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FATTY ACIDS SYNTHESIS
A large proportion of the fatty acids used by the body are supplied by the
diet. Carbohydrates, protein, and other molecules obtained from the diet
in excess of the body's needs for these compounds can be converted to
fatty acids, which are stored as triacylglycerols. In humans, fatty acid
synthesis occurs primarily in the liver and lactating mammary glands and,
to a lesser extent, in adipose tissue, the process incorporates carbons from
acetyl CoA into the growing fatty acid chain, using ATP and reduced
nicotinamide adenine dinucleotide phosphate (NADPH).
Three stages of fatty acid synthesis:
1. Transport of acetyl CoA into cytosol
2. Carboxylation of acetyl CoA
3. Assembly of fatty acid chain
The reactions of fatty acid synthesis all take place in the cytosol,
the
starting material for synthesis
of fatty acid
is acetyl CoA which
is made
in the mitochondria and can't cross the inner membrane .Note that the
acetyl-CoA is first joined to oxaloacetate to make citrate which is readily
transported out of the mitochondria using a co-transporter. The citrate is
then cleaved to acetyl-CoA and oxaloacetate by
the enzyme citrate lyase.
The oxaloacetate can return to the mitochondria as malate or pyruvate
.
Acetyl-CoA for fatty acid synthesis is now available in the cytosol. The
first committed step of fatty acid biosynthesis is
Carboxylation of acetyl
CoA to form malonyl CoA catalyzed by Acetyl-CoA carboxylase (ACC).
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The enzyme adds a CO2 to acetyl CoA. Note that this reaction is an
energy requiring process (1 ATP per Malonyl-CoA formed). This
carboxylation is both the rate-limiting and the regulated step in fatty acid
synthesis. The enzyme undergoes allosteric activation by citrate, and
inactivated by long-chain fatty acyl CoA (the end product of the pathway),
second mechanism of regulation is by reversible phosphorylation. In the
presence of counter regulatory hormones, such as epinephrine and
glucagon, acetyl CoA carboxylase is phosphorylated and, thereby,
inactivated.in the presence of insulin, acetyl CoA carboxylase is
dephosphorylated and, thereby, activated.
The remaining series of reactions of fatty acid synthesis is catalyzed by the
multifunctional dimer enzyme, fatty acid synthase. Each fatty acid
synthase monomer is a polypeptide with different enzymatic activities plus
a domain referred to as the acyl carrier protein (ACP).
The reactions are as
follow:
A. Loading of precursors
Transfer of the acetyl group of Acetyl-CoA to ACP by acetyl-CoA
ACPtransacylase.
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Now ACP accepts a three-carbon from malonyl CoA by Malonyl CoA-
ACP-transacylase
B. Condensation of the precursors
The malonyl group loses HCO3 originally added by acetyl CoA
carboxlyase, the result is a four-carbon unit attached to the ACP this
achieve by 3-Ketoacyl-ACP synthase.
The next three reactions convert the 3-ketoacyl group to the
corresponding saturated acyl group by a pair of reductions requiring
NADPH and a dehydration step.
The keto group is reduced to form beta-hydroxyacyl ACP by 3Ketoacyl-
ACP reductase.
A molecule of water is removed to introduce a double bond by
3Hydroxyacyl-ACP dehydratase.
A second reduction step occurs by Enoyl-ACP reductase
The result of these steps is production of a four-carbon compound (butyryl)
whose three terminal carbons are fully saturated, and which remains
attached to ACP. These steps are repeated. When the fatty acid reaches a
length of sixteen carbons, the synthetic process is terminated with
thioesterase which releases palmitate from the multienzyme complex,
producing a fully saturated molecule of palmitate (16:0). [Note: All the
carbons in palmitic acid have passed through malonyl CoA except the two
donated by the original acetyl CoA, which are found at the methyl-group
end of the fatty acid.] .The major fatty acid synthesized de novo is palmitic
acid.
Summary of fatty acid synthesis
acetyl CoA+7malonylCoA+14NADPH 1palmitate+7CO2+14 NADP +8CoA
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Fatty acid synthesis pathway
Elongation of fatty acid chains
Although palmitate, is the primary end-product of fatty acid synthase
activity, it can be further elongated by the addition of two-carbon units in
the endoblasmic reticulum (ER) and the mitochondria. These organelles
use separate enzymic processes. The brain has additional elongation
capabilities, allowing it to produce the very-long-chain fatty acids (up to
24 carbons) that are required for synthesis of brain lipids.
Desaturations of fatty acid chains
Enzymes present in the ER are responsible for desaturating fatty
acids
(that is, adding cis double bonds). Termed mixed-function oxidases, the
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desaturation reactions require NADPH .a variety of polyunsaturated fatty
acids (PUFA) can be made through additional desaturation combined
with elongation.[Note: Humans lack the ability to introduce double bonds
at carbon 9 therefore, must have the polyunsaturated linoleic and
linolenic acids provided in the diet .
Storage of fatty acids as components of triacylglycerols
Mono-, di-, and triacylglycerols consist of one, two, or three
molecules of fatty acid esterified to a molecule of glycerol. Fatty
acids are esterified through their carboxyl groups, resulting in a loss
of negative charge and formation of "neutral fat." The three fatty acids
esterified to a glycerol are usually not of the same type. A fatty acid must
be converted to its activated form (attached to coenzyme A) before it can
participate in TAG synthesis. This reaction is catalyzed by a family of
fatty acyl Co A synthetases (thiokinases).
Synthesis of a molecule of TAG from glycerol phosphate and
fatty acyl CoA involves four reactions; include the sequential addition of
two fatty acids from fatty acyl CoA, the removal of phosphate, and the
addition of the third fatty acid.