitoyl-CoA

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Cytoplasm

OUTER

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ACS

MITOCHONDRIAL

CPT-I

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[1]

[2]

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MEMBRANE

CoA

palmitoyl-CoA

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Intermembrane

palmitoyl-carnitine

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Space

carnitine

Activation of Palmitate to Palmitoyl CoA and conversion to Palmitoyl

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Carnitine

CPT-I

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palmitoyl-CoA

CoA

Intermembrane Space

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Palmitoyl-Carnitine

Carnitine

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INNER

CAT

[3]

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MITOCHONDRIAL

MEMBRANE

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Matrix

CPT-II

Carnitine

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palmitoyl-carnitine

[4]

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palmitoyl-CoA

CoA

Mitochondrial uptake via of Palmitoyl-Carnitine via the Carnitine-

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Acylcarnitine Translocase (CAT)
ATP + CoA AMP + PPi

Cytoplasm

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palmitate

palmitoyl-CoA

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OUTER

MITOCHONDRIAL

ACS

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CPT-I

MEMBRANE

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[1]

[2]

CoA

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Intermembrane

palmitoyl-CoA

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Space

palmitoyl-carnitine

Carnitine

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INNER

CAT

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[3]

MITOCHONDRIAL

MEMBRANE

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CPT-II

Matrix

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carnitine

palmitoyl-carnitine

[4]

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palmitoyl-CoA

CoA

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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

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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

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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.

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(Carnitine exits the matrix in step 2.)
The fatty acid is now esterified to CoA in the mitochondrial

matrix.

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Stage I I

Steps of Beta Oxidation Proper/Cycle

In Mitochondrial Matrix

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?Oxidation Reaction

?Hydration Reaction

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?Oxidation Reaction

?Cleavage Reaction
Site/Occurrence Of

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? Oxidation Proper

? In Mitochondrial Matrix of

Cel s.

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? After translocation of Acyl-

CoA in Mitochondrial matrix.

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Mechanism Of Reactions

Of

Beta Oxidation Proper

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of

Palmitoyl-CoA

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Step I: Oxidation by
FAD linked Acyl CoA Dehydrogenase

Step I : Hydration by Enoyl CoA Hydratase

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Step I I: Oxidation by NAD linked
eta Hydroxy Acyl CoA Dehydrogenase

Step IV: Thiolytic Cleavage by Keto

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Thiolase



Palmitoylcarnitine

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inner mitochondrial

Carnitine

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membrane

respiratory chain

translocase

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Palmitoylcarnitine

matrix side

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1.5 ATP2.5 ATP

Palmitoyl-CoA

FAD

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oxidation

FADH2

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hydration

H2O

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-Oxidation of

recycle

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NAD+

Palmitoyl CoA

oxidation

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6 times

NADH

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cleavage

CoA

CH3-(CH)12-C-S-CoA + Acetyl CoA

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Citric

O

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acid

cycle

2 CO2

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? Strategy of First 3 reactions of Beta

Oxidation proper is to

? Create a Carbonyl group (C=O) on

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-Carbon atom (CH2) of a Fatty

acid.

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? This weakens bond between and

Carbon atoms of Fatty acid.

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? Fourth reaction cleaves "-

Keto ester" in a reverse

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Claisen condensation reaction.


? Products of Each turn/cycle of

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beta oxidation proper are :

?Acetyl-CoA
?Acyl-CoA with two carbons

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shorter
Step 1

Role Of

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Acyl-CoA Dehydrogenase

To Bring

Oxidation of the C-C bond

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of Fatty acid

Acyl CoA Dehydrogenase is a

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FAD linked Enzyme

(Flavoprotein)
? Acyl CoA Dehydrogenase catalyzes

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Oxidation reaction

? Where there is a removal of

Hydrogen from alpha and beta

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carbon atoms of Acyl-CoA.

? There forms a double bond

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between C -C / C2 and C3 of

Fatty Acid.

? The product of this oxidation

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reaction is - Unsaturated Acyl

CoA /Trans Enoyl CoA.
? Coenzyme FAD is the temporary

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hydrogen acceptor in this oxidation

reaction .

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? The reduced FADH2 is generated by

oxidation reaction of Acyl CoA

Dehydrogenase.

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? FADH2 is then reoxidized, after its enter

into Electron Transport Chain

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? Mechanism of Acyl CoA

Dehydrogenase involves :

?Proton Abstraction/Removes

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Hydrogen

?Double bond formation
?Hydride removal by FAD

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?Generation of reduced FADH2

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? FADH2 is oxidized by entering into

ETC.

