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Fatty Acid Metabolism

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
FATTY ACIDS

from excess protein and carbohydrate


• FA synthesis uses ATP and NADPH as
energy sources
FA synthesis requires
lots of acetyl CoA
• Transfer of acetyl CoA from mitochondria to cytosol
involves the citrate shuttle
• Occurs when citrate concentration in mitrochondria is
high due to inhibition of isocitrate dehydrogenase by
high levels of ATP. (Note: High ATP levels are also
required for FA synthesis.)
FATTY ACIDS
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
FATTY ACIDS

• The reaction is catalyzed by


Acetyl CoA carboxylase
Acetyl CoA carboxylase
• A key regulatory enzyme
activated by citrate to
produce active polymers, and
deactivated (depolymerized)
by fatty acyl CoA

• Phosphorylation deactivates
FATTY ACIDS

the enzyme (in response to


epinephrine, c-AMP, protein
kinase cascade)
• Dephosphorylation (due to
insulin) activates the enzyme
Fatty acid synthase
• Catalyzes reactions of FA synthesis
– It is a multienzyme complex in bacteria
– It is a dimer with multiple (7) activities in animals

• Growing FA chain is tethered by a 4'-phospho-


pantetheine group (a component of CoA) to the acyl
carrier protein (ACP) subunit
FATTY ACIDS
Steps in FA synthesis
The multifunctional fatty acyl synthase molecule has
multiple enzymic domains that carry out the various
catalytic reactions
FATTY ACIDS
Steps in FA synthesis

1) Acetyl CoA + ACP-SH Acetyl-S-ACP + CoA


(primes the system)
FATTY ACIDS
Steps in FA synthesis

2) Acetyl-S-ACP + Enzyme-SH Acetyl-S-Enzyme + ACP-SH


FATTY ACIDS
Steps in FA synthesis

3) ACP-SH + Malonyl CoA Malonyl-S-ACP + CoA


FATTY ACIDS
Steps in FA synthesis

4) Malonyl-S-ACP + Acetyl-S-Enz Acetoacetyl-S-


ACP + CO2
FATTY ACIDS
Steps in FA synthesis
5) Acetoacetyl-S-ACP + NADPH + H+
β-hydroxybutyryl-S-ACP + NADP+
FATTY ACIDS
Steps in FA synthesis

6) β-hydroxybutyryl-S-ACP
crotonyl-S-ACP + H2O
FATTY ACIDS
Steps in FA synthesis

7) crotonyl-S-ACP + NADPH + H+ butyryl-S-ACP


+ NADP+
FATTY ACIDS
Steps in FA synthesis
Repeat steps 3 through 7. . .
FATTY ACIDS

for seven cycles, ultimately


yielding palmitate
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


FATTY ACIDS

palmitate + 8CoA + 14 NADP+ + 7ADP + 7 Pi + 7H2O


FA synthesis

• Further elongation and desaturation of palmitate and


dietary FAs (if required) occurs in mitrochondria and
ER by diverse enzymes
FATTY ACIDS
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
FATTY ACIDS
Fatty Acid Oxidation
FATTY ACIDS
Beta-oxidation of fatty acids

• β-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:
FATTY ACIDS
• Where does beta-oxidation of fatty
acids take place?
FATTY ACIDS
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
FATTY ACIDS

• So, when FA synthesis is


active, FA are not transported
into mitochondria
• Defects in FA transport
(including carnitine deficiency)
are known
Reactions of beta-
oxidation

• The cycle of reactions is


repeated until the fatty acid is
converted to acetyl CoA
FATTY ACIDS
Energy yield from beta-oxidation
of fatty acids

• For palmitate (16:0) 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
FATTY ACIDS

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?
Energy yield from beta-oxidation
of 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
FATTY ACIDS
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 = 2x7 = 14 ATP
FATTY ACIDS

7 NADH = 3x7 = 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)
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:


FATTY ACIDS

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
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)
FATTY ACIDS

• Methyl carbon is moved within


the molecule by methylmalonyl
CoA mutase (one of only two
Vitamin B12 cofactor enzymes) to
form succinyl CoA
Beta-oxidation of
unsaturated fatty acids

• Unsaturated FA yield a bit


less energy than saturated
FA because they are already
partially oxidized
FATTY ACIDS

• Less FADH2 is produced


Oxidation of FA in peroxisomes

• Very-long-chain FA (VLCA; > 20 carbons) are initially


oxidized in peroxisomes

• This process does not generate energy

• Shortened FA-CoA can subsequently be imported into


mitochondria for energy production
FATTY ACIDS
Beta-oxidation of FA
in peroxisomes
• Reaction requires FAD
• FADH2 that is generated is
oxidized by molecular
oxygen (generating H2O2)

• Diseases:
– Deficiency in peroxisomes
FATTY ACIDS

(Zellweger syndrome)
– Defect in peroxisomal
activation of VLCFA (X-linked
adrenoleuko-dystrophy)
– Lead to accumulation of
VLCFA
Alpha-oxidation of FA

• Branched-chain FA like
phytanic acid cannot be
oxidized by beta-oxidation
• Instead, hydroxylated on
alpha carbon
• Genetic deficiency
FATTY ACIDS

(Refsum disease)
Are fatty acids glucogenic?

• Fatty acids are not glucogenic in


animals
• Why can’t we make glucose from fatty
acids?
FATTY ACIDS

• Why are the statements above only


~99% true?
Pyruvate
dehydrogenase
FATTY ACIDS

reaction is
irreversible
Pyruvate
dehydrogenase
reaction is
irreversible
FATTY ACIDS
Ketone bodies
• Excess acetyl CoA (from FA or carbohydrate
degradation) is converted in liver to ketone
bodies: acetoacetate, acetone, and β-
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
FATTY ACIDS

for energy production via the TCA cycle


• Even brain can use ketone bodies as their
concentrations in blood rise enough
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
FATTY ACIDS

acetoacetate + acetyl CoA


• Reduction of acetoacetate to β-
hydroxybutyrate, or spontaneous
decarboxylation to acetone,
produces the other two ketone
bodies
• 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
FATTY ACIDS
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
FATTY ACIDS

utilization, ketonemia, ketonuria, and


acidemia can result