Download 26_Catabolism of tryacylglycerols oxidation of fatty acids a

LIPID METABOLISM:
MOBILIZATION OF
TRIACYLGLYCEROLS;
OXIDATION OF
GLYCEROL
Storage and Mobilization of
Fatty Acids (FA)
• TGs are delivered to adipose
tissue in the form of
chylomicrones and VLDL,
hydrolyzed by lipoprotein
lipase into fatty acids and
glycerol, which are taken up
by adipocytes.
• Then fatty acids are
reesterified to TGs.
• TGs are stored in adipocytes.
• To supply energy demands
fatty acids and glycerol are
released – mobilisation of
TGs.
adipocyte
At low carbohydrate and insulin concentrations (during
fasting), TG hydrolysis is stimulated by epinephrine,
norepinephrine, glucagon, and adrenocorticotropic
hormone.
TG
hydrolysis is
inhibited
by insulin
in fed
state
•Lipolysis - hydrolysis of
triacylglycerols by lipases.
•A hormone-sensitive lipase
converts TGs to free fatty
acids and monoacylglycerol
•Monoacylglycerol is
hydrolyzed to fatty acid
and glycerol or by a
hormone-sensitive lipase or
by more specific and more
active monoacylglycerol
lipase
Transport of Fatty Acids and Glycerol
• Fatty acids and glycerol diffuse
through the adipocyte membrane and
enter bloodstream.
• Glycerol is transported via the blood
in free state and oxidized or converted
to glucose in liver.
• Fatty acids are traveled bound to
albumin.
• In heart, skeletal muscles and liver
they are oxidized with energy release.
Oxidation of Glycerol
Glycerol is absorbed by the liver.
Steps: phosphorylation, oxidation and isomerisation.
Glyceraldehyde 3-phosphate is an intermediate in:
 glycolytic pathway
 gluconeogenic pathways
Isomerase
ATP Generation from Glycerol Oxidation
glycerol – glycerol 3-phosphate
- 1 ATP
glycerol 3-phosphate - dihydroxyaceton
phosphate
2.5ATP (1 NADH)
glyceraldehyde 3-phosphate – pyruvate
4,5 ATP (1NADH + 2 ATP)
pyruvate – acetyl CoA
2.5 ATP (1 NADH)
acetyl CoA in Krebs cycle
10 ATP (3NADH + 1 FADH2 + 1GTP)
Total
19,5-1 = 18,5 ATP
LIPID
METABOLISM:
FATTY ACID
OXIDATION
Stages of fatty acid oxidation
(1) Activation of fatty acids takes place
on the outer mitochondrial membrane
(2) Transport into the mitochondria
(3) Degradation to two-carbon
fragments (as acetyl CoA) in the
mitochondrial matrix (b-oxidation
pathway)
(1) Activation of Fatty Acids
• Fatty acids are converted to CoA thioesters by
acyl-CoA synthetase (ATP dependent)
• The PPi released is hydrolyzed by a
pyrophosphatase to 2 Pi
• Two phosphoanhydride bonds (two ATP equivalents)
are consumed to activate one fatty acid to a
thioester
(2) Transport of Fatty Acyl CoA into Mitochondria
• The carnitine shuttle
system.
• Fatty acyl CoA is first
converted to acylcarnitine
(enzyme carnitine
acyltransferase I (bound to
the outer mitochondrial
membrane).
• Acylcarnitine enters the
mitochondria by a
translocase.
• The acyl group is transferred
back to CoA (enzyme carnitine acyltransferase II).
• Carnitine
shuttle
system
• Path of
acyl group
in red
(3) The Reactions of b oxidation
• The b-oxidation pathway (b-carbon atom (C3)
is oxidized) degrades fatty acids two carbons
at a time
b

1. Oxidation of acyl
CoA by an acyl CoA
dehydrogenase to
give an enoyl CoA
Coenzyme - FAD
2. Hydration of the
double bond between
C-2 and C-3 by enoyl
CoA hydratase with
the 3-hydroxyacyl
CoA (b-hydroxyacyl
CoA) formation
3. Oxidation of
3-hydroxyacyl CoA to
3-ketoacyl CoA by
3-hydroxyacyl CoA
dehydrogenase
Coenzyme – NAD+
4. Cleavage of
3-ketoacyl CoA by
the thiol group of
a second molecule
of CoA with the
formation of
acetyl CoA and an
acyl CoA
shortened by two
carbon atoms.
Enzyme b-ketothiolase.
The shortened acyl
CoA then
undergoes another
cycle of oxidation
The number of
cycles: n/2-1,
where n – the
number of carbon
atoms
b-Oxidation
of
Fatty acyl CoA
saturated fatty
acids
• One round of b oxidation: 4 enzyme steps
produce acetyl CoA from fatty acyl CoA
• Each round generates one molecule each of:
FADH2
NADH
Acetyl CoA
Fatty acyl CoA (2 carbons shorter each round)
Fates of the products of b-oxidation:
- NADH and FADH2 - are used in ETC
- acetyl CoA - enters the citric acid cycle
- acyl CoA – undergoes the next cycle of oxidation
ATP Generation from Fatty Acid Oxidation
Net yield of ATP per one oxidized palmitate
Palmitate (C15H31COOH) - 7 cycles – n/2-1
• The balanced equation for oxidizing one palmitoyl
CoA by seven cycles of b oxidation
Palmitoyl CoA + 7 HS-CoA + 7 FAD+ + 7 NAD+ + 7 H2O
8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+
ATP generated
8 acetyl CoA
7 FADH2
7 NADH
10x8=80
7x1.5=10.5
7x2.5=17.5
108 ATP
ATP expended to activate palmitate
Net yield:
-2
106 ATP
LIPID METABOLISM:
FATTY ACID
OXIDATION
b-OXIDATION OF ODD-CHAIN FATTY ACIDS
• Odd-chain fatty acids
occur in bacteria and
microorganisms
• Final cleavage product is
propionyl CoA rather
than acetyl CoA
• Three enzymes convert
propionyl CoA to succinyl
CoA (citric acid cycle
intermediate)
Propionyl CoA Is Converted into Succinyl CoA
1. Propionyl CoA is carboxylated to yield the D
isomer of methylmalonyl CoA.
The hydrolysis of an ATP is required.
Enzyme: propionyl CoA carboxylase
Coenzyme: biotin
2. The D isomer of methylmalonyl CoA is
racemized to the L isomer
Enzyme: methylmalonyl-CoA racemase
3. L isomer of methylmalonyl CoA is converted
into succinyl CoA by an intramolecular
rearrangement
Enzyme: methylmalonyl CoA mutase
Coenzyme: vitamin B12 (cobalamin)
OXIDATION OF FATTY ACIDS IN
PEROXISOMES
Peroxisomes - organelles containing
enzyme catalase, which catalyzes
the dismutation of hydrogen
peroxide into water and molecular
oxygen
Acyl CoA
dehydrogenase
transfers electrons
to O2 to yield H2O2
instead of
capturing the highenergy electrons by
ETC, as occurs in
mitochondrial boxidation.