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? Electrons from FADH2 are passed to

Electron transport chain

components,

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? Coupled with phosphorylation to

generate 1.5 ATP

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(By Oxidative Phosphorylation).

Acyl-CoA Dehydrogenase

? There are different Acyl-CoA

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Dehydrogenases :

?Short Chain Fatty acids (4-6 C),
?Medium Chain Fatty Acids (6-10 C),

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?Long (12-18 C) and very long (22 and

more)chain Fatty acids.
Inhibitor Of

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Acyl CoA Dehydrogenase

?Acyl CoA Dehydrogenase is

inhibited by a Hypoglycin

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(from Akee fruit)

Step 2

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Role Of

Enoyl CoA Hydratase

To add water across the double bond

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C = C of Trans-Enoyl-CoA

Saturate the double bond of Enoyl-CoA

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Generate Hydroxyl group at beta carbon
?Enoyl-CoA Hydratase catalyzes

stereospecific hydration of the trans

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double bond

?It adds water across the double bond

at C2 and C3 of Trans Enoyl CoA

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?This hydration reaction generates

Hydroxyl (OH) group at beta

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carbon atom of FA

?Converts Trans-Enoyl-CoA to
L -Hydroxyacyl-CoA

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Step 3

Role Of

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Hydroxyacyl-CoA Dehydrogenase

To Oxidizes the -Hydroxyl Group of

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-Hydroxyacyl-CoA

And

Transform it into

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-Ketoacyl-CoA


? -Hydroxyacyl-CoA Dehydrogenase is

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NAD+ dependent

? It catalyzes specific oxidation of the

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Hydroxyl group in the b position (C3) to

form a ketone group.

? NAD+ is the temporary electron acceptor

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for this step which generates reduced

form NADH+H+

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? The oxidation of
-Hydroxyacyl CoA produces a

product - Ketoacyl-CoA.

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Step 4

Role Of b- Ketothiolase

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/Thiolase

Catalyzes Thiolytic cleavage of the

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two carbon fragment

by splitting the

bond between and carbons

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? An enzyme -Keto Thiolase attacks

the -carbonyl group of -Ketoacyl-

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CoA.

? This results in the cleavage of the
C-C bond.

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? Releases Acetyl-CoA(2C) and an Acyl-

CoA (-2carbons shorter ).

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Repetitions Of 4 Steps Of

Beta Oxidation Proper

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? The b-oxidation proper pathway

is cyclic.

? 4 Steps of Beta Oxidation proper

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are repeated

? Til whole chain of Fatty acid is

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oxidized completely.

? Product, 2 carbons shorter

Acyl -CoA,

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? Is input to another

round/turn of the beta

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oxidation proper pathway.


? Acyl CoA molecule released at end of

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Beta Oxidation

? Is the substrate for the next round of

oxidation starting with Acyl CoA

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Dehydrogenase.

? Repetition continues until all the carbon

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atoms of the original Fatty acyl CoA are

converted to Acetyl CoA.

The shortened Acyl

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CoA then undergoes

another cycle of beta

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oxidation

The number of beta

oxidation cycles:

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n/2-1, where n ? the

number of carbon atoms
Products Of Each Turn

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Of

Beta Oxidation Proper

? Each turn/cycle of oxidation proper

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generates one molecule each of:

?FADH2

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?NADH+H+
?Acetyl CoA
?Fatty Acyl CoA ( with 2 carbons shorter each round)
Steps Of

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-Oxidation Proper

of Fatty Acids Continues

With

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A Repeated Sequence

of 4 Reactions

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Til

A Long Fatty Acyl Chain Is

Completely Oxidized

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?For an oxidation of Palmitic

acid through beta oxidation

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? 7 turns/cycles of beta

oxidation proper steps occur.

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Beta Oxidation

Fates of the products

of

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-oxidation of Fatty Acid
? NADH+H+ and FADH2 - are

reoxidized in ETC to generate ATP

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? Acetyl CoA - Enters the Citric acid

cycle(TCA cycle) for its complete

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oxidation.

? Acyl CoA ? Undergoes the next

turn/cycle of oxidation proper.

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Complete Oxidation Of Fatty Acids
Fatty Acid

Oxidation

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Acetyl CoA +ATP

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TCA Cycle

CO2 +H2O and ATP

? Fatty acid is activated and oxidized via

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Beta Oxidation in specific number of

cycles depending upon chain length.

