ECDA
SEPT 2009
LIPOGENESIS
KETOGENESIS
AND
LIPOGENESIS
 Fatty acids are
formed by the action
of fatty acid synthase
from acetyl-CoA and
malonyl-CoA (a 3carbon compound)
precursors.
LIPOGENESIS
 In humans, fatty acids are predominantly
formed in the liver and adipose tissue, and in
mammary glands during lactation.
 Most acetyl-CoA is formed from pyruvate by
pyruvate dehydrogenase in the mitochondria.
 Acetyl-CoA produced in the mitochondria is
condensed with oxaloacetate to form citrate,
which is then transported into the cytosol and
broken down to yield acetyl-CoA and acetate by
ATP citrate lyase.
LIPOGENESIS
 Fatty acid synthesis is starts with acetyl-CoA,
which is carboxylated to malonyl-CoA.
 The ATP-dependent carboxylation provides
energy input. The CO2 is lost later during
condensation with the growing fatty acid.
The spontaneous decarboxylation drives the
condensation.
 Acetyl-CoA Carboxylase catalyzes the 2-step
reaction by which acetyl-CoA is carboxylated
to form malonyl-CoA
LIPOGENESIS
 As with other
carboxylation reactions
(e.g., Pyruvate
Carboxylase), the enzyme
prosthetic group is biotin.
 ATP-dependent
carboxylation of the biotin,
carried out at one active
site (1), is followed by
transfer of the carboxyl
group to acetyl-CoA at a
second active site (2).
LIPOGENESIS
 The overall reaction, which is is spontaneous,
may be summarized as:
HCO3- + ATP + acetyl-CoA
ADP + Pi + malonyl-CoA
 Acetyl-CoA Carboxylase, which converts acetylCoA to malonyl-CoA, is the committed step of
the fatty acid synthesis pathway.
LIPOGENESIS
LIPOGENESIS
 Fatty acid synthesis, from acetyl-CoA and
malonyl-CoA, occurs by a series of reactions.
 NADPH serves as electron donor in the two
reactions involving substrate reduction. The
NADPH is produced mainly by the Pentose
Phosphate Pathway.
 Fatty acid synthase, the enzyme responsible
for fatty acid synthesis, has many catalytic
domains.
LIPOGENESIS
 Prosthetic groups of Fatty Acid Synthase
include:
 the thiol of the side-chain of a cysteine residue in
the Condensing Enzyme domain of the complex.
 the thiol of phosphopantetheine, which is
equivalent in structure to part of coenzyme A.
 Phosphopantetheine (Pant) is covalently linked via
a phosphate ester to a serine hydroxyl of the acyl
carrier protein domain of Fatty Acid Synthase. The
long flexible arm of phosphopantetheine helps its
thiol to move from one active site to another within
the complex.
LIPOGENESIS
thiol cysteine residue
thiol of phosphopantetheine
LIPOGENESIS
 Each of the substrates acetyl-CoA and
malonyl-CoA bind to the complex
(designated steps 1 & 2) Malonyl/acetyl-CoA
Transacylase enzyme domain.
 The condensation reaction (step 3) involves
decarboxylation of the malonyl moiety,
followed by attack of the resultant carbanion
on the carbonyl carbon of the acetyl (or acyl)
moiety.
LIPOGENESIS
LIPOGENESIS
 In steps 4-6, the b-ketone is reduced to an
alcohol, by electron transfer from NADPH.
 Dehydration yields a trans double bond.
 Reduction at the double bond by NADPH yields a
saturated chain.
LIPOGENESIS
 Following transfer of the growing fatty acid from
phosphopantetheine to the Condensing Enzyme's
cysteine sulfhydryl, the cycle begins again, with another
malonyl-CoA.
LIPOGENESIS
 The primary structure of the mammalian
Fatty Acid Synthase enzyme is summarized
below.
LIPOGENESIS
 When the fatty acid is 16 carbon atoms long,
a Thioesterase domain catalyzes hydrolysis of
the thioester linking the fatty acid to
phosphopantetheine. The 16-C saturated
fatty acid, palmitic acid, is the final product
of the Fatty Acid Synthase complex.
