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.
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
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 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.
"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 (Acyl-CoA 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 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)
Detailed
mechanism-click here
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)
Click for
Mechanism of 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 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.
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.