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? Acetyl CoA an end product of Beta

oxidation of Fatty acid

? Is further completely oxidized via

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TCA cycle.


1

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Palmitoylcarnitine

inner mitochondrial

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Carnitine

membrane

respiratory chain

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translocase

Palmitoylcarnitine

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matrix side

1.5 ATP2.5 ATP

Palmitoyl-CoA

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FAD

oxidation

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FADH2

Figure 4.

hydration

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H2O

Processing and

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NAD+

-oxidation of

recycle

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oxidation

Palmitoyl CoA

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6 times

NADH

cleavage

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CoA

CH3-(CH)12-C-S-CoA + Acetyl CoA

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Citric

O

acid

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cycle

2 CO2

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-Oxidation

Overal Flow

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CAPILLARY

Lipoproteins

(Chylomicrons

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L [2]

FABP

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MITOCHONDRION

P

or VLDL)

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FA

L

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acetyl-CoA

TCA

A

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[7]

[3]

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cycle

[4] C

FA

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FA

-oxidation

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S

[6]

FA

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FA

albumin

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acyl-CoA

acyl-CoA

FABP

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FABP

FA

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[5]

carnitine

CYTOPLASM

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transporter

[1]

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from

fat

cel membrane

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cel

FA = fatty acid

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LPL = lipoprotein lipase

FABP = fatty acid binding protein

ACS = acyl CoA synthetase

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Figure 2. Overview of fatty acid degradation
Energetics Of Beta oxidation

Of Palmitate

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? Oxidation of Palmitic Acid C16

Number of turns of fatty acid

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spiral = 8-1 = 7 Cycles of beta

oxidation proper.

? Generates 8 Acetyl CoA

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During Electron Transport and

Oxidative Phosphorylation

Each FADH2 yield 1.5 ATP

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and NADH 2.5 ATP

Energetics of Fatty Acid Beta Oxidation

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e.g. Palmitic (16C):

1.-oxidation of Palmitic acid will be repeated in 7

cycles producing 8 molecules of Acetyl COA.

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2.In each cycle 1 FADH2 and 1 NADH+H+ is produced

and will be transported to the respiratory chain/ETC.

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? FADH2 1.5 ATP

? NADH + H+ 2.5 ATP

? Thus Each cycle of -oxidation 04 ATP

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? So 7 cycles of -oxidation 4 x 7 = 28 ATP
1 Acetyl CoA

Yields 10 ATPs

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via

TCA Cycle

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? Review ATP Generation ?TCA/ Citric Acid

Cycle which start with Acetyl CoA

? Step

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ATP produced

? Step 4 (NADH+H to ETC)

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2.5 ATP

? Step 6 (NADH+H to E.T.C.) 2.5 ATP

? Step 10 (NADH+H to ETC) 2.5 ATP

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

? Step 8 (FADH2 to E.T.C.)

1.5 ATP

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? 1 GTP

01 ATP

? NET per turn of TCA Cycle 10 ATP

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1 ATP converted to AMP

during activation of

Palmitic acid to Palmitoyl-CoA

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is equivalent to 2ATPs utilized

3. Each Acetyl COA which is oxidized

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completely in citric cycle/TCA cycle gives 10

ATP

4. Hence 8 Acetyl CoA via TCA cycle (8 x 10 =

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80 ATP)

5. 2 ATP are utilized in the activation of Fatty

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acid

6. Energy gain = Energy produced - Energy

utilized

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7. 28 ATP + 80 ATP - 2 ATP = 106 ATP
Thus On Complete Oxidation of

One molecule of Palmitate

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106 molecules of ATP

are generated

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ATP Generation from Palmitate Oxidation

Net yield of ATP per one oxidized Palmitate

Palmitate (C15H31COOH) - 7 cycles ? n/2-1

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Palmitoyl CoA + 7 HS-CoA + 7 FAD+ + 7 NAD+ + 7 H2O

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8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+
ATP generated

8 Acetyl CoA(TCA)

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10x8=80

7 FADH2

7x1.5=10.5

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7 NADH

7x2.5=17.5

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108 ATP

ATP expended to activate Palmitate -2 ATP
Net yield of ATPs with Palmitate Oxidation: 106 ATP

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Total End Products

Of

Beta Oxidation

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Of

1 molecule of a Palmitic Acid

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Palmitic acid

With 7 Turns of

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Beta Oxidation Proper

Generates

8 Molecules Of Acetyl-CoA

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

7 FADH2+7 NADH+H+
Summary of one round/turn/cycle of the

b-oxidation pathway:

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

Fatty Acyl-CoA + FAD + NAD+ + HS-CoA

+Acetyl-CoA

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Fatty Acyl-CoA (2 C less) + FADH2 + NADH + H+



Stoichiometry for

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Palmitic Acid Oxidation


-Oxidation Proper of Acyl-CoA

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b F

-O at

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xi ty

da acyl

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tion CoA

of

Saturated fatty acids

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Regulation Of Beta Oxidation

Of Fatty Acids
?Lipolysis and

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Oxidation of Fatty acids

are well regulated under

Hormonal influence.

