Title: LIPID METABOLISM
1LIPID METABOLISM
2Lipid Metabolism
3Lipid Metabolism
4Where when are fatty acids synthesized?
- Synthesis of Fatty Acids (FA) occurs primarily in
the liver and lactating mammary gland, less so in
adipose tissue - FA are synthesized from acetyl CoA derived from
excess protein and carbohydrate - FA synthesis uses ATP and NADPH as energy sources
5FA synthesis requireslots of acetyl CoA
- Transfer of acetyl CoA from mitochondria to
cytosol involves the citrate shuttle - Occurs when citrate concentration in mitochondria
is high due to inhibition of isocitrate
dehydrogenase by high levels of ATP. (Note
High ATP levels are also required for FA
synthesis.)
6First step in FA synthesis is synthesis of
malonyl CoA
- Energy to form C-C bonds is supplied indirectly
by synthesizing malonyl CoA from acetyl CoA using
ATP and CO2 - The reaction is catalyzed by Acetyl CoA
carboxylase
7FA synthesis
- After 7 cycles, palmitoyl-S-ACP is produced and
palmitate is released by palmitoyl thioesterase - Overall reaction is
8 acetyl CoA 14 NADPH 14H 7ATP
palmitate 8CoA 14 NADP 7ADP 7 Pi 7H2O
8FA synthesis
- Further elongation and desaturation of palmitate
and dietary FAs (if required) occurs in
mitochondria and ER by diverse enzymes
9FA synthesis
- Sources of NADPH for FA synthesis are the hexose
monophosphate pathway and the malic enzyme
reaction that converts malate to pyruvate NADPH
in the cytosol
10Fatty Acid Oxidation
11Beta-oxidation of fatty acids
- ß-oxidation of FA produces acetyl CoA and NADH
and FADH2, which are sources of energy (ATP) - First, FA are converted to acyl CoA in the
cytoplasm
12- Where does beta-oxidation of fatty acids take
place?
13Carnitine shuttle
- For transport into mitochondria, CoA is replaced
with carnitine by acylcarnitine transferase I - Inside mitochondria a corresponding enzyme (II)
forms acyl CoA - Malonyl CoA inhibits acylcarnitine transferase I
- So, when FA synthesis is active, FA are not
transported into mitochondria - Defects in FA transport (including carnitine
deficiency) are known
14Reactions of beta-oxidation
- The cycle of reactions is repeated until the
fatty acid is converted to acetyl CoA
15Beta Oxidation
16Energy yield from beta-oxidationof fatty acids
- For palmitate (160) the overall reaction is
- Palmitate 8CoA 7NAD 7FAD 7H2O
- 8 Acetyl CoA 7NADH 7FADH2 7 H
- Energy yield as ATP for palmitate
- 7 FADH2 1.5 x 7 10.5 ATP
- 7 NADH 2.5 x 7 17.5 ATP
- 8 Acetyl CoA 10 x 8 80 ATP
- Total 108 ATP
- But, two high energy bonds used in acyl CoA
formation, so overall yield is 106 ATP. Why do
we subtract two ATPs?
17Energy yield from beta-oxidationof fatty acids
- Energy yield as ATP for palmitic acid
- 7 FADH2 1.5 x 7 10.5 ATP
- 7 NADH 2.5 x 7 17.5 ATP
- 8 Acetyl CoA 10 x 8 80 ATP
- Total 108 ATP
- Two high energy bonds used in acyl CoA formation,
so overall yield is 106 ATP
18Beta-oxidation of unsaturated fatty acids
- Unsaturated FA yield a bit less energy than
saturated FA because they are already partially
oxidized - Less FADH2 is produced
19Why do the Lippincott and Garrett Grisham texts
give different ATP yields for complete oxidation
of palmitate?
- Beta oxidation occurs in mitochondria, so NADH
and FADH2 can be used directly in electron
transport, and acetyl CoA can also be used
directly for production of energy via TCA cycle. - Theoretical yield of ATP from NADH or FADH2
- 2 ATP per FADH2
- 3 ATP per NADH
- Energy yield as ATP for palmitic acid
- 7 FADH2 2 x 7 14 ATP
- 7 NADH 3 x 7 21 ATP
- 8 Acetyl CoA 12 x 8 96 ATP
- Total 131 ATP
- Two high energy bonds used in fatty acyl CoA
(palmitoyl CoA) formation, so overall yield is
129 ATP (according to the Lippincott book)
20Actual yield of ATP from NADH or FADH2 is thought
to be lower than the theoretical yield because
- Membranes leak some H without forming ATP
- Some of the proton gradient drives other
mitochondrial processes - So, actual yield is thought to be closer to
- 1.5 ATP per FADH2
- 2.5 ATP per NADH
- Actual energy yield as ATP for palmitic acid is
therefore - 7 FADH2 1.5 x 7 10.5 ATP
- 7 NADH 2.5 x 7 17.5 ATP
- 8 Acetyl CoA 10 x 8 80 ATP
- Total 108 ATP
- Minus the two high energy bonds used in fatty
acyl CoA formation - 106 ATP
21Beta-oxidation of odd-chain fatty acids
- Odd-chain FA degradation yields acetyl CoAs and
one propionyl CoA - Propionyl CoA is metabolized by carboxylation to
methylmalonyl CoA (carboxylase is a biotin
enzyme) - Methyl carbon is moved within the molecule by
methylmalonyl CoA mutase (one of only two Vitamin
B12 cofactor enzymes) to form succinyl CoA
22Are fatty acids glucogenic?
- Fatty acids are not glucogenic in animals
- Why cant we make glucose from fatty acids?
- Why are the statements above only 99 true?
23Ketone bodies
- Excess acetyl CoA (from FA or carbohydrate
degradation) is converted in liver to ketone
bodies acetoacetate, acetone, and
ß-hydroxybutyrate - Ketone bodies are soluble in blood and can be
taken up and used by various tissues (muscle,
heart, renal cortex) to regenerate acetyl CoA for
energy production via the TCA cycle - Even brain can use ketone bodies as their
concentrations in blood rise enough
24Regulation of Beta Oxidation
- Largely by concentration of free fatty acids
available - Malonyl CoAinhibits carnitine transferase which
will inhibit entry of acyl CoA into mitochondria
25Ketone bodies
- Acetoacetyl CoA is formed by incomplete FA
degradation or by condensation of two acetyl CoAs
by thiolase - Acetoacetyl CoA condenses with a third acetyl CoA
to form hydroxymethylglutaryl CoA (HMG-CoA) - HMG-CoA is cleaved to produce acetoacetate
acetyl CoA - Reduction of acetoacetate to ß-hydroxybutyrate,
or spontaneous decarboxylation to acetone,
produces the other two ketone bodies
26KETONE BODIES
- Are an easy way of transporting the energy stored
in fat from the liver to other tissues because
they are soluble in the blood.
27- In tissues that use ketone bodies, acetoacetate
is condensed with CoA by transfer from succinyl
CoA - acetoacetyl CoA can then be converted to two
acetyl CoAs
28Ketone bodies
- Excessive ketone bodies can be produced in
diabetes mellitus or starvation (a lot of acetyl
CoA in liver) - When rate of production exceeds utilization,
ketonemia, ketonuria, and acidemia can result
29acknowledgement
https//www-s.med.uiuc.edu/m1/biochemistry
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