Download Lehninger Principles of Biochemistry 5/e

David L. Nelson and Michael M. Cox
LEHNINGER
PRINCIPLES OF BIOCHEMISTRY
Fifth Edition
CHAPTER 17
Fatty Acid Catabolism
© 2008 W. H. Freeman and Company
Introduction
1. The oxidation of long-chain fatty acids to acetyl-CoA as a
central energy-yielding pathway- in mammalian heart and
liver; it provide 80% of energetic need
2. Fatty acid are converted into acetyl-CoA by repetitive fourstep processes, b-oxidation
3. Advantage of fatty acid as storage fuel
- highly reduced structure with high energy
- do not raise the osmolarity
- no undesired chemical reaction with other cellular
constituents
4. Fatty acid oxidation in mitochondria
1. Three sources: in the diet, in cells as lipid droplet,
synthesized in one organ (liver)
2. Dietary Fats are absorbed in the small intestine
When low levels of glucose in the blood
trigger the release of glucagon, 1 the
hormone binds its receptor in the adipocyte
membrane and thus 2 stimulates adenylyl
cyclase, via a G protein, to produce cAMP.
This activates PKA, which phosphorylates 3
the hormone-sensitive lipase and 4 perilipin
molecules on the surface of the lipid
droplet. Phosphorylation of perilipin permits
hormone-sensitive lipase access to the
surface of the lipid droplet, where 5 it
hydrolyzes triacylglycerols to free fatty
acids. 6 Fatty acids leave the adipocyte,
bind serum albumin in the blood, and are
carried in the blood; they are released from
the albumin and 7 enter a myocyte via a
specific fatty acid transporter. 8 In the
myocyte, fatty acids are oxidized to CO2,
and the energy of oxidation is conserved in
ATP, which fuels muscle contraction and
other energy-requiring metabolism in the
myocyte.
1. The enzymes of fatty acid oxidation in animal cells are
located in the mitochondrial matrix.
2. Fatty acid are activated.
Fatty acid are transported into mitochondria
Three stages
1. Fatty acids undergo oxidative
removal of successive twocarbon units in the form of
acetyl –CoA, starting from
the carboxyl end of the fatty
acyl chain
2. Aceyl-CoA are oxidized to
CO2 in the citric acid cycle
3. Electrons from first and
second stage are transferred
to ETS chain, passing to
oxygen with the formation of
ATP.
1. Acyl-CoA dehydrogenase: dehydrogenation
of fatty-acyl CoA produces a double bond
between a and b carbon, FAD is a
prosthetic group. Similar to succinate
dehydrogenation system (bound inner
membrane of Mito.; transfer electron to
ETS)
2. Enoyl-CoA hydratase:
water is added to the double bond of the
trans-enoyl-CoA, analogous to the
fumarase reaction
3. b-Hydroyacyl-CoA deghydrogenase
NADH formed and then transfer electorn to
NADH dehydrogenase in ETS. Analogous
to the malate dehydrogenase
4. Thiolase
thiolysis reaction
1. C>12, trifunctional protein (TFP(a4b4)), multienzyme complex
associated with inner membrane, catalyzed the reaction
2. a subunit: enoyl-CoA hadratase and b-hydroxyacyl-CoA
dehydrogenase activities
3. b-subunit: thiolase  substrate channeling
4. C<12, catalyzed by four soluble enzyme
5. Methylene group (-CH2-) in fatty acid is relatively stable
 first three step create a much less stable C-C bond, in which the a
carbon is bonded to two carbonyl carbon
 then b-carbon makes it a good target for nucleophilic attack by the –
SH of CoA
6. The four b-oxidation steps are repeated to yield Acetyl-CoA and ATP
palmitoyl-CoA + 7CoA + 7 FAD + 7NAD + 7H2O -
8acetyl-CoA + 7FADH2 + 7NADH + 7H+
-8acetyl-CoA + 28 ATP + 7H+
7. Acetyl-CoA can be further oxidized in the citric acid cycle
- 10 ATP/1turn  80 ATP
-108 ATP/palmitoryl-CoA
- for activation of palmitoryl, 2 phosphoanhydride bond was used -
106 ATP/palmitate
Oxidation of unsaturated fatty acid
Oxidation of unsaturated fatty acid
Complete oxidation of odd number fatty acids requires three
extra reactions
Fatty acid oxidation is tightly regulated
1. The three step process (carnitine shuttle) is rate-limiting for fatty acid oxidation
and is an important point of regulation
2. Malonyl-CoA, the first intermediate in the cytosolic biosynthesis of fatty acid
from acetyl-CoA, inhibits carnitine acyltransferase I.
3. [NADH]/[NAD+] ration is high, b-hydroxyl-CoA dehydrogenase is inhibited.