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Insulin secretion is

In Wel Fed Condition

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? Insulin inhibits Lipolysis of Adipose

Fat (TAG) and mobilization of Free

Fatty acids.

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

? Insulin decreases Oxidation of

Fatty acids.
Glucagon In Emergency Condition

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? When Cellular or Blood Glucose

lowers down there is secretion of

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

Glucagon.

? Glucagon and Epinephrine

stimulates Lipolysis in emergency

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condition.

? Glucagon stimulates the Enzyme

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

Hormone sensitive Lipase and

hydrolyzes depot Fat(TAG).

? Glucagon mobilizes Free fatty

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

acids out into blood circulation

? Increases Oxidation of Fatty

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

acids.
Regulation Of

Beta Oxidation Of Fatty Acid

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

At Two Levels

? Carnitine Shuttle
? Beta Oxidation Proper

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

Transport of Fatty Acyl CoA

from Cytosol

into Via Carnitine Shuttle

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Mitochondrial Matrix

Is a Rate-limiting step
Malonyl-CoA

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Regulates Beta Oxidation

At Carnitine Transport

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Level

Malonyl-CoA an intermediate of

Lipogenesis Is an Inhibitor of Carnitine

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

Acyl Transferase I

Malonyl-CoA is produced from Acetyl-CoA by the enzyme

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

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

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step of Fatty acid entry into mitochondria.
Acyl-CoA Dehydrogenase is

Regulatory or Key Enzyme

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of

Beta Oxidation Of Fatty Acids

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

Significance Of Beta oxidation

of a Fatty acid
?Beta oxidation cycles

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helps in cleaving and

shortening of a long

chain Fatty acid

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

? Oxidation of Beta carbon

atom of a Fatty acid

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transforms stronger bond

between alpha and beta

carbon atom to a weaker

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bond.
? Transformation to a weaker bond

helps in easy cleavage between

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

alpha and beta carbon

? During oxidation there is

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dehydrogenation of beta carbon

atom (CH2 to C=O)

? Hydrogen atoms removed during beta

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oxidation are

? Temporarily accepted by the oxidized

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coenzymes (FAD and NAD+) to form

reduced coenzymes

? Reduced coenzymes then final y enter

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

ETC and get reoxidized

? The byproduct of ETC is ATP
? Thus Beta oxidation of

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Fatty acid

? Metabolizes a long chain

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fatty acid with liberation of

chemical form of energy

ATP for cel ular activities.

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

Summary of -Oxidation

Repetition of the -Oxidation Cycle yields a succession of

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

Acetate units

? Palmitic acid yields eight Acetyl-CoAs
? Complete -oxidation of one Palmitic acid yields

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106 molecules of ATP

? Large energy yield is consequence of the highly

reduced state of the carbon in fatty acids

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

? This makes fatty acid the fuel of choice for

migratory birds and many other animals
Disorders OF Beta Oxidation

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Of Fatty Acids

Deficiencies of Carnitine

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

OR

Carnitine Transferase

OR

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

Translocase Activity

Are

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

Related to Disease State
Biochemical Consequences of

Carnitine Shuttle Defect

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

? Defect in Carnitine shuttle system
? No Beta Oxidation of Fatty acids
? No ATP generation
? All ATP dependent processes will be

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

ceased

? Cell deaths
? Organ failures

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

Carnitine Shuttle Defects

?Affects normal

function of Muscles,

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

Kidney, and Heart.
? Symptoms include Muscle

cramping, during exercise, severe

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weakness and death.

? Muscle weakness occurs since

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they are related with Fatty acid

oxidation for long term energy

source.

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Management Of Individuals with

Carnitine Shuttle Defects

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

? Note people with the Carnitine

Transporter Defect

?Should be supplemented with a diet

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with medium chain fatty acids


?Since MCFAs do not require Carnitine

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shuttle to enter Mitochondria.
Sudden Infant Death Syndrome

(SIDS)

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SIDS

? SIDS is a congenital rare disorder with

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

an incidence of 1 in 10,000 births.

