Activation of fatty acid

1. Subject Name: Intermediary Metabolism
Subject Code: MTI 502
Unit No:1
Unit Name: Lipid Metabolism
Dr. Arpita Gupte

2. Role of carnitine
β –Oxidation of fatty acids

3. Digestion of fat

4. Utilization Stage 1 : Mobilization
Hormone Sensitive Lipase
Epinephrine, glucagon, ACTH triggers lipolysis
Insulin inhibits lipolysis

5. The glycerol released -
converted to glyceraldehyde-3-PO4
- glycolysis
- gluconeogenesis
Fate of glycerol

6. Utilization stages
1.Fatty acid must be activated: bound to coenzyme A
2.Fatty acid must be transported into mitochondrial matrix:
uses a shuttle mechanism
3.Fatty acid repeatedly oxidized, cycling through 4 reactions:
produces Acetyl CoA, FADH2, & NADH

7. Utilization Stage 2 : Activation
Fatty acid activation
N
N
N
N
NH2
O
OH
OH
H
H
H
CH2
H
O
P
O
P
O
P

O
O
O
O
O O
O
N
N
N
N
NH2
O
OH
OH
H
H
H
CH2
H
O
P
O
C
O
O
R
O
S
C
R
O
CoA
R C
O
O
PPi
CoA SH
AMP
2 Pi
fatty acid
ATP
acyl-
adenylate
acyl-CoA
Acyl-CoA Synthases (Thiokinase) of ER &
outer mitochondrial membranes catalyze
activation of long chain fatty acids,
esterifying them to coenzyme A.
This process is ATP-dependent, & occurs in
2 steps.
There are different Acyl-CoA Synthases for
fatty acids of different chain lengths.

8. fatty acid + ATP + CoA-SH acyl-CoA + AMP + 2 Pi
Summary of fatty acid activation:
fatty acid + ATP  acyl-adenylate + PPi
PPi  2 Pi
acyladenylate + HS-CoA  acyl-CoA + AMP
Overall:
Acyl CoA synthase
Inorganic pyrophosphatase

9. The longer chain fatty acids cannot diffuse across mitochondrial membrane
- So must be transported
- Uses a carrier protein: carnitine (derivative of amino acid lysine) :
β-hydroxy, γ-trimethyl ammonium butyrate
-Found in red meats & dairy products,
can also be synthesized by the body.
Utilization Stage 3 : Transport into mitochondria – Role of carnitine
-Oxidation
pathway in
matrix
Fatty acyl-CoA formed in cytosol by enzymes
of outer mitochondrial membrane & ER
Mitochondrion

10. Utilization Stage 3 : Transport into mitochondria
H3C N CH2 CH CH2
CH3
CH3
OH
COO
+
R
C
SCoA
O
+
H3C N CH2 CH CH2
CH3
CH3
O
COO
+
C
R
O
+ HSCoA
carnitine
fatty acyl carnitine
Carnitine Palmitoyl
Transferase
• Transfer of the fatty acid
across the inner
mitochondrial membrane
involves carnitine.
• Carnitine Palmitoyl
Transferases catalyze transfer
of a fatty acid between the
thiol of Coenzyme A and the
hydroxyl on carnitine

11. Utilization Stage 3 : Transport into mitochondria
Carnitine-mediated transfer of the fatty acyl into
the mitochondrial matrix is a 3-step process:
1. Carnitine Palmitoyl Transferase I, an enzyme
on the cytosolic surface of the outer
mitochondrial membrane, transfers a fatty acid
from CoA to the OH on carnitine.
2. An antiporter in the inner mitochondrial
membrane mediates exchange of carnitine for
acylcarnitine.
3. Carnitine Palmitoyl Transferase II, an enzyme
within the matrix, transfers the fatty acid from
carnitine to CoA. (Carnitine exits the matrix in
step 2.)
The fatty acid is now esterified to CoA in the
matrix.

12. Thank You