fatty acid oxidation

1. Fatty Acid Oxidation
DR MUHAMMAD MUSTANSAR

2. FATTY ACID OXIDATION
1) Steps prior to FA oxidation (β-oxidation).
2) Steps involved in FA oxidation (β-oxidation).
3) Metabolism of ketone bodies.
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3. Importance
The process of FA oxidation is termed β-
oxidation since it occurs through the sequential
removal of 2-carbon units by oxidation at the
β-carbon position of the fatty acyl-CoA
molecule.
Although FAs are both oxidized to acetyl-CoA
and synthesized from acetyl-CoA, FA
oxidation is not the simple reverse of FA
biosynthesis but an entirely different process
taking place in a separate compartment of the
cell.
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4. The oxidation of FAs yields significantly more
energy per carbon atom than does the oxidation
of carbohydrates.
The net result of the oxidation of one mole of
oleic acid (18-carbon FA) will be 146 moles of
ATP (2 mole equivalents are used during the
activation of the FA), as compared to 114
moles from an equivalent number of glucose
carbon atoms.
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5. Increased FA oxidation is a characteristic
of starvation and of diabetes mellitus,
leading to ketone body production by the
liver.
Ketone bodies are acidic and when
produced in excess over long periods, as
in diabetes, cause ketoacidosis, which is
ultimately fatal.
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6. 6

7. Steps prior to fatty acid
oxidation (β-oxidation).
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8. FAs Are Transported in the Blood.
 In the circulatory system, longer-chain FA are
combined with albumin, and in the cell they are
attached to a fatty acid-binding protein (FAbP).
 FA enter cells by diffusion through the lipid
plasma membrane and binds to FAbP
intracellularly and facilitate its transport to the
mitochondrion.
 Shorter-chain fatty acids are more water-soluble
and exist as the unionized acid or as a fatty acid
8 anion.

9. FAs Are Activated before Being
catabolized.
FAs must first be converted to an active
intermediate before they can be catabolized.
This is the only step in the complete
degradation of a FA that requires energy
from ATP.
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10. In the presence of ATP and coenzyme A,
the enzyme acyl-CoA synthetase
catalyzes the conversion of a FA to an
"active FA" or acyl-CoA, which uses one
high-energy phosphate with the formation
of AMP and PPi.
This occurs at the outer mitochondrial
membrane.
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11. Transport of long-chain FA into the
mitochondria.
The transport of fatty acyl-CoA into the
mitochondria is accomplished via an acyl-
carnitine intermediate, which itself is
generated by the action of carnitine
palmitoyltransferase I (CPT I, also called
carnitine acyltransferase I, CA I) an
enzyme that resides in the outer
mitochondrial membrane.
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12. The acyl-carnitine molecule then is
transported into the mitochondria
where carnitine palmitoyltransferase
II (CPT II, also called carnitine
acyltransferase II, CA II) catalyzes
the regeneration of the fatty acyl-CoA
molecule.
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13. Figure: Transportation of FAs.
 Role of carnitine in the transport
of long-chain FAs through the inner
mitochondrial membrane.
 Long-chain acyl-CoA cannot
pass through the inner
mitochondrial membrane, but its
metabolic product which is
acylcarnitine, can.
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14. 14

15. Steps involved in FA oxidation (β-oxidation).
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16. FAs with an odd number of carbon atoms
are oxidized by the pathway of β-
oxidation, producing acetyl-CoA, until a
three-carbon (propionyl-CoA) residue
remains.
This compound is converted to succinyl-
CoA, a constituent of the TCA cycle.
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17. Figure: Conversion of Propionyl-CoA to Succinyl-CoA.
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18. β-Oxidation of FAs Involves
Successive Cleavage with Release
of Acetyl-CoA.
In β-oxidation, two carbons at a time
are cleaved from acyl-CoA
molecules, starting at the carboxyl
end.
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19. The chain is broken between the
α(2)- and β(3)-carbon atoms—hence
the name β-oxidation.
The two-carbon units formed are
acetyl-CoA; thus, palmitoyl-CoA
forms eight acetyl-CoA molecules.
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20. 20 Figure: Overview of β-oxidation of FAs.

21. Figure: Summary of FA oxidation.
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22. Figure: Cont’.
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23. Figure: Cont’.
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24. Figure: β-oxidation.
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25. 25
Figure: β-oxidation.