? Biochemical Defect: Due to congenital

defect of Enzyme Acyl-CoA

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

Dehydrogenase a regulatory enzyme

of Oxidation of Fatty acid.
? Biochemical Consequences Of SIDS

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

? Deficiency of Acyl-CoA Dehydrogenase
? Blocks Oxidation of Fatty acid.
? Stops liberation and supply of energy in

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

form of ATPs in fasting condition

? Leads to unexpected death of an infant.

Symptoms in defective Beta Oxidation of Fatty

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

acids include:

wHypoglycemia
wLow Ketone body production during

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

fasting

wFatty Liver
wHeart and/or Skeletal muscle defects

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

wComplications of pregnancy
wSudden infant death (SID).
? Hereditary deficiency of Medium

Chain Acyl-CoA Dehydrogenase

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

(MCAD)

? Most common genetic disease

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

relating to fatty acid catabolism,

has been linked to SIDS.

Jamaican Vomiting Sickness

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

? Jamaican Vomiting Syndrome

is due to ingestion of unripe

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

Ackee fruit by people in

Jamaica

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

(Jamaica-Country of Caribbean)

Ackee Fruit
? Ackee fruit is rich in Hypoglycin ?A

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

? Hypoglycin is an inhibitor of

regulatory Enzyme Oxidation

Proper Acyl-CoA Dehydrogenase.

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

? Jamaican Vomiting Disease leads to

complications characterized by :

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

?Severe Vomiting (throwing out)
?Hypoglycemia
?Water Electrolyte Imbalance
?Convulsions
?Coma

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

?Death
Beta Oxidation

Of

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Odd Chain Saturated Fatty Acids

?Ingestion of Odd chain

carbon Fatty acids are less

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common in human body.

?Odd chain Fatty acids are

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

formed by some bacteria in

the stomachs of ruminants

and the human colon.

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

? -oxidation of odd chain Saturated Fatty

acid occurs same as even chain Fatty

acid oxidation

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

? Releasing Acetyl CoA (2C) in every turn.

? Until the final Thiolase cleavage

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

? Which results in a 3 Carbon Acyl-CoA

/Propionyl-CoA in last cycle and last

step of beta oxidation.

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

End Products Of

Odd Chain Fatty Acid Oxidation
? End products of b-oxidation of

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

an odd-number Fatty acid is :

?Acetyl-CoA(C2)
?Propionyl-CoA(C3)

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

Fate Of Acetyl-CoA

? Acetyl CoA released from beta

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

oxidation of odd chain fatty

acid

? Enter in TCA cycle and get

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completely oxidized.
Fate Of Propionyl-CoA

OR

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Metabolism Of Propionyl CoA

Propionyl CoA (3C)

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

An End Product Of Odd Chain

Fatty Acid

Is Converted into

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

Succinyl CoA (4C)

A TCA intermediate

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

Metabolism Of Propionyl-CoA

? Metabolism of Propionyl-CoA

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

? The Propionyl-CoA is converted to

Succinyl-CoA.

? Which is an intermediate of

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

TCA/Citric acid cycle
? Propionyl CoA metabolism is

dependent on Two Vitamin B

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

complex members:

?Biotin
?Vitamin B12

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

? Special set of 3 Enzymes are

required to further metabolize

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

Propionyl-CoA to Succinyl -CoA.

? Final Product Succinyl-CoA enters

TCA cycle and get metabolized.

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

? Three Enzymes convert Propionyl-

CoA to Succinyl-CoA:

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

1. Carboxylase
2. Epimerase
3. Mutase

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

Step1

? Propionyl CoA is Carboxylated to yield
D Methylmalonyl CoA.

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

? Enzyme: Propionyl CoA Carboxylase
? Coenzyme: Cyto Biotin
? An ATP is required

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

Step2

? The D Methylmalonyl CoA

is racemized to the

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

L Methylmalonyl CoA.

? Enzyme: Methylmalonyl-CoA

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

Racemase/ Epimerase


Step 3

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

? L Methylmalonyl CoA is converted

into Succinyl CoA by an

intramolecular rearrangement

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

? Enzyme: Methylmalonyl CoA

Mutase

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

? Coenzyme of Vitamin B12 :Deoxy

Adenosyl Cobalamin
Fates Of Succinyl CoA

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

? Succinyl CoA

? Enters TCA cycle and get metabolized
? Serve as Glucogenic precursor for Glucose

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

biosynthesis in emergency condition

? Used as a precursor for Heme biosynthesis
? Involves in Thiophorase reaction of

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

Ketolysis.


