In this article we will discuss about the mechanisms of oxidation of fatty acids in living organisms with the help of suitable diagrams.
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 atom > less is formed. This 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 aceto-acetic acid. Consequently, the original fatty acid molecule is converted into several molecules of acetic acid and one molecule of aceto-acetic acid (ketone). Both of these compounds undergo final oxidation into CO2 and H2O in normal health.
Subsequent discovery of coenzyme A (HS—CoA) by Lipmann and acetyl coenzyme A or active acetate by Lynen and his colleagues has laid a new pathway in the intermediary metabolism of fat. 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 hydrolysed 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 oxidation in the liver and breaks down into smaller fragments.
Each fragment contains two-carbon atoms. In the first phase of the oxidation process, there is a chemical reaction between the fatty acid, ATP and CoA activating the fatty acid by forming a thiol ester of coenzyme A.
This is the first step and is known as:
(a) The activation stage.
The ester thus formed undergoes successively the following reactions:
(d) Dehydrogenation, and
(e) Thiolytic cleavage.
Fatty acid is activated by thiokinase in presence of coenzyme A, ATP and Mg++ and activated fatty acid or coenzyme A ester formed. There are at least three kinases that catalyse 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 – C18) has little action on short-chain acids.
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 the kinases, there are at least three dehydrogenases, viz., G, Y1 and Y2. G is green-coloured dehydrogenase which catalyses oxidation of C4 – C8 acids. Y1 is yellow, having optimal action on C8 – C12 acids and Y2 being more active on C8 – C16 acids.
Then α-β-unsaturated fatty acid passes through a 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.
There is removal of two hydrogen atoms from β-carbon atoms, and β-keto activated fatty acid is produced. NAD acts as a hydrogen acceptor being converted into NADH2. This reaction is catalyzed by β-hydroxyacyl CoA dehydrogenase.
(e) Thiolytic Cleavage:
β-keto activated fatty acid is cleavaged at β-carbon atom, by thiolase β-ketothiolase) in presence of CoASH and thus two-carbon fragment as acetyl CoA is separated leaving activated fatty acid less by 2C. This process is repeated and an acetyl CoA is separated off in each complete oxidation process till the fatty acid is completely splitted into two-carbon fragments (acetyl CoA), e.g., palmitic acid which contains 16-carbon atoms is broken down into eight fragments of acetyl CoA (Fig. 10.23).
Evencarbon fatty acids, undergoing p-oxidation, 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.g., isobutyric and isocaproic acids, etc.) are also splitted into acetyl CoA and propionyl CoA during their oxidation.
The propionyl CoA is converted to methyl malonyl CoA and finally isomerized to succinyl CoA. The succinyl CoA may be utilized for the synthesis of carbohydrate 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 in 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. In diabetes mellitus and starvation, etc., where carbohydrate oxidation is depressed, the fatty acid oxidation becomes incomplete. There is formation of more aceto-acetic acid and this may lead to ketosis.
Role of Liver:
Three changes occur in liver.
They are follows:
i. The fats from the fat depot at first pass to the liver. The neutral fat is hydrolised in the liver into fatty acid and glycerol. The fatty acids are oxidized and acetyl CoA (2C compounds) is formed. These units may be dissimilated in the liver through citric acid cycle, or condensed to form aceto-acetic acid which is transported to the peripheral tissue for oxidation. Aceto-acetic acids reach the tissues and are oxidised into CO2 and H2O or resynthesized to fat (Fig. 10.22).
ii. In case of carbohydrate deficiency, more aceto-acetic acid is produced and ketosis may develop.
iii. Substances which reduce liver fats are called lipotropes or lipotropic factors. They are choline, methionine, betaine and lecithin, etc. They all help in the synthesis of phospholipids in which form liver fat may be easily mobilized out. The opposite groups of substances, which increase liver fat, are known as antilipotropic factors. Cholesterol is an important member of this class.
Role of Carbohydrates:
It is found that oxidation of fatty acids cannot be complete unless enough carbohydrates burn at the same time. Combustion stops at the intermediate stage and aceto-acetic acid (ketone body) and β-hydroxybutyric acid are produced. These are highly toxic substances and give rise to various ill effects. If sufficient carbohydrates burn, these ketone bodies are fully oxidized and no ketosis results.
Thus ketosis occurs in diabetes mellitus when sugar is not burnt even in the presence of enough sugar, Similar condition is also observed in starvation where there is no sugar to be oxidized. The general pathway of catabolism of fatty acids involves the β-oxidation. However, to some extent, certain fatty acid can undergo oxidation at the carbon atom farthest from the carboxyl group—the omega (co) carbon, producing a dicarboxylic acid. This is then subjected to β-oxidation and cleavaged to form smaller dicarboxylic acids.
α-oxidation occurs in brain microsomes where it has been found that brain sphingolipids contain α-hydroxy acids and odd-carbon fatty acids.
Role of Endocrines Fat Metabolism:
Certain endocrine factors take part in fat metabolism.
They are as follows:
i. Anterior Pituitary:
(a) Hypofunction of anterior pituitary is associated with unusual deposition of fat.
(b) The growth or somatotrophic hormone (STH) of anterior pituitary mobilizes fat from depots and increases production of ketone bodies in the liver. ACTH exerts a direct action on adipose tissue increasing lypolysis and mobilization of unsaturated fatty acids into the blood plasma. There is increase ketogenesis and decrease in R.Q., similar to the effect of STH.
Administration of insulin removes the condition of ketosis in diabetes mellitus. Insulin helps complete combustion of fatty acids, probably through its indirect influence on carbohydrate metabolism. Insulin helps in the formation of fat (lipogenesis) from glucose and deposition in adipose tissue. Insulin decreases the cholesteremia and lipaemia. It prevents breakdown of fat in the adipose tissue.
iii. Adrenal Cortex:
Glucocorticoids of adrenal cortex help fat metabolism in number of ways:
(a) Through its influence on sterol metabolism,
(b) Through its probable influence on phosphorylation, and
(c) Through its effect on carbohydrate metabolism.
Cortisol helps in the redistribution of fat in the body. Increased deposits of fats occur in the trunk when there is excessive secretion of Cortisol.
Thyroxine stimulates the combustion of fats, as it also does in case of other foodstuffs
v. Adrenaline (Epinephrine):
It stimulates mobilization of unesterified fatty acids from adipose tissue. The presence of ACTH and thyroid hormones is necessary for this action. There is associated increase in liver lipids and in ketogenesis.
Role of Vitamins on Fat Metabolism:
i. Thiamine (Vitamin B1):
Thiamine helps the enzyme system which is responsible for the synthesis of fats from carbohydrates and proteins.
It helps in the conversion of sugar into fats.
iii. Nicotinic Acid (Niacin):
Nicotinic acid helps in the formation of fats from carbohydrates.
iv. Pantothenic Acid (Vitamin B3):
Pantothenic acid in the form of CoA takes part in the reaction of both the synthesis and metabolism of fatty acids and cholesterol.
v. Cyanocobalamin (Vitamin B12):
This vitamin plays a very important role in the conversion of carbohydrate to fat.
vi. Pyridoxine (Vitamin B15):
It is related to the metabolism of unsaturated fatty acids and also helps in the synthesis of fats from carbohydrates. Pyridoxine, with the help of thiamine, accelerates the formation of fats from protein.