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Last Update: 2 November 2017 Part - I

M - 112
Beta Oxidation of Fatty Acid
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Beta oxidation of fatty acids takes place in the
mitochondrial matrix for the most part. However,
fatty acids have to be activated for degradation by
coenzyme A by forming a fatty acyl-CoA thioester.
For short and medium length fatty acids, they undergo
this reaction in the mitochondria. The long chain fatty
acids can't go through the membrane though, so this
reaction occurs at the outer mitochondrial membrane
and the product has to be carried by carnitine across
the inner mitochondrial membrane. They are made
into acylcarnitine derivatives by carnitine transferase I
on the outer side of the inner membrane. These are

then transported across the membrane by a


translocaseand then they are passed to carnitine
acyltransferase II on the matrix side which puts
the fatty acyl group back on CoA leaving the
original fatty acyl-CoA.

Along with this "activation" step, Beta oxidation


of saturated fatty acids consists of a recurring
cycle of a series of four steps.

What are the inputs of this pathway?

The molecules that start this cycle (the inputs) are


the saturated fatty acid and coenzyme A products
(fatty acyl-CoA). The fatty acids involved can be
even numbered carbon chains with no double
bonds. (The ones with double bonds are
unsaturated and will be discussed later.) Some
other inputs that are added after the cycle has
started are FAD, water, ATP, and NAD+.

What are the outputs of this pathway?

The products of this pathway (the outputs) include


FADH2, NADH, acetyl-CoA, and of course, the
final products. The final fatty acid products are

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acetyl-CoA for the even numbered fatty acids (without double bonds), and for those with an odd number of
carbons, it is 3-carbon propionyl-CoA instead.

The First Reaction of Beta Oxidation (Acyl-CoA Dehydrogenase)


This first reaction is the oxidation of the Ca-Cb bond. It is catalyzed by acyl-CoA dehydrogenases. This
catalyst is a family of three soluble matrix enzymes. These enzymes carry noncovalently bound FAD that is
reduced during the oxidation of the fatty acid. This is an oxidation reaction and it should be similar to that
of the succinate dehydrogenase reaction of the TCA cycle because the first three steps of this pathway are
directly analogous to the steps needed to get succinate to oxaloacetate. The *G should therefore be
approximately +0.4 kJ/mole.

The Second Reaction of Beta Oxidation


(Enoyl-CoA Hydratase)
The second reaction in this pathway is one in which
water is added across the new double bond to make
hydroacyl-CoA. The catalyst in this reaction is Enoyl-
CoA hydratase. This is also called a crotonase and it
converts trans-enoyl-CoA to L-B-Hydroxyacyl-CoA.
This reactio would be classified as a hydration reaction
because you are adding water. The *G of this reaction
should be similar to that of the Fumarase reaction in the
TCA cycle, since the first three reactions are directly
analogous to the steps to get succinate to oxaloacetate.
Therefore, it should be around -3.8 kJ/mole.

The Third Reaction in Beta Oxidation


(L-Hydroxyacyl-CoA Dehydrogenase)
The third reaction of this pathway is the oxidation of the
hydroxyl group at the beta position which forms a beta-
ketoacyl-CoA derivative. This is the second oxidation
step in this pathway and it is catalyzed by L-
Hydroxyacyl-CoA Dehydrogenase. This enzyme needs
to have NAD+ as a coenzyme and the NADH produced
represents metabolic energy because for every NADH
produced, it drives the synthesis of 2.5 molecules of ATP
in the electron transport pathway. So, this reaction is
classified as an oxidation reaction and its *G should be
similar to that of the Malate Dehydrogenase reaction in
the TCA cycle for the same reasons as the ones above.
Therefore, it should be approximately +29.7 kJ/mole.

The Fourth Reaction in Beta Oxidation


(Thiolase)
The fourth and final reaction of this pathway is the
thiolase catalyzed reaction. This reaction cleaves the
beta-ketoacyl-CoA. The products of this reaction are an
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acetyl-CoA and a fatty acid that has been shortened by two carbons. So, this reaction is classified as a
cleavage reaction and it is actually a reverse Claisen condensation which means that it should have about the
same *G as the Isocitrate Dehydrogenase reaction in the TCA cycle. It should be somewhere around -8.4
kJ/mole.

Repetition of the Beta Oxidation Cycle


The shortened fatty acyl-CoA that was the product of the last reaction now goes through another beta
oxidation cycle. This keeps happening until eventually you wind up with two molecules of acetyl-CoA in
the final step. This acetyl-CoA is then available to be further metabolized in the TCA cycle, or it can be
used as a substrate in amino acid biosynthesis. It cannot be used as a substrate for gluconeogenesis!

Beta Oxidation of Odd Carbon Fatty Acids


Fatty acids with an odd number of carbons are common in plants and marine organisms. Therefore, humans
and animals that include these things in their diets must metabolize them in the beta oxidation pathway.
Therefore, the end product, instead of acetyl-CoA, is propionyl-CoA which has three carbons. This must
then be changed to succinyl-CoA to enter the TCA cycle.

Beta Oxidation of Unsaturated Fatty Acids


Unsaturated fatty acids are catabolized by the beta oxidation pathway, but they require two additional
enzymes to handle the cis-double bonds. These fatty acids (with one cis-double bond) go through the beta
oxidation cycle as many times as they can before coming to the double bond. The Enoyl-CoA Isomerase
makes the cis-double bond into a trans-double bond and moves it over one carbon. This product can then
continue through the beta oxidation pathway.

For polyunsaturated fatty acids (with more than one cis-double bond) it goes through the same thing, but it
only goes through one more round of beta oxidation because then you get to a fatty acid with a trans and a
cis double bond. For this we use 2,4-dienoyl-CoA reductase to produce a trans-3-enoyl product which is
converted by an enoyl-CoA isomerase to a trans-2-enoyl-CoA which then goes normally through the
pathway. An example of this is on pg. 795 in the text book.

Regulation of Beta Oxidation


Malonyl-CoA can act to prevent fatty acyl-CoA derivatives from entering the mitochondria by inhibiting the
carnitine acyltranferase that is responsible for this transport. Thus, inhibiting the beta oxidation pathway.
When fatty acyl-CoA levels rise, beta oxidation is stimulated. Increased citrate levels; however, inhibit beta
oxidation. Because this reflects an abundance of acetyl-CoA, it too inhibits beta oxidation.

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FIGURE The Beta-oxidation pathway. (a) In each pass through this four-step sequence, one acetyl residue
(shaded in pink) is removed in the form of acetyl-CoA from the carboxyl end of the fatty acyl chain in this
example palmitate (C16), which enters as palmitoyl-CoA.

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