Transcript 10B-Oxidation and Ketone bodies

* Lipid Biosynthesis
- These are endergonic and reductive reactions, use ATP as source of energy
and reduced electron carrier usually NADPH as reductant.
* Fatty acid synthesis:
- F.A synthesis is not the reversal of the degradative pathway,
different sets of enzymes.
using
1-synthesis in cytosol, degradation in mitochondria (mitochondrial matrix)
2-intermediates of F.A synthesis are covalently linked to -SH group of ACP, at
higher organism single polypeptide called fatty acid synthase. (while in F.A
degradation are bonded to CoA)
3-the growing F.A is elongated by sequential addition of 2-carbon units.
4-the reductant in fatty acid synthesis is NADPH, while the oxidant in F.A
degradation are NAD+, FAD
5-elongation of F.A is stopped at C16 and further elongation or insertion of
double bonds are carried by other enzyme systems.
* Large proportion of F.A used in the body is supplied by diet excess CHO and
protein are converted into F.A.
- F.A are synthesized mainly in liver and lacting mammary gland and to lesser
extent in adipose tissue and kidney.
-oxidation of Saturated Fatty Acids
* Fatty acids are activated and transported into mitochondria
* F.As enter to cytosol from the blood and should move to mitocondrial matrix where the
enzymes are exist in three steps “CARNITINE SHUTTLE”
F.A
fatty acyl CoA
Found at outer
mitocondrial membrane
The hydrolysis of
Pull the
rxn to the
formation
of fatty
acyl CoA
This
process
occurs in
the outer
mitocondrial
membrane
* Fatty acyl CoA esters : don’t cross the inner mitocondrial membrane intact.
But it binds to the -OH group of Carnitine to form fatty acyl-Carnitine complex
this complex enters the matrix by facilitated diffusion.
In the matrix Carnitine and fatty acyl CoA are regenerated.
Acyl-Carnitine / Carnitine
transporter
Inner face
of the
membrane
Outer face of
the membrane
Inner membrane
Entrance of F.A to mitocondrial matrix (Carnitine shuttle)
1- Esterification to CoA
2- Transestrification to Carnitine followed by transport.
3- Transestrification back to CoA.
* The -oxidation of saturated F.A has
four basic steps
1- Dehydrogenation (oxidation)
1-oxidation
- 3 isomers of AD
a) LCAD (long chain acyl-CoA
dehydrogenase)
2e- electron
transfer chain
act on fatty acids 12 - 18 carbons
b) MCAD : 4 - 14 C
c) SAD : 4 - 8 C
2-Hydration
- AD bound to the inner membrane of
mitochondria
- AD has FAD as prosthetic group
2- Hydration (addition of water)
3-oxidation
- water is added to the double bond.
3- Dehydrogenation (oxidation)
- the enzyme is specific only for L-isomer
NADH
NAD+ and e- are transported to
O2 to produce ATP via e-transport chain
4-Thiolysis
NADH NADH dehydrogenase (complex I)
4- Thiolysis
- free CoA-SH split off the carboxy terminal
two carbons
Thio ester of fatty acid + 2 carbon
1-oxidation
2e- electron
transfer chain
2-Hydration
3-oxidation
4-Thiolysis
Thio ester of fatty acid + 2 carbon
-oxidation of Fatty acids
In each cycle of -oxidation one acetyl-CoA, 2 pairs of e- and
4H+ are removed from the fatty acid
C16-CoA + CoA + FAD + NAD+ + H2O
C14-CoA + acetyl-CoA +
FADH2 + NADH + H+
Palmitoyl CoA 7 cycles of -oxidation
8 acetyl CoA + 7 FADH2 + 7 NADH
+ 7H+
- The four steps are repeated
7 times
* Mitocondrial oxidation of
F.A
- oxidation: four reactions
results in shortening the F.A
by 2 carbon units, and these
four steps are repeated until
the complete degradation of
F.A
* The energy released by fatty
acid oxidation is conserved as
ATP
Are oxidized to CO2 in
the mitocondrial matrix
7 cycles
8 acetyl CoA
16 C palmitic acid
* Energy yields from complete oxidation of palmitic acid
(129 ATP resulted from complete oxidation)
Palmitoil-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O
8 acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+
acyl-CoA dehydrogenase
7 FADH2
- hydroxyacyl-CoA dehydrogenase
7 NADH
8 acetyl CoA : citric acid cycle produce
isocitrate dehydrogenase
8 NADH
ketoglutirate dehydrogenase
8 NADH
succinyl CoA-CoA synthatase
8 GTP
succinate dehydrogenase
8 FADH2
malate dehydrogenase
8 NADH
24 NADH
+ 8 FADH2
+ 8 GTP
8 ATP
Total = 31 NADH + 15 FADH2 + 8 ATP
93
+
30
+
8
= 131 ATP
- For each fatty acid to be activated by thiokinase (fatty acyl CoA synthetase) two
high energy bonds are consumed and these should be considered
So
131 - 2 = 129 ATP
Energy yields from complete oxidation of
palmitic acid
Complete oxidation of odd number
of Fatty acids (require additional
three reactions)
* F.A with an odd number of C are
common in plants.