O
CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 C
O
LIPOGENESIS
 Regulation of Acetyl-CoA Carboxylase by
local metabolites:
 Palmitoyl-CoA, the product of Fatty Acid Synthase,
inhibits Acetyl-CoA Carboxylase , diminishing
production of malonyl-CoA, the precursor of fatty acid
synthesis. This is an example of feedback inhibition.
 Citrate allosterically activates Acetyl-CoA
Carboxylase. Citrate concentration is high when there
is adequate acetyl-CoA entering Krebs Cycle. Excess
acetyl-CoA is then converted via malonyl-CoA to fatty
acids for storage.
LIPOGENESIS
KETOGENESIS
KETOGENESIS
Ketogenesis is the process
by which KETONE BODIES or
compounds are produced
from acetyl CoA molecules as
a result of fatty acid
degradation.
KETOGENESIS
 Ketone bodies are produced mainly in the
mitochondria of hepatocytes.
 Its synthesis occurs in response to low
glucose levels in the blood, and after
exhaustion of cellular carbohydrate stores,
such as glycogen.
 The production of ketone bodies is then
initiated to make available energy that is
stored as fatty acids.
KETOGENESIS
 However, if the amounts of acetyl-CoA
generated in fatty-acid β-oxidation
challenge the processing capacity of the
TCA cycle or if activity in the TCA cycle is
low due to low amounts of intermediates
such as oxaloacetate, acetyl-CoA is then
used instead in biosynthesis of ketone
bodies via acetoacyl-CoA and β-hydroxyβ-methylglutaryl-CoA (HMG-CoA).
KETOGENESIS
REVIEW!
 Fatty acids undergo βoxidation to form acetylCoA.
 Normally, acetyl-CoA is
further oxidized and its
energy transferred as
electrons to NADH,
FADH2, and GTP in the
Krebs cycle.
KETOGENESIS
KETOGENESIS
 The three ketone bodies are:
 Acetoacetate - if not oxidized to form usable
energy, it is the source of the two other ketone
bodies below.
 Acetone - is not used as an energy source, but is
instead exhaled or excreted as waste.
 β-hydroxybutyrate - it is not technically a ketone
according to IUPAC nomenclature.
 Each of these compounds are synthesized from acetyl-
CoA molecules.
KETOGENESIS
 Ketogenesis may or may not occur,
depending on levels of available
carbohydrates in the cell or body.
 When the body has ample carbohydrates available
as energy source, glucose is completely oxidized
to CO2.
 When the body has excess carbohydrates
available, some glucose is fully metabolized, and
some of it is stored by using acetyl-CoA to create
fatty acids.
KETOGENESIS
 When the body has no free carbohydrates
available, fat must be broken down into acetylCoA in order to get energy. Acetyl-CoA is not
being recycled through the citric acid cycle
because the citric acid cycle intermediates (mainly
oxaloacetate) have been depleted to feed the
gluconeogenesis pathway, and the resulting
accumulation of acetyl-CoA activates ketogenesis.
 Ketogenesis provides energy for vital organs’
functions during prolonged starvation
KETOGENESIS
KETOGENESIS
KETOGENESIS
 Ketone bodies are created at moderate levels
in our bodies, such as during sleep and other
times when no carbohydrates are readily
available.
 However, when ketogenesis is happening at
higher than normal levels, the body is said to
be in a state of ketosis. Ketone bodies
accumulation in the body may result to
negative long term effects.
KETOGENESIS
 Abnormally high concentration of ketone
bodies in the body results in the decrease of
pH level of the blood. This state is called
ketoacidosis.
 Ketoacidosis is very rare to occur. It is,
however, more seen in people suffering from
untreated Diabetes mellitus (DM) and in
those alcoholics after binge drinking and
subsequent starvation.
Diabetes and Ketoacidosis
 When there is not enough insulin in the blood,
glucose is not used efficiently to produce energy.
Thus, the body must break down lipids for its
energy.
 Lipid degradation leads to ketones build up in
the blood. Ketone then spill over into the urine
so that the body can get rid of them. Acetone
can be exhaled through the lungs. This gives the
breath a fruity odor. Ketones that build up in the
body for a long time lead to serious illness and
coma. (Diabetic ketoacidosis)
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