Oxidation of Fatty Acids (β-oxidation)
Introduction
The process of
successive β-oxidation was described by Knoop in 1905. In this process the
oxidation takes place in the carbon atom at the β-position (third from the
carboxyl group). This carbon atom is converted into a carboxyl (-COOH) group
and the outer two-carbon atoms are split off. Thus a fatty acid with two-carbon
atoms less is formed. That substance again undergoes β-oxidation and the
process is repeated successively, Thus fatty acid oxidation takes place in a
process known as alternate successive β-oxidation where two-carbon atoms are
removed at a time as acetic acid, until a four-carbon atom residue is left as
butyric acid. Butyric acid is oxidized in the β-position to form acetoacetic
acid. Consequently, the original fatty acid molecule is converted into several
molecules of acetic acid and one molecule of acetoacetic acid (ketone). Both of
these compounds undergo final oxidation into CO, and H₂O in normal health.
Stages
Discovery of coenzyme A
(HS-CoA) by Lipmann and acetyl coenzyme A or active acetate by Lynen and his
colleagues has explained the process further. Coenzyme A has been found to be
in large quantity in the liver. Coenzyme A is a dinucleotide and consists of
2-thiol-ethylamine and pantothenic acid linked with pyrophosphate and
adenosine. Active acetate is an acetylated derivative of this coenzyme. The
sulphur atom is linked to acetyl group. The neutral fat is hydrolyzed in the
liver into long-chain fatty acids (Palmitic, Stearic and Oleic acids containing
16 or 18 carbon atoms) and glycerol.
The fatty acid radical
undergoes successive oxidation in the liver and breaks down into smaller fragments
in the following stages-
1. Stage of activation- Fatty acid is activated by thiokinase in
presence of coenzyme A, ATP and Mg++ and activated fatty acid or
coenzyme ester is formed. There are at least three kinases that catalyze the
acylation of fatty acid. Acetic kinase shows a high specificity for acetic acid
and slightly for propionic acid. A second kinase acts on acids C4-C12,
optimum chain length being C8. The long-chain kinase (C8-C16)
has little action on short-chain acids.
2. Stage of Dehydrogenation- The activated fatty acid is oxidized by
the removal of two hydrogen atoms by acyl-CoA dehydrogenase along with a
coenzyme derived from flavin adenine dinucleotide (FAD) and α-β-unsaturated
activated fatty acid is produced. Just as in case of kinases, there are at
least three dehydrogenases, viz., G, Y, and Y₂. C green-colored dehydrogenase
which catalyses oxidation of C4-C8 acids, Y₁ is yellow,
having optimal action on C8-C12 acids and Y₂ being m
active on C8-C16 acids.
3.Stage of Hydration-Then a-ß-unsaturated fatty acid passes through
process of hydration with the addition of H₂O under the influence of enoyl
hydrase (crotonase) and β-hydroxy activated fatty acid is produced which
undergoes dehydrogenation again.
4. Stage of Dehydrogenation-There is removal of two hydrogen atoms from
ß-carbon atoms, and ß -keto activated fatty acid is produced. NAD acts as a
hydrogen acceptor being converted into NADH2. This reaction is catalysed
by ß-hydroxyacyl CoA dehydrogenase.
(V) Stage of thiolytic cleavage-β-keto
activated fatty acid is cleavaged 3-carbon atom, by thiolase (8-ketothiolase)
in presence of CoASH and thus two-carbon fragment as acetyl CoA is separated
leaving activate fatty acid less by 2C. This process is repeated again and
again and an acetyl CoA is separated off in each complete oxidation process
till the fatty acid completely split into two-carbon fragments (acetyl CoA).
Even-carbon
fatty acids, undergoing β-oxidation, even carbon
fatty acids give rise to acetyl CoA whereas odd-carbon fatty acids also give
rise to acetyl CoA and a molecule of propionyl CoA, the latter being formed
from the 3 terminal carbon atoms from the methyl end of fatty acid.
Branched-chain
fatty acids (e, isobutyric and isocaproic acids,
etc.) are also split into acetyl CoA and propionyl CoA during their oxidation.
The propionyl CoA converted to methyl malonyl CoA and finally isomerized to
succinyl CoA. The succinyl CoA may be utilized for the synthesis of
carbohydrate through pyruvic acid and porphyrin with glycine or may be oxidized
through TCA cycle after being converted into succinic acid to supply energy as
ATP. Acetyl CoA is oxidized in the TCA cycle and the coenzyme A thus set free after
oxidation helps further fatty acid oxidation. If acetyl CoA is not properly
oxidized, aceto-acetic acid is produced,
Fatty acid oxidation
depends upon simultaneous oxidation of carbohydrate.
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