Emmanuel water-soluble precursors such as acetate. Like other biosynthetic

Emmanuel Espinoza

CHM 460

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Lipid Biosynthesis and

Lipids play a variety of cellular
roles,  some still being researched today.
They are the main form of stored energy in most organisms, as well as major
part of cell membranes. Specialized lipids serve as pigments (retinal),
cofactors (vitamin K), detergents (bile salts), transporters (dolichols),
hormones (vitamin D derivatives, sex hormones), extracellular and intracellular
messengers (eicosanoids and derivatives of phosphatidylinositol), and anchors
for membrane proteins (covalently attached fatty acids, prenyl groups, and
phosphatidylinositol). The ability to synthesize a variety of lipids is
therefore essential to all organisms. There are many biosynthetic pathways for
some of the principal lipids present in most cells, that are used for assembling
these water-insoluble products from simple, water-soluble precursors such as
acetate. Like other biosynthetic pathways, these reaction sequences are
endergonic and reductive. They use ATP as a source of metabolic energy and a
reduced electron carrier, typically NADPH as a reducing agent.  

During the synthesis of fatty acids,
acetyl-CoA is the precursor of the methyl end in the growing chain of the fatty
acid. The carbons will be derived from the acetyl group in the acetyl-CoA .
This will only happen after the acetyl-CoA is modified in order to provide the
substrate first the fatty acid synthase, which is malonyl-CoA. The malonyl-CoA
has a three carbon dicarboxylic acid derivative known as malonate which is
bound to the coenzyme A. Malonate will be  formed from acetyl-CoA when the
addition of the carbon dioxide is complete. The biotin factor of the enzyme
acetyl-CoA carboxylase will be responsible for the addition of the CO2. This is
known as the commitment step of fatty acid synthesis. This is because the
malonyl-CoA has no other metabolic roles in the body other than serving as the
precursor to fatty acids, but research is being done to find out if it has any
other metabolic functions.

of the more important enzymes in this reaction is the fatty acid synthase. This
enzyme is in charge of carrying out the elongation steps of the fatty acid
synthesis scheme. Fatty acid synthase is a part of a multienzyme complex; in
mammals this complex will contain two subunits. Each of the subunits of this
complex has a variety of enzymatic activities in the cell. In bacteria and
plants, some of these proteins will associate into other complexes in order to
catalyze the steps of fatty acid synthesis.

The synthesis of fatty acids will begin with
acetyl?CoA; the fatty acid chain grows from the back end in order to have  the carbon 1 and the alpha?carbon of the
complete fatty acid added at the end. In order to start synthesis, the first
reaction will be the transfer of the acetyl group to a pantothenate group
of acyl carrier protein (ACP),
which is a region of the large mammalian FAS protein. The acyl carrier protein
is a small, independent peptide in bacterial fatty acid synthase. The
pantothenate group of acyl carrier protein is the same on Coenzyme A, so the transfer
requires no energy input. In the previous
reaction, the S and SH refer to the thio group on the end of Coenzyme A or the
pantothenate groups. The bond between the carbonyl carbon of the acetyl group
and the thio group is a very high energy bond, because the activated acetyl
group is easily donated to an acceptor and the energy is very high. The second
reaction is another acetyl group transfer, this time, from the pantothenate of
the ACP to cysteine sulfhydral (–SH) group on fatty acid synthase.

The pantothenate group will be primed in
order to accept a malonyl group from malonyl?CoA: at this point, the fatty acid synthase has
two different activated substrates, one of which is the acetyl group bound on
the cysteine –SH and the other is the malonyl group bound on the pantothenate
–SH. The transfer of the two carbon acetyl group unit from Acety S?cysteine to
malonyl?CoA has two distinct features: first,  the release of the carbon dioxide group
of malonyic acid that was originally put on by acetyl?CoA carboxylase. The next
step will be the generation of a 4?carbon ?? keto acid derivative, bound
to the pantothenate of the acyl carrier protein. This ketoacid will now be reduced to the methylene
(CH 2) state in a three?step reaction sequence. This three step
reaction will first start off with the reduction by NADPH to the ?? hydroxy acid
derivative. Next, the water is removed via dehydration reaction to make the
trans-double bond. Lastly, NADPH will reduce the molecule in order to make the
saturated fatty acid. At this point, the elongated 4?carbon
chain is now ready to accept a new 2?carbon unit from malonyl?CoA. The 2?carbon
unit, which is added to the growing fatty acid chain, becomes carbons 1 and 2
of hexanoic acid (6?carbons). The cycle of transfer, elongation, reduction,
dehydration, and reduction continues until palmitoyl?ACP is made. Then the thioesterase activity of
the FAS complex releases the 16?carbon fatty acid palmitate from the fatty acid

Fatty acid synthesis provides an
extreme example of the phenomenon of metabolic channeling: neither free fatty acids with more
than four carbons nor their CoA derivatives can directly participate in the
synthesis of palmitate. Instead they must be broken down to acetyl?CoA and
reincorporated into the fatty acid.

