7. Oxidation of Fatty Acid
Requires different stges:
1. Activation of fatty acid in cytoplasm
2. Transfer of Acyl CoA from cytosol to
mitochondria (Carnitine Shuttle system)
3. Beta Oxidation in mitochondria
Dehydrogenation
Hydration
2nd dehydrogenation
Thyolytic cleavage
11. Fatty Acid oxidation
• Major Pathway
– β-oxidation
• Minor Pathway
– α-oxidation
(branch-chain FA,e.g. Phytanic acid)
– ω-oxidation
12. β-oxidation Pathway• Oxidation of fatty acids takes place in
mitochondria where the various enzymes for
fatty acid oxidation are present close to the
enzymes of the electron transport chain.
• Fatty acid oxidation is a major source of cell
ATP
• Oxidation of FAs occur at the β-carbon atom
resulting in the elimination of the two terminal
carbon atoms as acetyl CoA leaving fatty acyl
CoA which has two carbon atoms less than
the original fatty acid.
• β-oxidation has 4 steps:
1-Dehydrogenation (FAD-dependent)
2- Hydration
3-Dehydrogenation (NAD-dependent)
4-Cleavage (Remove 2C as acetyl CoA)
13. Calculations
Carbons in Fatty
Acid
Acetyl CoA
C/2
β-oxidation cycles
(C/2) -1
12 6 5
14 7 6
16 8 7
18 9 8
Note: In each round of β-oxidation one molecule of FADH2 and
one molecule of NADH+H+ are produced which generates 2 and
3 ATP molecules, respectively
14. Example: Energy of palmitoyl ~Co A
(16 C) oxidation
• Number of cycles= n/2 -1 = 7 cycles
• Number of acetyl ~Co A = n/2 =8
So, 7 NADH, each provide 3 ATP when oxidized in the ETC
7X3=21 ATP
7 FADH2 each provide 2 ATP when oxidized in the ETC
7x 2=14 ATP
8 acetyl ~Co A , each provides 12 ATP when converted to
CO2& H2O by the TCA cycle 8x12= 96 ATP
So total energy yield of oxidation of palmitoyl ~Co A = 21 +
14 + 96 = 131 ATP
• As 2 molecules of ATP are used in the activation of a
molecule of fatty acid Therefore, there is a net yield of
129 molecules of ATP
15. Regulation of fatty acid β-oxidation
1- The level of ATP in the cell :If it is high in the cell, the rate of β-
oxidation will decrease (Feed back inhibition)
2- Malonyl-CoA
* (which is also a precursor for fatty acid synthesis) inhibits Carnitine
Palmitoyl Transferase I and thus, inhibits β-oxidation
* Malonyl-CoA is produced from acetyl-CoA by the enzyme Acetyl-CoA
Carboxylase
16. Oxidation of Unsaturated Fatty
Acid
• Slightly more complicated Requires additional enzymes
• Oxidation of unsaturated FAs produce less energy than that
of saturated FAs (because they are less highly reduced,
therefore, fewer reducing equivalents can be produced from
these structures)
17. Oxidation of Odd Numbered Fatty
Acid
• Requires three additional extra
reactions.
• Odd numbered lipids are present in
plants and marine organisms
• Fatty acids with odd number of
carbon atoms are also oxidized by
the same process β-oxidation as
even chain FAs, removing 2
carbons as acetyl CoA in each
round of the oxidative process BUT
the final round of β-oxidation of a
fatty acid with an odd number of C
atoms yields acetyl-CoA &
propionyl-CoA (3C).
18. α-Oxidation Pathway
• α-oxidation occurs in brain tissue in
order to oxidize short chain FAs
• Inα-oxidation,there is one carbon
atom removed at time from α
position
• It does not require CoA and does
not generate high- energy
phosphates
• This type of oxidation is significant
in the metabolism of dietary FAs
that are methylated on β-carbon
e.g. phytanic acid (peroxisomes)
19. ω-Oxidation Pathway
• ω-oxidation is a minor
pathway and occurs in the
endoplasmic reticulum of
many tissues rather than
the mitochondria, the site
of β-oxidation.
• This process occurs
primarily with medium
chain FAs of adipose
tissue which are mobilized
to the liver under
conditions of ketosis
21. The entry of acetyl CoA into the citric acid cycle
depends on the availability of oxaloacetate.
The concentration of oxaloacetate is lowered if
carbohydrate is unavailable (starvation) or improperly
utilized (diabetes).
Oxaloacetate is
normally formed from
pyruvate by pyruvate
carboxylase
(anaplerotic reaction).
Fats burn in the flame
of carbohydrates.
KETONE BODIES
22. In fasting or diabetes the gluconeogenesis is activated
and oxaloacetate is consumed in this pathway.
Fatty acids are oxidized producing excess of acetyl CoA
which is converted to ketone bodies:
b-Hydroxybutyrate
Acetoacetate
Acetone
Ketone bodies are fuel
molecules (can fuel brain and
other cells during starvation)
Ketone bodies are synthesized
in liver mitochondria and
exported to different organs.
