Fatty Acid
β-Oxidation
• Carbon in fatty acids (CH2 groups) is almost
completely reduced; therefore, oxidation of fatty
acids will yield more energy (ATP) than any other
form of carbon (i.e., sugars, amino acids).
• Fatty acids in general are not as hydrated as
sugars and can pack more closely in storage
tissues.
• Fatty acids provide 30-60% of the calories in the
diets of most Americans.
• Triacylglycerols are the major storage form
of fatty acids.
• Fatty acids are mobilized in response to
hormones such as glucagon and adrenaline.
• A c-AMP cascade activates
hormone-sensitive lipase, which can cleave
fatty acids from C1 and C3 of a
triacylglycerol.
• A separate enzyme (monoacylglycerol
lipase) cleaves the fatty acid at C2.
hormone
receptor
adenylate
cyclase
c-AMP protein
kinase (inactive)
c-AMP
Adipocyte
c-AMP protein
kinase (active)
P
hormone sensitive
lipase (active)
hormone sensitive
lipase (inactive)
triacylglycerol
H 2O
diacylglycerol
monoacyl
glycerol
monoacyl- lipase
glycerol
H 2O
H 2O
free fatty
acid
glycerol
free fatty
acid
free fatty
acid
Occurs in the cytosol:
PPi
+
AMP
ATP
R-COO- + HS-CoA
O
R-C-S-CoA
Acetyl CoA Synthetase
2 high energy phosphate
bonds are used!!
Activation
Fatty Acyl CoA
• Fatty Acyl CoA is transported into
the mitochondrial matrix by the
Carnitine Shuttle
• This shuttle process is carried out by
two acyltransferase enzymes located
on opposite sides of the inner
mitochondrial membrane.
• First, the fatty acid is transferred from
CoA to Carnitine.
O
R-C-S-CoA
+
COOCH2
HO C H
CAT I
CH2
+N(CH3)3
COOO
CH2
R-C O C H
CH2
Acyl Carnitine
+N(CH3)3
• Acyl Carnitine then crosses the inner
mitochondrial membrane in exchange
for a free carnitine via the
Carnitine:acylcarnitine translocase
• In the matrix, carnitine acyltransferase II
(CAT II) catalyzes the reverse reaction of
CAT I to form carnitine and fatty acyl
CoA.
Intermembrane
space
carnitine
acylcarnitine
fatty acyl CoA
CAT I
Carnitine:acylcarnitine
translocase
CAT II
fatty acyl CoA
Matrix
acylcarnitine
carnitine
β-Oxidation proceeds by the following
steps:
1) Οxidation
2) Hydration
3) Οxidation
4) Thiolysis
• This cycle of 4 steps is repeated until the
fatty acid is completely degraded.
O
R-CH2-CH2-CH2-C-S-CoA
Fatty acyl CoA
ETF:FAD
ETF:FADH2
Q
ETF:ubiquinone
reductase
QH2
Acyl CoA D’hase
O
R-CH2-CH=CH-C-S-CoA
Enoyl CoA
Oxidation
O
R-CH2-CH=CH-C-S-CoA
Enoyl CoA
H2O
Enoyl CoA
Hydratase
H
O
R-CH2-C-CH2-C-S-CoA
OH
Hydroxyacyl CoA
Hydration
H
O
R-CH2-C-CH2-C-S-CoA
OH
NAD+
Hydroxyacyl CoA
NADH
Hydroxyacyl
CoA D’hase
O
O
R-CH2-C-CH2-C-S-CoA
Ketoacyl CoA
Oxidation
O
O
R-CH2-C-CH2-C-S-CoA
HS-CoA
Ketoacyl CoA
Thiolase
O
CH3-C-S-CoA
Acetyl CoA
O
R-CH2-C-S-CoA
+
Fatty acyl CoA shortened
by 2 carbons
Thiolysis
• Breakdown of plamitate (C16) yields 129 ATP:
Palmitoyl CoA + 7 CoASH + 7Q +7 NAD+ + 7 H2O
8 Acetyl CoA + 7QH2 + 7NADH + 7H+
ATP
8 Acetyl CoA (TCA Cycle; Ox. Phos.)
96
7 QH2 (Ox. Phos.)
14
7 NADH (Ox. Phos.)
21
Activation Step
-2
129
Comparison of Glucose oxidation to
Fatty acid oxidation:
Oxidation of 1 glucose to CO22 and water
yields 38 ATPs.
Oxidation of palmitate yields 129 ATPs.
Normalizing based on the number of
carbons:
16/6 X 38 = 101 ATPs = less than 80% of
the yield of palmitate.
Regulation:
• Release of fatty acids by epinephrine increases blood
levels of albumin-bound fatty acids which enter cells
for oxidation.
• CAT I is allosterically inhibited by malonyl CoA, a
metabolite unique to fatty acid synthesis.
• Thus, a rise in malonyl CoA signals active fatty acid
synthesis and inhibition of CAT I decreases the rate
of breakdown.
• Fatty acid synthesis and breakdown are therefore
reciprocally regulated.
Oxidation of Unsaturated Fatty Acids
Requires Two Additional Reactions:
12
9
C=O
S-CoA
(cis)
β-oxidation (3 rounds)
4 3
C=O
S-CoA
4 3
C=O
S-CoA
Enoyl CoA Isomerase
2
3
C=O
S-CoA
(trans)
β-oxidation (1 cycle; 1st oxidation of second cycle)
Acetyl CoA
C=O
S-CoA
4
C=O
S-CoA
3
2,4-dienoyl CoA
reductase
3
NADPH
NADP+
C=O
S-CoA
4
Enoyl CoA Isomerase
3
4
2
C=O
S-CoA
β-Oxidation of Odd-Carbon Fatty Acids
Yields Propionyl CoA:
O
CH3-CH2-C-SCoA
propionyl CoA
+ ATP + CO2 + H2O
Propionyl CoA
Carboxylase
-OOC O
CH3-C-C-SCoA D-Methylmalonyl CoA
H
-OOC O
CH3-C-C-SCoA
H
Methylmalonyl CoA
Epimerase
D-Methylmalonyl CoA
H 3C O
Methylmalonyl CoA
Mutase
-OOC-C-C-SCoA
H
L-Methylmalonyl CoA
O
CH2-C-SCoA
-OOC-CH2
Succinyl CoA
Succinyl CoA
can enter the
TCA cycle