Fatty acids are typically generated
cytoplasmically, while acetyl?CoA is made in the mitochondrion by pyruvate
dehydrogenase. This implies that a shuttle system must
exist to get the acetyl?CoA or its equivalent out of the mitochondrion. The
shuttle system operates in the following way: Acetyl?CoA is first converted to
citrate by citrate synthase in the TCA?cycle reaction. Then citrate is
transferred out of the mitochondrion by either of two carriers, driven by the
electroosmotic gradient: either a citrate/phosphate antiport or a
citrate/malate antiport. After it is in the cytosol, citrate is cleaved to its
2? and 4?carbon components by citrate lyase to
make acetyl?CoA and oxaloacetate. Citrate lyase requires ATP.

Fatty acid biosynthesis and most
biosynthetic reactions require NADPH to supply the reducing equivalents.
Oxaloacetate is used in order to generate NADPH for biosynthesis in a two?step reaction
sequence. The first step is the malate dehydrogenase reaction found in the TCA
cycle. This reaction results in the formation of NAD from NADH; this NADH
primarily comes from the glycolysis reactions. The malate formed is a substrate
for the malic enzyme reaction, which makes pyruvate, CO 2, and
NADPH. Next, pyruvate is transported into the mitochondria where pyruvate
carboxylase uses ATP energy to regenerate oxaloacetate.

starting point for most fatty acids in with palmitate; from palmitate, the head
groups and the modified chains of lipid classes are made. There are microsomal
enzymes which are primarily responsible for the catalysis of the chain
modifications. Oxygen molecule is used as the ultimate electron acceptor in the
desaturation reaction; which will introduce the double bonds to the five, six,
and nine positioned carbons in the acetyl-CoA. During the elongation step, malonyl-CoA
is used as the intermediate which is very similar to the palmitate synthesis

Hydrolysis of triacylglycerols into free fatty acids and glycerol will
result in production of energy. Lipases, are catalytic enzymes that will
catalyze the reaction and carry out the hydrolysis of the triacylglycerols. The
hydrolysis reaction will release the three fatty acids and the glycerol; from
here, an intestinal carrier will absorb the glycerol which will then rejoin
with the fatty acids later, in the intestinal cells.

Absorption of the fatty acids released by the lipases will require the
use of a very complex mechanism. It is known that fatty acids are poorly
soluble in water, but they are more soluble than triacylglycerols. Due to the
nonpolar nature of lipids; when they come into contact, they will form lipid
droplets.  Protein based enzymes are
water soluble and will not to be able to easily access entry into the lipid
droplets. In order for the lipids to be digested, they must emulsified into
smaller droplets, with large surface areas. With larger and more open surface
area, the hydrophobic interaction that force lipids into large droplets will be
easier to overcome. Bile salts or bile acids are the molecules that are
primarily responsible for carrying out these functions. The liver will
metabolically create and secrete them into the gall bladder to which they will
be then be pumped into the duodenum.

These bile salts are derived
from cholesterol and will be a major end product of the cholesterol metabolism
pathway. Bile salts have strong detergent properties, with large hydrophobic components
and the carboxylic end that has the negative charge; this charge is present on
physiological conditions of the small intestine. The hydrophobic component of
the bile acid will associate at a point known as the critical micelle
concentration, which well form a disk shaped micelle structure known as a
droplet. Micelles in the gut all contain cholesterol, triacylglycerol, and
fatty acids as well as bile salts; these are all known as mixed micelles. The bile salts form the edge of the micelle and also
appear, in fewer numbers (when compared to the lipids),  dispersed throughout the inside of the
micelle. The lipids exist in a bilayer on the inside of the disc. Bile acids
are important for fatty acid absorption.

mixed micelles will have enough surface area for the pancreatic lipases to
complete their actions, and digest the lipids. Pancreatic lipases use a
cofactor called colipase, which is used to bind both to the lipase and to the
micelle surfaces. The actions of these lipases will lead to the free fatty
acids that will be in the aqueous phase when located in the gut. Cells in the
small intestine will most likely absorb the free fatty acids and any that are
missed will be absorbed by the bacteria of the large intestine. These bacteria
can metabolize the free fatty acids as well. Bile salts are reabsorbed in the further
end of the small intestine.

metabolism of bile salts can help to explain the ability of certain dietary
fibers to help lower serum cholesterol. One molecule of bile salts will
circulate through the liver and the intestine a least four times, or more
before it will be eliminated. Certain soluble fibers, like the ones found in
oat bran; will bind bile acids which cannot be eliminated in this state. This
is the reason why they are eliminated in the stool as fiber bound bile acids. Since
bile salts are derived from cholesterol, whenever they are made, the body will
deplete its storage of cholesterols. This depletion will lead to a reduction of
serum cholesterol and will low the risk for coronary artery diseases. Ingestion
of dietary oat fiber cannot alone overcome an excessive dietary cholesterol
consumption though. Using this method but continuing to eat certain amounts of
foods high in cholesterol will not help overcome the effects of high
cholesterol consumption.

