Download LIPID METABOLISM

Objectives
By the end of lecture the student should:
 Discuss β oxidation of fatty acids.
 Illustrate α oxidation of fatty acids.
 Understand ω oxidation of fatty acids.
 List sources and fates of active acetate.
Oxidation of
Fatty Acids
1- β-Oxidation (knoop’s oxidation):
 Removal of 2 carbon fragment at a time form
Acyl CoA (active FA).
The 2 carbon removed as acetyl CoA.
It occurs in many tissues including liver,
kidney & heart
FAs to be oxidized must be
entered the following 2 steps
1-Activation of FA
2- Transport of acyl
COA to mitochondria
1-FA activation
Acyl COA synthetase
RCOOH
COASH
ATP
RCO~SCOA
AMP+P~P
2Pi + E
Pyrophosphatase
2- Transport of acyl COA to
mitochondria:
 Role of carnitine in the transport of LCFA
through the inner mithochochondrial
membrane
Functions of
carnitine
1- Transport long chain acyl COA across mitochondrial
membrane into the mitochondria so it increases the rate
of oxidation of LCFA
2- Transport acetyl-CoA from mitochondria to cytoplasm
So it stimulates fatty acid synthesis
α
H3C
H3 C
α
H3C
α
β
Cβ
β O ~ S – CoA
Palmitoyl-CoA
Palmitoyl-CoA
H3C
CoA-SH
CoA-SH
α
ββ CO
CO
– CoA
~ S~ –SCoA
β
+
+
CH3 – CO ~ S –CoA
Successive removal of C2 units
Acetyl-CoA
8CH3 – CO ~ S – CoA
8CH3 – CO ~ S –Acetyl-CoA
CoA
Acetyl-CoA
Steps of βOxidation of
FAs
Energetics of FA
oxidation
Palmitic (16C):
 β-oxidation of palmitic acid will be repeated 7
cycles producing 8 molecules of acetyl COA
 In each cycle FADH2 and NADH+H+ is
produced & transported to respiratory chain
FADH2 ------------------ 2 ATP
NADH+H+ ------------- 3 ATP
So 7 cycles 5X7=35 ATP

each acetyl-CoA which is oxidized in citric
cycle gives 12 ATP (8X 12= 96 ATP)
2 ATP is utilized in the activation of fatty acid
(it occurs once)
Energy gain = Energy produced-Energy utilized
= 35 ATP+ 96 ATP-2 ATP= 129 ATP
Calculation of Energetics of any FA Oxidation:
[(N/2-1)X 5 ATP]+[N/2X12 ATP]-2ATP
(N= Number of carbons of fatty acid)
2- α – Oxidation
This type of oxidation occurs in α
position with the removal of one carbon
from the carboxyl end of fatty acids.
Site: microsomes of
brain
liver tissues
Does not require coenzyme A & does
not generate ATP.
Mechanism
O2
CH3
H2O
CH3 OH
Hydroxylase
R.CH2 – CH – CH– COOH
R.CH2 – CH – CH2 – COOH
α hydroxyl FA
Even long chain FA
NADH+H+
NAD
NAD
L ascorbic acid
CO2
CH3
β oxidation
R.CH2 – CH – COOH
Odd long chain FA
½ O2
NADH+H+
CH3 O
R.CH2 – CH – C– COOH
α Keto FA
Functions:
1- Formation of α hydroxyl fatty acids which is a
constituent of brain lipids
2- Modification of FA with methyl groups on the β
carbon which block β oxidation e.g. phytanic acid
present in certain plants, it has 4 CH3 groups at
position 3, 7, 11, 15, by initial α oxidation &
removal of one carbon, CH3 groups is at α
position, FA undergo β oxidation
•rare neurological disorder
Refsum’s
disease
• caused by accumulation of phytanic
acid, a constituent of chlorophyll found in
plant foodstuffs
• Phytanic acid contains a CH3 gp on C3
that block β oxidation. SO an initial α
oxidation required to remove CH3 group
•Pathology
inherited defect in α oxidation leads to
accumulation of phynatic acid
3- Omega Oxidation
• Occurs at terminal methyl group
acid (HOOC R COOH)
• Site: microsomes of the liver
dicarboxylic
O2
CytCytP450
P450
H2O
OH – CH2 – R– COOH
CH3 – R – COOH
NADH+H+
NADP
β oxidation
HOOC – CH2– COOH
In both sides
Dicarboxylic acid
3- Omega Oxidation
•The dicarboxylic acid formed may be shorted from both
ends by β oxidation
2 molecules of acetyl COA
each time
• Oxidation continues usually to adipic (C6) & suberic
(C6) acids which are excreted in urine
Of active acetate (acetyl
COA)
1- Carbohydrates:
Glucose undergoes glycolysis forming pyruvic acid,
which enters the mitochondria where it undergoes
oxidation decarboxylation to form acetyl-CoA
2- Fats:
Fats are hydrolysed into glycerol and FA
•
Glycerol joins glycolysis at the step of dihydroxy
acetone phospate
pyruvic acid
acetyl – CoA
•
The fatty acid undergoes β – oxidation
CoA
acetyl –
3-Proteins:
 Proteins are hydrolyzed to amino acids:
•
The ketogenic amino acids form acetyl- CoA directly
or through the formation of aceto acetate
•
The glucogenic amino acids first form pyruvate
either directly or through the formation of Kreb’s
cycle intermediates
Fate of acetyl
CoA
1- Oxidation:
Acetyl-CoA + oxalacetate
citrate
enter
the Kreb’s cycle
CO2 + water + 12 ATP
2- Formation of Fatty Acids (lipogenesis):
The excess acetyl-CoA resulting from the
oxidation of carbohydrates, or less commonly
proteins, may be converted into fatty acids
3- Formation of Ketone Bodies:
The excess acetyl-CoA resulting from oxidation of FA
in the liver may form ketone bodies (ketogenesis)
4- Formation of Steroids:
Acetyl-CoA
cholesterol
bile acids & vitamin D3
steroid hormones,
5- Acetylation of Some Compunds:
Acetyl-CoA is used for the acetylation of choline,
glucosamine and aromatic amines
Summary
Questions