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.  

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 fir 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 id 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 synthase.

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 reaction.

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. Fat?soluble vitamins (A, D, E, and K)
absolutely require bile acids for absorption.

mixed micelles will provide enough surface area for the pancreatic lipases to
take action, 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.

Free fatty acids are transported as complexes
with serum albumin. Cholesterol, triacylglycerols, and phospholipids are
transported as protein?lipid complexes called lipoproteins.
Lipoproteins are spherical, with varying amounts and kinds of proteins at their
surfaces. The protein components, of which at least ten exist, are called apolipoproteins.
Lipoproteins are classified in terms of their density. The lightest and largest of the apolipoproteins are
the chylomicrons, which are less dense than water by virtue of their
being composed of more than 95 percent lipid by weight (remember that oils
float on water because they are less dense than water). Triacylglycerols make
up most of the lipid component of chylomicrons, with small amounts of
phospholipid and cholesterol. Chylomicrons contain several kinds of

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 body.

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.




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