Download CH 2 -CH 2 -CH 2 -CH 2

Metabolism of lipids I.
Triacylglycerols
Major energy reserve
Oxidation: 9 kcal/g
(for carbohydrates: 4 kcal/g)
11 kg of 70 kg total body weight
Site of accumulation:
cytoplasm of ADIPOSE CELLS
Specialized for synthesis,
storage, mobilization of
lipids
Lipases
Hormone-sensitive lipase - Regulated by hormones: adrenaline,
noradrenaline, glucagone, ACTH
cAMP   stimulation of protein kinase A  phosphorylation of
lipase  LIPOLYSIS
Hormone-sensitive lipase
Fatty acids
• Long hydrocarbon chain and terminal
carboxyl group
• ( D double bound)
.
Physiological roles of fatty acids:
*Stored as triacylglycerols (triglycerides)
*Hormones, intracellular messengers
*Fuel molecules
*Building blocks of phospholipids, glycolipids
The most important fatty acids
Number of carbons
Number of
double bonds
Name
16
0
Palmitate
18
0
Stearate
20
0
Arachidate
16
1
Palmitoleate
Cis D9
18
1
Oleate
Cis D9
18
2
Linoleate
Cis D9, D12
18
3
Linolenate
Cis D9, D12, D15
20
4
Arachidonate
Cis D5, D8, D11, D14
The most important fatty acids
• Unbranched, if unsaturated, double
bonds always cis
• Short chain length and unsaturation –
lower melting point - enhanced fluidity
Activation of fatty acids
Activation of fatty acids:
Fatty acid + ATP + CoA <------> Acyl-CoA + PPi + AMP
Acyl-CoA synthase
O
1.
R-COOH
+
ATP
R
C AMP
+
PPi
O O
R
C
P
O Ribose
Adenin
O
acyl-adenylate
O
O
2.
R
C AMP
+
HS-CoA
R
C
S
CoA + AMP
acyl-CoA
Activation of fatty
acids:
on the outer mitochondrial
membrane
Partial reactions are
reversible (equilibrium
constant ~ 1)
Reaction is driven by
hydrolysis of
pyrophosphatase
PPi  2Pi
(two high energy bonds are
consumed, one is
formed)
Activation of fatty acids
Transport of fatty acids (long chain) in the
mitochondrial matrix
The mitochondrial Carnitine System
CPT I
carnitinepalmitoyl
transferase I;
CT
carnitine:acylcarnitine
translocase;
CPT II
carnitinepalmitoyl
transferase II;
CAT
carnitine-acetyl
transferase;
The Mitochondrial Carnitine System
ß-oxydation of fatty acids
• One round:
– chain is shortened
by two carbon
atoms
• FADH2
• NADH
• Acetyl~CoA
ß-oxydation of fatty acids
• One round:
– chain is
shortened by two
carbon atoms
• FADH2
• NADH
• Acetyl~CoA
Next cycle starts
ß-oxydation of fatty acids
Energy yield
O
CH3
CH2
7
CH2
CH2
CH2
1 cycle 1 FADH2
(2)
1 NADH + H+ (3)
1 Ac-CoA
(12)
CH2
CH2
CH2
C
O
CH3 C
S
CoA
O
CH3
CH2
7
CH2
CH2
CH2
Palmitoyl-CoA + 7 FAD + 7 NAD + 7 CoA +
7 H2O  8 Ac-CoA + 7 FADH2 + 7
NADH + 7 H+
8 x 12
7x 2
7x 3
131 - 2 (for activation) net: 129 ATP
CH2
CH2
CH2
C
S
O
CH3 C
S
CoA
O
CH3
CH2
7
CH2
CH2
CH2
C
S
CoA
O
CH3 C
O
CH3
CH2
7
CH2
C
S
CoA
S
CoA
CoA
S
CoA
For our example using a 16 carbon fatty acid (palmitate) the overall reaction for one
round of oxidation is (myristol CoA is palmitoyl CoA minus 2 carbons):
Palmitoyl CoA + FAD + NAD + CoA + H2O
NADH + H+ + acetyl CoA
Myristoyl CoA + FADH2 +
Of course to completely degrade palmitoyl CoA would require 7 rounds of beta
oxidation:
1) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA
2) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA + CH3CO-CoA
3) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA + CH3-CO-CoA
4) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA + CH3-CO-CoA
5) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA + CH3-CO-CoA
6) CH3-CH2-CH2-CH2-CH2-CO-CoA + CH3-CO-CoA
7) CH3-CH2-CH2-CO-CoA + CH3-CO-CoA
After the 7th round you are left with an 8th acetyl CoA (CH2-CO-CoA).
So the equation for the complete degradation of palmitate is:
Palmitoyl CoA + 7FAD + 7NAD + 7CoA + 7H2O
7NADH + 7H+
8 Acetyl CoA + 7FADH2 +
What is the ATP yield from oxidation of palmitate?
•8 acetyl CoA enter citric acid cycle and give:
•24 NADH = 72 ATP (by oxidative phosphorylation)
•8 FADH2 = 16 ATP (by oxidative phosphorylation)
•8 GTP = 8 ATP
•7 NADH generated by beta oxidation itself = 21 ATP (by oxidative phosphorylation)
•7 FADH2 generated by beta oxidation itself = 14 ATP (by oxidative phosphorylation)
Total number of ATP from 1 molecule of palmitate = 72 + 16 + 8 + 21 + 14 = 131.
But remember we used to high energy phosphate bonds (equivalent of 2 ATP) to
activate palmitate to palmitoyl CoA. Therefore, the ATP yield is 129.
Oxydation of unsaturated fatty acids
• Two additional
enzymes are required
– Isomerase
– Epimerase
H H
O
C1
CH3 CH2 5 C4 C3 CH
2 2
S
CoA
cis D3 - enoyl-CoA
Double bound, cis
Wrong position
Isomerase
• Palmitoleate (C16 D9)
– three cycles and in
the third round isomerase
O
H
3
C1
CH3 CH2 5 C4 C CH
2 2
H
S
CoA
trans D2 - enoyl-CoA
Oxydation of unsaturated fatty acids
CH3
CH2
5
H
H
CH2 C
C
O
C
S
CoA
cis enoyl-CoA
Double bound, cis
right position
Hydration
enoyl CoA hydratase
O
H
CH3
CH2
CH2 C
5
CH2 C
S
CoA
D-hydroxyacyl-CoA
CoA
L-hydroxyacyl-CoA
OH
Epimerase
OH
CH3
CH2
CH2 C
5
H
O
CH2 C
S
Conversion of glycerol
Glycerol is converted to the Glycolysis intermediate dihydroxyacetone
phosphate, by reactions catalyzed by:
(1) Glycerol Kinase
(2) Glycerol Phosphate Dehydrogenase.
Glycolysis  Pyruvate
Gluconeogenesis  Glucose
Fatty acids oxidation
Sequential removal of two carbon units – 1904 – Franz Knoop
Dogs food
in the urine
COOH
CH2 CH2 COOH
phenylpropionate
CH2 CH2 CH2 COOH
phenylbutyrate
benzoate
CH2 COOH
phenylacetate
Oxidation of odd chain fatty acids
Control of fatty acid oxidation
Energy charge
(high)
Hormones
(adrenaline, glucagon)
stimulate
hormone-sensitive lipase
Malonyl-CoA 
NADH 
inhibits carnitine
acyltransferase I.
3-hydroxiacyl CoA
Dehydrogenase
&
thiolase
Free fatty acids 
Oxidation 
no entry of fatty acyl CoA
into mitochondria
ß-oxidation inhibited
Oxidation 