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Beta Oxidation of Fatty
Acids
An Overview
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 acylCoA.
Along with this "activation" step, Beta oxidation of saturated
fatty acids consists of a recurring cycle of a series of four
steps.
reactions
repetition of the cycle
odd numbers of carbons
unsaturated fatty acids
regulation of beta oxidation
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 acylCoA). 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 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.
Reactions of this pathway.
"Activation Step" (Coenzyme A Activates
Fatty Acids for Degradation)
Transport into Mitochondria (important
control point between synthesis and
degradation)
The First Reaction of Beta Oxidation (AcylCoA Dehydrogenase)
Detailed mechanism -- Click here
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 hydroacylCoA. 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)
Detailed mechanism-click here
The third reaction of this pathway is the oxidation of the
hydroxyl group at the beta position which forms a betaketoacyl-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)
Click for Mechanism of Thiolase
The fourth and final reaction of this pathway is the thiolase
catalyzed reaction. This reaction cleaves the beta-ketoacylCoA. The products of this reaction are an 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 cisdouble 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.