4. High concentrations of aceyl-CoA inhibit thiolase.
5. [AMP] is high, AMPK is activated and phosphorylated acetyl-CoA
carboxylase, which catalyze the formation of malonyl-CoA, thereby decreasing
the malonyl-CoA concentration.  allowing b-oxidation
6. Transcription factors turn on the synthesis
of proteins for lipid catabolism:
- PPARa acts in muscle, adipose tissue, and
liver to turn on a set of genes essential for
fatty acid oxidation.
- Glucagon  [cAMP]  CREB  turn
on a set of genes essential for fatty acid.
Coordinate regulation of fatty acid synthesis and breakdown
Two enzymes are key to the coordination of fatty acid metabolism: acetyl-CoA carboxylase (ACC), the first
enzyme in the synthesis of fatty acids, and carnitine acyltransferase I, which limits the transport of fatty acids
into the mitochondrial matrix for b-oxidation. Ingestion of a high-carbohydrate meal raises the blood glucose
level and thus 1 triggers the release of insulin. 2 Insulin-dependent protein phosphatase dephosphorylates
ACC, activating it. 3 ACC catalyzes the formation of malonyl-CoA (the first intermediate of fatty acid synthesis),
and 4 malonyl-CoA inhibits carnitine acyltransferase I, thereby preventing fatty acid entry into the mitochondrial
matrix . When blood glucose levels drop between meals, 5 glucagon release activates cAMP-dependent
protein kinase (PKA), which 6 phosphorylates and inactivates ACC. The concentration of malonyl-CoA falls,
the inhibition of fatty acid entry into mitochondria is relieved, and 7 fatty acids enter the mitochondrial matrix
and 8 become the major fuel. Because glucagon also triggers the mobilization of fatty acids in adipose tissue,
a supply of fatty acids begins arriving in the blood.
Peroxisome also carry out b oxidation
1. Peroxisome: membrane-inclosed organelles
of animal and plant cells.
2. Dehydrogenation, addition of water, oxidation
of b-hydroxyacyl-CoA to a ketone, thiolytic
cleavage by conezyme A.
3. Difference between peroxisome and
mitochondria.
- In peroxisome, the flavoprotein acyl-CoA
oxidase passes electrons directly to O2,
producing H2O2 and cleaved to H2O and
O2 by catalase
- Specificity for fatty acyl-CoA: much more
active on very-long cahin fatty acid such as
hexacosanoic acid (26:0).
4. In mammal, high concentration of fats in the
diet result in increase synthesis of the
enzymes of peroxisomal b-oxidation in liver.
long fatty acids are catabolized to
shorter-chain products and then are
exported to mitochondria.
Plant peroxisome and glyoxysome use acetyl-CoA from boxation as a biosynthetic precursor
1. In plant, fatty acid oxidation
does not occur primarily in
mitochondria but in the
peroxisomes of leaf tissue and
in the glyoxysomes of
germinating seeds
2. The biological role of b-oxidation
is to use stored lipid primarily to
provide biosynthetic precursors.
3. Glyoxylate cycle to four-carbon
precursors for gluconeogenesis.
4. Glyoxysomes contain high
concentrations of catalase.
Omega-oxidation of fatty acids occurs in the endoplasmic
reticulum
1. There is another pathway in some
species, including vertebrates, that
involves oxidation of the omega
carbon.
2. The enzymes unique to omega
oxidation are located the ER of liver
and kidney
3. The preferred substrate are fatty acid
of 10 to 12 carbon.
4. The first step introduces a hydroxyl
group on to omega carbon by mixed
function oxidase involved in
cytochrome p450 and NADPH
5. Produce a carboxyl group at each end.
6. In each pass through the b-oxidation
pathway, the double-ended fattyacid
yield dicarboxylic acid such as succinic
acid, which can enter citric acid cycle.
Ketone bodies
1. In human and most other
mammals, acetyl-CoA formed in
the liver during fatty acid oxidation
can either enter the citric acid cycle
or undergo conversion to the
ketone bodies.
2. Acetoacetate and bhydorxybutyrate are transported by
the blood to extrahepatic tissues,
where they converted to acetylCoA and oxidized in citric acid
cycle.
3. The brain can adapt to the use for
acetoacetate or b-hydorxybutyrate
under starvation condition.
Ketone bodies are overproduced in diabetes and starvation
1. During starvation,
gluconeogenesis depletes
citric acid cycle intermediates,
diverting acetyl-CoA to ketone
body production.
2. Untreated DM  insulin down
 cannot uptake glucose 
malonyl-Co A fall  fatty acid
oxidation increase  ketone
body  acidosis (ketosis)
3. Individual on very low-calorie
diets, using the fats stored in
adipose tissue as their major
energy source, also have
increased level of ketone
bodies in their blood and urine.