26. 26 Figure: Cont.’

27. Approximately half of the FAs in the human
diet are unsaturated, consisting of cis double
bonds, with oleate and linoleate being the most
common.
The oxidation of unsaturated FA is essentially
the same process as for saturated fats, except
when a double bond is encountered.
In such a case, the bond is isomerized by a
specific enoyl-CoA isomerase and oxidation
continues.
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28. In the case of linoleate, the presence of the Δ 12
unsaturation results in the formation of a dienoyl-
CoA during oxidation.
This molecule is the substrate for an additional
oxidizing enzyme, the NADPH requiring 2,4-
dienoyl-CoA reductase.
β-oxidation of saturated FA creates the trans double
bond between the α- and β- carbons. So in
unsaturated FA, the cis double bonds must be
isomerized to trans double bonds.
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29. Figure: Sequence of reactions in
the oxidation of unsaturated FAs,
e.g. linoleic acid.
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30. Figure: Cont.’
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31. At the end of this class, students should be able to
know that / the:-
1) Steps prior to fatty acid oxidation (β-oxidation).
2) Steps involved in fatty acid oxidation (β-oxidation).
3)Metabolism of ketone bodies.
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32. During high rates of FA oxidation, primarily in the
liver, large amounts of acetyl-CoA are generated.
These exceed the capacity of the TCA cycle, and
one result is the synthesis of ketone bodies, or
ketogenesis.
The ketone bodies are acetoacetate, β-
hydroxybutyrate, and acetone and they serve as
major fuels for tissues.
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33. Ketogenesis allows the heart and skeletal
muscles mainly to use ketone bodies for
energy, thereby preserving the limited
glucose for use by the brain.
However, the brain, intestine, adipocytes,
and the fetus can use ketone bodies as fuel
during prolonged fasting with the only
exception of liver and RBC that are not
able to utilize ketone bodies.
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34. Figure: Interrelationships of the ketone bodies.
 D(–)-3-hydroxybutyrate dehydrogenase is a mitochondrial enzyme.
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35. Figure: Ketogenesis.
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36. Figure: Utilization of the Ketone Bodies.
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37. The first enzyme is present in all tissues
except the liver.
Importantly its absence allows the liver to
not utilize ketone bodies.
This ensures that extrahepatic tissues
have access to ketone bodies as a fuel
source during prolonged fasting and
starvation.
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38. Figure: Transport of ketone bodies from the liver and pathways of
utilization and oxidation in extrahepatic tissues.
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39.  In extrahepatic tissues, acetoacetate is activated to acetoacetyl-
CoA by succinyl-CoA-acetoacetate CoA transferase.
 CoA is transferred from succinyl-CoA to form acetoacetyl-
CoA.
 With the addition of a CoA, the acetoacetyl-CoA is split into
two acetyl-CoAs by thiolase and oxidized in the TCA cycle.
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40.  In vivo, the liver appears to be the only organ in nonruminants
to add significant quantities of ketone bodies to the blood.
 Extrahepatic tissues utilize them as respiratory substrates
(acetone).
 The net flow of ketone bodies from the liver to the extrahepatic
tissues results from active hepatic synthesis coupled with no
utilization of ketone bodies by liver.
 The reverse situation occurs in extrahepatic tissues.
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41. Figure: Formation, utilization, and excretion of ketone
41 bodies. (The main pathway is indicated by the solid arrows.)

42. In most cases, ketonemia is due to
increased production of ketone bodies
by the liver rather than to a deficiency in
their utilization by extrahepatic tissues.
While acetoacetate and hydroxybutyrate
are readily oxidized by extrahepatic
tissues, acetone is difficult to oxidize in
vivo and to a large extent is volatilized in
the lungs.
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43. Clinical Significance
 Diabetic ketoacidosis (DKA) is the situation of increased
production of acetyl-CoA that leads to ketone body
production that exceeds the ability of peripheral tissues to
oxidize them.
 Ketone bodies are relatively strong acids (pK a around 3.5),
and their increase lowers the pH of the blood.
 This acidification of the blood is dangerous chiefly
because it impairs the ability of hemoglobin to bind
oxygen.
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44. Ketoacidosis can be smelled on a
person's breath. This is due to
acetone, a direct byproduct of the
spontaneous decomposition of
acetoacetate.
It is often described as smelling like
fruit or nail polish remover.
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