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12-13-17

Lipid Biosynthesis and
Degradation

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.

One
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 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.

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.

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 are
not as dense as chylomicrons. These lipoproteins are based on protein
components not as much lipids. Both vldl and ldl are known as bad cholesterols
since their serum concentration levels are responsible for different heart and
artery diseases like strokes. HDL are about half and half when it comes to the
lipid and protein ratio. They are good cholesterols since they to lower the
rate of artery diseases.  

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.

Triacylglycerols in chylomicrons and will circulate
through the blood. These triacylglycerols are used as substrates for cellular
lipases, which will then hydrolyze them to make fatty acids in several
different steps. Many carrier proteins transport the lipids into the cell using
many different pathways. There are carriers that can be used for varying chain?length
lipids.

Energy production from triacylglycerols begins
with their hydrolysis into free fatty acids. When analyzing this fat?storing tissue,
we can see that a cellular lipase will be carrying out the hydrolysis. Next the
fatty acid will be taken up through the bloodstream and the liver. The liver is
responsible for glycerol absorption and the fatty acids by the blood. This can be
sent to the glycolytic pathway by glycerol kinase and glycerol three phosphate dehydrogenase.
This enzyme can be used as energy via glucose or the TCA cycle via intermediates.

Fatty acids are broken down through the
?? oxidation pathway that
releases two?carbon units. 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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