Oxidation of Odd-chain Fatty Acids

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

Conversion of Propionyl-CoA to Succinyl-CoA

Defects In Propionyl CoA Metabolism
? Deficiency of Enzyme Propionyl-CoA

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

Carboxylase will block the

metabolism of Propionyl-CoA.

? Accumulates Propionyl-CoA in blood

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

leading to Propionicacidemia.

? Deficiency of Vitamin B Complex

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

members affects Propionyl CoA

metabolism to Succinyl ?CoA.

? Vitamin B12 deficiency blocks the

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

Mutase reaction

? Accumulates L-Methyl Malonyl-

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

CoA leading to Methyl

Malonylaciduria.
Alpha Oxidation Of Fatty Acid

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

OR

Oxidation Of

Branched-Chain Fatty Acid

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

OR

Phytanic Acid Oxidation

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

3,7,11,15-tetramethyl

Hexadecanoic acid

? Source of Phytanic acid in

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

human body is through

ingestion of animal Foods.

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

? Phytanic acid is a breakdown

product of Phytol component

of plant chlorophyl .

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Why Phytanic Acid

Does Not Initiate With

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Beta Oxidation Process?

? Phytanic acid is a 16 Carbon

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

Branched chain Fatty Acid.

? Has Four Methyl branches at odd-

number carbons 3,7,11 and 15.

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

? Which is not good substrates for -

oxidation.
? Branched chain Phytanic acid

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

contains Methyl (CH3) group at

Carbon atom.

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

? Hence it cannot get oxidized

initial y via oxidation

pathway

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

?Thus initially Phytanic acid

fol ows Oxidation

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

?Modify Phytanic acid to

Pristanic acid and

?Further present it for

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

Beta Oxidation process.
Occurrence Of Alpha

Oxidation Of Phytanic Acid

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

Predominantly Alpha Oxidation

Of Phytanic Acid

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

Takes Place in

Endoplasmic Reticulum

of Brain Cel s

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

Also In Peroxisomes
Mechanism Of Alpha

Oxidation Of Phytanic Acid

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

? Phytanic acid 3,7,11,15-

Tetramethyl Hexadecanoic

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

acid

? Alpha oxidation removes

Methyl groups at beta carbon.

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

? Later making Fatty acid ready

for beta oxidation process.

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

? During Oxidation there occurs:

? Hydroxylation at Carbon in

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

presence of Enzyme Hydroxylase or

Monoxygenase .

? This reaction is Vitamin C dependent

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

forming Hydroxy Acyl-CoA.
? Hydroxy Acyl-CoA is then

oxidized to Keto Acyl-CoA.

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

? Ketonic group at Carbon atom is

decarboxylated

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

? Yielding CO2 molecule and a Fatty

acid with one Carbon atom less.

? Phytanic acid on alpha oxidation is

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

converted to Pristanic acid

? Which is further metabolized via

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

beta oxidation process to

generate Propionyl-CoA.
Products of Phytanic Acid Oxidation

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

? Alpha oxidation of Phytanic acid

Generates

?Acetyl-CoA

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

?Propionyl-CoA

?Isobutryl-CoA

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

Disorders Associated

With

Defective Oxidation

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

Of Phytanic Acid
Refsums Disease

?Refsums disease is a rare

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

but severe neurological

disorder.

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

?Caused due to defect in

Oxidation of Phytanic

acid

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

The Enzyme Defects

? Deficiency of Enzyme Phytanic

acid Oxidase/ Phytanol-CoA

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

Dioxygenase leads to Refsum's

disease.

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

? Autosomal Recessive

? Biochemical Consequence Of Refsums

disease Is:

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

? No Oxidation of Phytanic acid
? Accumulation of Phytanic acid in

Brain cel s and Other Tissues

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

? Dysfunction of Brain
? Manifesting Neurological disorder

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

? Management Of Refsums

disease is :

? Avoid eating diet containing

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

Phytol /Phytanic acid.
Omega Oxidation Of Fatty Acids

?Omega Oxidation of Fatty

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

acid is:


?Oxidation of Omega Carbon

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

atom (CH3) of a Fatty acid.
When Does Omega Oxidation

Of Fatty Acid Occurs?

