Fatty%20acid%20Catabolism

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• Fatty acid Catabolism
• (b-oxidation)

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Beta Oxidation of Fatty Acids

• Process by which fatty acids are degraded by
  removal of 2-C units
• b-oxidation occurs in the mitochondria matrix
• The 2-C units are released as acetyl-CoA, not
  free acetate
• The process begins with oxidation of the carbon
  that is "beta" to the carboxyl carbon, so the
  process is called"beta-oxidation"

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Fatty acids must first be activated by formation
of acyl-CoA

• Acyl-CoA synthetase condenses fatty acids with
  CoA, with simultaneous hydrolysis of ATP to AMP
  and PPi
• Formation of a CoA ester is expensive
  energetically
• Reaction just barely breaks even with ATP
  hydrolysis DGoATP hydroysis -32.3 kJ/mol, DGo
  Acyl-CoA synthesis 31.5 kJ/mol.
• But subsequent hydrolysis of PPi drives the
  reaction strongly forward (DGo 33.6 kJ/mol)

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Import of acyl-CoA into mitochondria

• b-oxidation occurs in the mitochondria, requires
  import of long chain acyl-CoAs
• Acyl-CoAs are converted to acyl-carnitines by
  carnitine acyltransferase.
• A translocator then imports Acyl carnitine into
  the matrix while simultaneously exporting free
  carnitine to the cytosol
• Acyl-carnitine is then converted back to acyl-CoA
  in the matrix

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Deficiencies of carnitine or carnitine
transferase or translocator activity are related
to disease state

• Symptons include muscle cramping during exercise,
  severe weakness and death.
• Affects muscles, kidney, and heart tissues.
• Muscle weakness related to importance of fatty
  acids as long term energy source
• People with this disease supplement diet with
  medium chain fatty acids that do not require
  carnitine shuttle to enter mitochondria.

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b-oxidation

• Strategy create a carbonyl group on the ?-C
• First 3 reactions do that fourth cleaves the
  "?-keto ester" in a reverse Claisen condensation
• Products an acetyl-CoA and a fatty acid two
  carbons shorter

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b-oxidation

• B-oxidation of palmitate (C160) yields 106
  molecules of ATP
• C 160-CoA 7 FAD 7 NAD 7 H20 7 CoA ? 8
  acetyl-CoA 7 FADH2 7 NADH 7 H
• 2.5 ATPs per NADH 17.5
• 1.5 ATPs per FADH2 10.5
• 10 ATPs per acetyl-CoA 80
• Total 108 ATPs
• 2 ATP equivalents (ATP? AMP PPi, PPi ? 2 Pi)
  consumed during activation of palmitate to
  acyl-CoA
• Net yield 106 ATPs

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Acyl-CoA Dehydrogenase

• Oxidation of the C?-C? bond
• Mechanism involves proton abstraction, followed
  by double bond formation and hydride removal by
  FAD
• Electrons are passed to an electron transfer
  flavoprotein, and then to the electron transport
  chain.

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Acyl-CoA Dehydrogenase
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Enoyl-CoA Hydratase

• aka crotonases
• Adds water across the double bond
• Uses substrates with trans-D2-and cis D2 double
  bonds (impt in b-oxidation of unsaturated FAs)
• With trans-D2 substrate forms L-isomer, with cis
  D2 substrate forms D-isomer.
• Normal reaction converts trans-enoyl-CoA to
  L-?-hydroxyacyl-CoA

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Hydroxyacyl-CoA Dehydrogenase

• Oxidizes the ?-Hydroxyl Group to keto group
• This enzyme is completely specific for
  L-hydroxyacyl-CoA
• D-hydroxylacyl-isomers are handled differently
• Produces one NADH

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Thiolase

• Nucleophillic sulfhydryl group of CoA-SH attacks
  the b-carbonyl carbon of the 3-keto-acyl-CoA.
• Results in the cleavage of the Ca-Cb bond.
• Acetyl-CoA and an acyl-CoA (-) 2 carbons are
  formed

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b-oxidation of odd chain fatty acids

• Odd chain fatty acids are less common
• Formed by some bacteria in the stomachs of
  rumaniants and the human colon.
• b-oxidation occurs pretty much as w/ even chain
  fatty acids until the final thiolase cleavage
  which results in a 3 carbon acyl-CoA
  (propionyl-CoA)
• Special set of 3 enzymes are required to further
  oxidize propionyl-CoA
• Final Product succinyl-CoA enters TCA cycle

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b-oxidation of unsaturated fatty acids

• b-oxidation occurs normally for 3 rounds until a
  cis-D3-enoyl-CoA is formed.
• Acyl-CoA dehydrogenase can not add double bond
  between the a and b carbons.
• Enoyl-CoA isomerase converts this to trans- ?2
  enoly-CoA
• Now the b-oxidation can continue on w/ the
  hydration of the trans-D2-enoyl-CoA
• Odd numbered double bonds handled by isomerase

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b-oxidation of fatty acids with even numbered
double bonds
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Ketone Bodies

• A special source of fuel and energy for certain
  tissues
• Produced when acetyl-CoA levels exceed the
  capacity of the TCA cycle (depends on OAA levels)
• Under starvation conditions no carbos to produced
  anpleorotic intermediates
• Some of the acetyl-CoA produced by fatty acid
  oxidation in liver mitochondria is converted to
  acetone, acetoacetate and ?-hydroxybutyrate
• These are called "ketone bodies"
• Source of fuel for brain, heart and muscle
• Major energy source for brain during starvation
• They are transportable forms of fatty acids!

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Re-utilization of ketone bodies
Formation of ketone bodies
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Ketone Bodies and Diabetes

• Lack of insulin related to uncontrolled fat
  breakdown in adipose tissues
• Excess b-oxidation of fatty acids results in
  ketone body formation.
• Can often smell acetone on the breath of
  diabetics.
• High levels of ketone bodies leads to condition
  known as diabetic ketoacidosis.
• Because ketone bodies are acids, accumulation can
  lower blood pH.