* Odd F.A oxidized normally by oxidation, in the last step, Propionyl
CoA and acetyl CoA are produced.
Propionyl CoA
carboxylase
Methylmalonyl CoA
epimerase
biotin
Coenzyme
B12
Methylmalomyl CoA
mutase
- oxidation of polyunsaturated F.A (18 : 2 9,12 linoleate) need
additional two enzymes
Is removed by continuing
the - oxidation.
Cis 4
First oxidation step of
the second cycle
FAD
FADH2
Acyl CoA
dehydrogenase
Is not a substrate for
enoyl-CoA hydratase
* oxidation of unsaturated Fatty acids need additional reactions
(Monounsaturated)
* F.A with double
bond is in Cisconfiguration can’t
acted by enoyl-CoA
hydratase that add
H2O to the Trans
double bond of 2
enoyl-CoA
generated during oxidation.
Oxidation of
oleate 18 C
18 : 19
Is not a substrate
for enoyl-CoA
hydratase
This is a substrate
for hydratase
enzyme and oxidation is
continued
-oxidation of unsaturated F.A
* Regulation of fatty acid oxidation
- In the liver :
Fatty CoA formed in the cytosol has two routs
A. enter the mitochondria
- oxidation for energy.
B. Synthesis of triglycerols. This depends on the rate of transfer of fatty CoA
into the mitochondria.
Malonyl CoA : the first intermediate in the cytosolic synthesis of F.A from
acetyl CoA
•
When there is no need for energy, high level of glucose
increase
acetyl CoA
increase malonyl CoA that inhibit the Carnitine acyl
•
transferase I.
Oxidation of fatty acid is inhibited whenever there is excess CHO and
glucose and the extra glucose is converted into fatty acid. While excess
fatty acid can’t be converted to glucose .
Also when NADH / NAD+ ratio is high
inhibition of - hydroxyacyl
•
CoA dehydrogenase.
When high concentration of acetyl CoA
•
inhibition of thiolase.
Ketone Bodies
* Acetyl CoA in the liver cells can enter the citric acid cycle, or can be
converted into ketone bodies.
synthesized in the liver to be exported to other tissues by the blood,
then they can be oxidized by citric acid cycle.
Produced in smaller
amounts and exhaled
•The brain uses glucose as fuel
if it is not available it can use
acetoacetate and -hydroxybutyrate.
* Ketone bodies can be used as
fuel for heart, skeletal muscles
and kidney.
Ketone bodies formed in the
liver are exported to other
organs
*Acetone is formed in
very small amount in
healthy people.
* Untreated diabetes or
(starvation)
large
quantities of acetoacetate
is produced
increase
acetone amount odor to the
breath.
Or even spontaneous
decarboxylation
Specific for D not L
Extra hepatic tissues use ketone bodies as fuels
Acetoacetate and hydroxybutyrate is converted
into 2 acetyl CoA that enter
the citric acid cycle to
produce energy.
Extra hepatic tissues use ketone bodies as fuels
Over production of ketone bodies during the diabetes and starvation
* During starvation,
gluconeogenesis which depleted
citric acid cycles intermediates
diverting the acetyl CoA to ketone
body production.
* In diabetes, low level of insulin
Tissues can’t uptake glucose to use
as fuel
Malonyl CoA is not
formed
the entrance of fatty
acids into mitochondria are not
inhibited
accumulation of acetyl
CoA that can’t go through citric acid
cycle
accelerate the ketone
body production, causing low pH and
keto acidosis or ketosis.