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

? Omega Oxidation takes

place when there is defect

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

in Oxidation of fatty acid.
?During Oxidation of

Fatty acid

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

? Carbon atom (CH3)

of a Fatty acid is

transformed to -COOH

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

? Omega oxidation forms

Dicarboxylic acid

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

? Which further undergo oxidation
? Form more short Dicarboxylic

acids Adipic acid and Succinic acid

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

? Which are more polar excreted

out in Urine.
-Oxidation of Fatty acids

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

Occur in

Endoplasmic Reticulum

of Liver Cells

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

Mechanism Of Oxidation

? Oxidation of Fatty

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

acid is a minor

alternative oxidative

Pathway.

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

? Omega Oxidation of a Fatty

acid takes place with:

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

?Hydroxylation Reaction
?Oxidation Reaction

=Omega,last

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

letterinGreek
alphabet


? In Oxidation of Fatty acid there occurs

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

Hydroxylation at Carbon atom

? Converting into Primary terminal Alcohol
(-CH2OH) group.

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

? This reaction is catalyzed by NADPH+H+

dependent Cytochrome P450 system

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

? Next primary terminal Alcohol group is

oxidized to form -COOH group .
? Further Dicarboxylic acid

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

generated through Omega

Oxidation undergoes beta

oxidation

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

? To produce short chain

Dicarboxylic acids as Adipic acid

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

and Succinic acid

? Which are polar and excreted

out through Urine.

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

Significance Of Omega Oxidation

? Omega Oxidation transforms a

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

non polar Fatty acid to polar

Dicarboxylic fatty acid.

? Omega Oxidation of fatty acid

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

facilitates excretion of

accumulated fatty acids due to

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

defective normal Oxidation in

cel s.
Peroxisomal Oxidation Of

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

Fatty Acids

OXIDATION OF FATTY ACIDS IN PEROXISOMES

? Peroxisomes ? Cell organelles

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

containing Enzymes Peroxidase and

Catalase

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

? These Enzymes catalyzes

dismutation of Hydrogen peroxide

into water and molecular oxygen

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

When ? Why? How?

Does

Peroxisomal Oxidation

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

OF

Fatty Acid Occurs?
vb-Oxidation of very long-chain

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

fatty acids(>C22) occurs within

Peroxisomes initial y

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

v Later undergoes

Mitochondrial Oxidation .

? Carnitine is involved in transfer

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

of Very long Chain Fatty acids

(VLCFAS >C22) into and out of

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

Peroxisomes.
? Peroxisomal Fatty acid oxidation

is induced by a high Fat diet with

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

VLCFAs.

? To shortens VLCFAs into LCFAs
? Which are further degraded by

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

Beta oxidation process.

Peroxisomal -Oxidation

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

? Similar to Mitochondrial -

oxidation,

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

? Initial double bond formation

is catalyzed by Flavoprotein

Acyl-CoA Oxidase

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

Acyl CoA Oxidase?FAD transfers electrons to

O2 to yield H2O2.

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

? Coenzyme FAD is e- acceptor for

Peroxisomal Acyl-CoA Oxidase,

which catalyzes 1st oxidative step

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

of pathway.

? FADH2 generated at this step

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

instead of transferring high-

energy electrons to ETC, as

occurs in Mitochondrial beta-

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

oxidation.

? Electrons of FADH2 directly go

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

to O2 at reaction level to

generate H2O2 in Peroxisomes.
? Thus FADH2 generated in

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

Peroxisomes by Fatty acid oxidation

do not enter ETC to liberate ATPs.

? Instead peroxisome, FADH2

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

generated by fatty acid oxidation by

Acyl CoA Oxidase is reoxidized

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

producing Hydrogen peroxide.

FADH2 + O2 FAD + H2O2

Peroxisomal enzyme Catalase degrades

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H2O2:

2 H2O2 2 H2O + O2

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These reactions produce No ATP.
? Once Very Long Chain Fatty acids

are reduced in length within the

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Peroxisomes

? They may shift to Mitochondrial

beta oxidation for further

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catabolism of fatty acids.

?No ATPs result from

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steps of Peroxisomal

oxidation of VLCFAs.
?Steps of Peroxisomal

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Oxidation of Fatty acid

does not generate ATPs

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?Instead energy dissipated

in form of heat.

? Many drugs commercially available

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in market for reducing obesity

? Stimulate Peroxisomal beta

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oxidation

? Where Fatty acids are oxidized

without much liberation of calories

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(ATPs).


