Transcript b-oxidation - mustafaaltinisik.org.uk

Fatty acid Catabolism
(b-oxidation)
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 acetylCoA, not free acetate
• The process begins with oxidation of the
carbon that is "beta" to the carboxyl
carbon, so the process is called"betaoxidation"
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 DGo’ATP 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)
Import of acyl-CoA into mitochondria
•
b-oxidation occurs in the
mitochondria, requires
import of long chain acylCoAs
• 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 acylCoA in the matrix
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.
b-oxidation
• Strategy: create a carbonyl
group on the b-C
• First 3 reactions do that;
fourth cleaves the "b-keto
ester" in a reverse Claisen
condensation
• Products: an acetyl-CoA and a
fatty acid two carbons
shorter
b-oxidation
• B-oxidation of palmitate (C16:0) yields 106 molecules
of ATP
• C 16:0-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
Acyl-CoA Dehydrogenase
• Oxidation of the C-Cb
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.
Acyl-CoA Dehydrogenase
Enoyl-CoA Hydratase
• aka crotonases
• Adds water across the double
bond
• Uses substrates with trans-D2and cis D2 double bonds (impt in
b-oxidation of unsaturated FAs)
• With trans-D2 substrate forms Lisomer, with cis D2 substrate
forms D-isomer.
• Normal reaction converts transenoyl-CoA to L-b-hydroxyacylCoA
X
Hydroxyacyl-CoA
Dehydrogenase
• Oxidizes the bHydroxyl Group to keto
group
• This enzyme is
completely specific for
L-hydroxyacyl-CoA
• D-hydroxylacyl-isomers
are handled differently
• Produces one NADH
Thiolase
• Nucleophillic sulfhydryl
group of CoA-SH
attacks the b-carbonyl
carbon of the 3-ketoacyl-CoA.
• Results in the cleavage
of the C-Cb bond.
• Acetyl-CoA and an
acyl-CoA (-) 2 carbons
are formed
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
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 
and b carbons.
Enoyl-CoA isomerase converts this
to trans- D2 enoly-CoA
Now the b-oxidation can continue
on w/ the hydration of the transD2-enoyl-CoA
Odd numbered double bonds
handled by isomerase
b-oxidation of fatty acids with even
numbered double bonds
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 b-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!
Formation of
ketone bodies
Re-utilization
of
ketone bodies
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.