Serum albumin will complex with the free
fatty acids in order to transport them. Many other lipid derived molecules including
cholesterols and phospholipids, are all transported as protein lipid complexes
which are known as lipoproteins. The protein complexes are sphere shaped and will
have many different kinds of proteins on the surfaces. The different components
of the proteins are called apolipoproteins. Lipoproteins can be classified in
many different ways. Most of them are separated based on the density of each one.
The lightest of proteins are known as chylomicrons and have a lower density than
water. Chylomicrons are made up of high lipid levels by weight. Triacylglycerols
are the main part of the chylomicrons. Chylomicrons also contain some cholesterol
and other apolipoproteins.

Very?Low?Density Lipoproteins
(VLDL) are less dense than chylomicrons. They contain more protein, although
lipids (fatty acids, cholesterol and phospholipid, in that order) still make up
90 to 95 percent of their weight. Low?density lipoproteins (LDLs) are about 85
percent lipid by weight and contain more cholesterol than any other kind of
lipid. VLDL and LDL contain large amounts of Apolipoprotein B. The VLDL and LDL
are sometimes referred to as “bad cholesterol” because elevated serum
concentrations of these lipoproteins correspond with a high incidence of artery
disease (stroke and heart disease). The LDLs carry cholesterol and fatty acids
to sites of cellular membrane synthesis.

High?density lipoproteins (HDLs) will
contain a different apolipoprotein form, Apolipoprotein A which is different
than those of low density. These proteins are just about half lipid and half
protein by weight. Phospholipids and cholesterol esters are the most important
lipid components. HDL can be sometimes referred to as “good cholesterol”
because a higher ratio of HDL to LDL corresponds to a lower rate of coronary
artery disease.

In summary, these triacylglycerols
from the diet are digested by lipase and associate with bile salts into mixed
micelles. The free fatty acids are absorbed by the cells in the small
intestine, from which they are transported via the lymph system to the liver. From
the liver, they are released as apolipoproteins in the circulation, which can
be used for carrying fatty acids and cholesterol to the cells throughout the

Triacylglycerols in chylomicrons and LDLs will circulate
through the blood system; the former carries dietary lipids while the latter
carries lipids that are synthesized by the liver. These triacylglycerols are used
as substrates for cellular lipases, which hydrolyze them to make fatty acids
and glycerol in several different steps. Many carrier proteins transport the
lipids into the cell in different pathways. There are many different carriers that
exist for different chain?length lipids.

Energy production from triacylglycerols
starts with their hydrolysis into free fatty acids and glycerol. When analyzing
this adipose (fat?storing)
tissue, this hydrolysis will be carried out by a cellular lipase, which
catalyzes the hydrolysis reaction to release the free fatty acids and glycerol.
The fatty acid is carried through the bloodstream by being adsorbed to serum
albumin, while the glycerol goes to the liver. In the liver, glycerol can be
sent to the glycolytic pathway by the action of two enzymes, glycerol kinase
and glycerol?3?phosphate dehydrogenase. Glyceraldehyde?3?phosphate can also be
used as a source of glucose or, after conversion to phosphoenolpyruvate, as a
source of tricarboxylic acid cycle (TCA?cycle) intermediates.

In target tissues, fatty acids are
broken down through the ?? oxidation
pathway that releases 2?carbon units in succession. For example,
palmitic acid has 16 carbons. Its initial oxidation produces eight
acetyl?Coenzyme A (CoA) molecules, eight reduced FAD molecules, and eight NADH
molecules. The fatty acid is first activated at
the outer mitochondrial surface by conjugating it with CoA, then transported through the inner
mitochondrial membrane to the matrix, and then, for each 2?carbon unit, broken
down by successive dehydrogenation,
water addition, dehydrogenation, and hydrolysis reactions. The first reaction will involve the
catalization by the  isoforms of
acyl-CoA dehydrogenase (AD) on the inner-mitochondrial membrane. This reaction
will result in trans double bond, different from naturally occurring
unsaturated fatty acids. Analogous to succinate dehydrogenase reaction in the
citric acid cycle; the electrons from bound FAD transferred directly to the
electron- transport chain via electron-transferring flavoprotein (ETF) which is catalyzed by
two isoforms of enoyl-CoA hydratase. Next, water adds across the double bond yielding
alcohol, analogous to fumarase reaction in the citric acid cycle
with the same stereospecificity. Following this reaction, the one is  catalyzed by b-hydroxyacyl-CoA
dehydrogenase which  uses NAD cofactor
as the hydride acceptor. In this reaction, only L-isomers of hydroxyacyl CoA
act as substrates which is analogous to malate dehydrogenase reaction in
the citric acid cycle. The next reaction is catalyzed by acyl-CoA acetyltransferase
(thiolase) via covalent mechanism: The carbonyl carbon in b-ketoacyl-CoA
is electrophilic, active site thiolate acts as nucleophile and releases
acetyl-CoA, and the terminal sulfur in CoA-SH acts as nucleophile and
picks up the fatty acid chain from the enzyme. This will result in the net
reaction of thiolysis of carbon-carbon bond.