? Peroxisomal Oxidation of Fatty

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acid efficiently takes place in:

?Obese persons
?Persons taking Hypolipidemic

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drugs(Clofibrate).


Zel wegers Syndrome

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OR

Cerebrohepatorenal Syndrome

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Peroxisomal Disorder

? Zellweger

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Syndrome

? Cerebro-Hepato-

Renal Syndrome

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Biochemical Causes
?Rare genetic autosomal

recessive disorder.

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?Characterized by

absence of functional

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Peroxisomes.

?Gene mutations in

PEX Genes leads to

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Zel wegers Syndrome.
Biochemical Alterations

? No oxidation of very long

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chain Fatty acids and

branched chain fatty acids

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in Peroxisomes

?Accumulation of large

abnormal amounts of VLCFAs

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in Peroxisomes of tissues.

?No normal function of

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Peroxisomes.
? Progressive degeneration of

Brain/Liver/Kidney, with

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death ~6 month after onset.

Signs and Symptoms

? Defect in normal function of multiple organ

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system.

? Impaired neuronal migration, positioning and

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brain development.

? Hypomyelination affecting nerve impulse

transmission.

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? Hepatomegaly
? Renal Cysts
? Typical Dysmorphic facies.

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Diagnosis

?Detection of Increased

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levels of Serum Very

Long Chain Fatty Acids-

VLCFAs

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Oxidation Of Unsaturated

Fatty Acids

? PUFAs having double bonds in their

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structure are unstable.

? Double bonds are hydrolyzed and

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metabolized faster than saturated

bonds.

? Thus dietary intake of PUFA get

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readily metabolized

? Which reduces risk of

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Atherosclerosis.
? PUFAs are less reduced than

SFAs

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? Hence PUFAs are less

energetic than SFAs

Mechanism Of Oxidation

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Of Unsaturated Fatty

Acids
? Initial and later Oxidation of

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PUFAs is by

? Similar steps of Oxidation

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in parts, of saturated bonds.

? Double bonds of UFAs are cleaved by

action of Extra Enzymes:

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? Isomerase (Enoyl CoA Isomerase)
(For odd numbered double bonds MUFAs)
?Reductase (2,4 Dienoyl CoA Reductase)
(For even numbered double bonds PUFAS)

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?Epimerase
(Converts D-Isomer to L-Isomer)
? Enoyl CoA Isomerase handles

odd numbered double bonds

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in MUFAs.

? 2,4 Dienoyl CoA Reductase

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handles even numbered

double bonds in PUFAs.

? Usually natural unsaturated fatty

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acids have cis double bonds.

? Which is transformed to trans

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double bonds by the action of an

Isomerase .

? As next enzyme to act is Enoyl

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Hydratase ,which acts only on

trans double bonds.
? Enoyl-CoA Isomerase converts

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Cis unsaturated Fatty acids to

Trans- 2 Enoyl-CoA

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? Now -oxidation can continue

with hydration of trans- 2-

Enoyl-CoA by Enoyl CoA

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Hydratase

Oxidation Of

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Monounsaturated Fatty Acids

? Oleic acid, Palmitoleic acid
? Normal -oxidation for three cycles
? Cis-3 Acyl-CoA cannot be utilized by

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Acyl-CoA dehydrogenase

? Enoyl-CoA Isomerase converts this to

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trans- 2 Acyl CoA

? -oxidation continues from this point

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Oxidation Of

Polyunsaturated Fatty Acids

Slightly more complicated

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? Same as for Oleic acid, but only up to a point:

? 3 cycles of -oxidation

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? Enoyl-CoA Isomerase

? 1 more round of -oxidation

? Trans- 2, cis- 4 structure is a problem.

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? 2,4-Dienoyl-CoA Reductase transform it to odd numbered.


? NADPH dependent 2,4-Dienoyl- Co A

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Reductase reduces and merges two

double bonds to form one Trans at C3

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? That is then isomerized by Enoyl CoA

Isomerase to C2- Trans double bond.

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Oxidation of Unsaturated Fatty Acids (Remember they are cis!)


b-oxidation of fatty acids with even

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numbered double bonds
? The Oxidation of PUFAs provide less

energy than saturated Fatty acids as

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they are less reduced compounds.

? At double bonds the Isomerase act

and convert it into Trans ?Enoyl

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CoA.

? This bypasses the Acyl-CoA

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Dehydrogenase ?FAD linked beta

oxidation reaction.

? 1.5 ATP less per double bond.

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