23. A. Synthesis of ketone bodies
Two molecules
of acetyl CoA
condense to
form
acetoacetyl CoA.
Enzyme –
thiolase.
26. 3-Hydroxybutyrate is
formed by the reduction of
acetoacetate by
3-hydroxybutyrate
dehydrogenase.
Acetoacetate also
undergoes a slow,
spontaneous
decarboxylation to
acetone.
The odor of acetone may
be detected in the breath
of a person who has a high
level of acetoacetate in
the blood.
27. B. Ketone bodies are a major fuel
in some tissues
Ketone bodies diffuse from the liver
mitochondria into the blood and are transported
to peripheral tissues.
Ketone bodies are important molecules in energy
metabolism.
Heart muscle and the renal cortex use
acetoacetate in preference to glucose in
physiological conditions.
The brain adapts to the utilization of
acetoacetate during starvation and diabetes.
28. 3-Hydroxybutyrate is oxidized to produce
acetoacetate as well as NADH for use in
oxidative phosphorylation.
3-hydroxybutyrate
dehydrogenase
29. Acetoacetate is activated
by the transfer of CoA
from succinyl CoA in a
reaction catalyzed by a
specific CoA transferase.
Acetoacetyl CoA is cleaved
by thiolase to yield two
molecules of acetyl CoA
(enter the citric acid
cycle).
CoA transferase is present
in all tissues except liver.
Ketone bodies are a water-
soluble, transportable
form of acetyl units
30. Impairment of the tissue function, most importantly in the central
nervous system
KETOSIS
The absence of insulin in diabetes mellitus
liver cannot absorb glucose
inhibition of glycolysis
activation of gluconeogenesis
deficit of oxaloacetate
activation of fatty acid
mobilization by adipose tissue
large amounts of acetyl CoA which can not be
utilized in Krebs cycle
large amounts of ketone bodies (moderately strong acids)
severe acidosis (ketosis)
31. Pathways for Pyruvate
• The pyruvate produced from glucose during
glycolysis can be further metabolized in three
possible ways
• For aerobic organisms, when oxygen is plentiful the
pyruvate is converted to acetyl coenzyme A (acetyl
CoA)
• For aerobic organisms, when oxygen is scarce, and
for some anaerobic organisms, the pyruvate is
reduced to lactate
• For some anaerobic organisms (like yeast), the
pyruvate is fermented to ethanol
32. Conversion of Pyruvate to Acetyl CoA
• Under aerobic conditions, pyruvate from glycolysis is
decarboxylated to produce acetyl CoA, which enters
the citric acid cycle as well as other metabolic
pathways
- the enzyme involved is pyruvate dehydrogenase
and the coenzyme NAD+ is also required
• This pathway provides the most energy from glucose
O
||
CH3—C—COO- + HS—CoA + NAD+
pyruvate
O
||
CH3—C—S—CoA + CO2 + NADH + H+
acetyl CoA
33. Conversion of Pyruvate to Lactate
• For aerobic organisms under anaerobic conditions,
pyruvate is reduced to lactate, which replenishes NAD+
to continue glycolysis
• During strenuous exercise, muscle cells quickly use up
their stored oxygen, creating anaerobic conditions
- lactate accumulates, leading to muscle fatigue and
soreness
• Anaerobic bacteria can also produce lactate, which is
how we make pickles and yogurt (among other things)
O lactate
|| dehydrogenase
CH3—C—COO- + NADH + H+
pyruvate
OH
|
CH3—CH—COO- + NAD+
lactate
34. Conversion of Pyruvate to Ethanol
• Anaerobic microorganisms such as yeast, convert
pyruvate to ethanol by fermentation
- pyruvate is decarboxylated to acetaldehyde, which is
reduced to ethanol
- NAD+ is regenerated to continue glycolysis
• The CO2 produced during fermentation make the
bubbles in beer and champagne, and also makes bread
rise
• Alcoholic beverages produced by fermentation can be
up to around 15% ethanol
- above that concentration the yeast die
O
O
O
pyruvate
decarboxylase
H+
CO2
H
O
OH
alcohol
dehydrogenase
NADH + H+
NAD+
Pyruvate Acetaldehyde Ethanol
36. Cori Cycle
• When anaerobic conditions occur in active muscle,
glycolysis produces lactate
• The lactate moves through the blood stream to the
liver, where it is oxidized back to pyruvate.
• Gluconeogenesis converts pyruvate to glucose,
which is carried back to the muscles
• The Cori cycle is the flow of lactate and glucose
between the muscles and the liver
38. Michaelis-Menten equation
• Michaelis-Menten equation is the rate equation for an enzyme –
catalyzed reaction and is the mathematical description of the
hyperbolic curve we have discussed earlier. The formula is
][
][max
0
SK
SV
V
m
Where,
V0 is the initial velocity
Vmax is the maximum velocity
[S] is the substrate concentration
Km (Michaelis-Menten constant) is the substrate concentration
at which the reaction velocity is the half of the maximum velocity.
