Download Beta Oxidation of Fatty Acids

Beta Oxidation of Fatty Acids
PROF. S. KAJUNA
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.
The activation occurs the cytoplasm
L-3-hydroxy-4-trimethylammoniumbutyrate
Activation (the fatty acyl-CoA synthase step)
 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
translocase and 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.
Inputs of the 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+.
Outputs of the 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.
β-Oxidation
Overall Flow
 Stage one is β-oxidation breaking palmitic acid
(above) to acetyl-S-CoA and NADH and FADH2.
Each acetyl-S-CoA can enter the CAC to produce
more NADH and FADH2. All the NADH and
FADH2 produced is then oxidized by the respiratory
electron transport to generate the proton motive
force that produces ATP. As you can see in Stage 1
each round of β-oxidation produces one acetyl-SCoA and leaves the fatty-acyl-S-CoA two carbons
shorter…see next slide.
One Round (a) and Further Rounds (b) of βOxidation
Acyl-CoA DH is just like succinate DH: both oxidizing an “ane” to an
“ene”, both using FAD.
Enoyl-CoA hydratase is just like fumarase in CAC: adding a water to the
double bond with an alcohol being a product.
Energetics of Oxidation of Palmitic Acid
Reactions of the pathway
 Activation Step" (Coenzyme A activates Fatty Acids
for Degradation)
 Transport into Mitochondria (important control
point between synthesis and degradation)
(Acyl-CoA Dehydrogenase) step
 This first reaction is the oxidation of the Cα-
Cβbond. 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 Second Reaction of Beta Oxidation (Enoyl-CoA hydratase
step)
 The second reaction in this pathway is one in
which water is added across the new double
bond to make hydroxyacyl-CoA. The catalyst
in this reaction is Enoyl-CoA hydratase. This
converts trans-enoyl-CoA to L-BHydroxyacyl-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.
(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.
reaction)
 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.
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 acetylCoA, is propionyl-CoA which has three
carbons. This must then be changed to
succinyl-CoA to enter the TCA cycle.
β-Oxidation of Odd Numbered Fatty Acids Results in Propionyl-SCoA
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 transdouble bond and moves it over one carbon.
This product can then continue through the
beta oxidation pathway.
Oxidation of Unsaturated Fatty Acids (Remember they are cis!)
Multiple points of unsaturation can require energy to get them through βOxidation
Note:
 The take away message here is that this pathway
takes a lot of energy and NADPH to get the
molecules into β-oxidation. The general lesson here
is that each point of unsaturation reduces the
amount of energy harvested by β-oxidation.
 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.
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.
