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LIPID METABOLISM

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LIPID METABOLISM BY Dr OJ Tsotetsi Lipid Metabolism Lipid Metabolism Where & when are fatty acids synthesized? Synthesis of Fatty Acids (FA) occurs primarily in the ... – PowerPoint PPT presentation

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Title: LIPID METABOLISM


1
LIPID METABOLISM
  • BY
  • Dr OJ Tsotetsi

2
Lipid Metabolism
3
Lipid Metabolism
4
Where 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

5
FA 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.)

6
First 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

7
FA 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
8
FA synthesis
  • Further elongation and desaturation of palmitate
    and dietary FAs (if required) occurs in
    mitochondria and ER by diverse enzymes

9
FA 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

10
Fatty Acid Oxidation
11
Beta-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?

13
Carnitine 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

14
Reactions of beta-oxidation
  • The cycle of reactions is repeated until the
    fatty acid is converted to acetyl CoA

15
Beta Oxidation
16
Energy 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?

17
Energy 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

18
Beta-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

19
Why 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)

20
Actual 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

21
Beta-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

22
Are 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?

23
Ketone 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

24
Regulation of Beta Oxidation
  • Largely by concentration of free fatty acids
    available
  • Malonyl CoAinhibits carnitine transferase which
    will inhibit entry of acyl CoA into mitochondria

25
Ketone 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

26
KETONE 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

28
Ketone 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

29
acknowledgement
https//www-s.med.uiuc.edu/m1/biochemistry
Medical biobhemistry
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