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Minor pathways of fatty acids oxidation- A quick review
Over view of minor pathways of biological importance of fatty acid oxidation
1) α- Oxidation- Oxidation occurs at C-2 instead of C-3, as in β oxidation
2) ω- Oxidation – Oxidation occurs at the methyl end of the fatty acid molecule.
3) Peroxisomal fatty acid oxidation- Occurs for the chain shortening of very long chain fatty acids.
Details of α- Oxidation
- Takes place in the microsomes of brain and liver,
- Involves decarboxylation process for the removal of single carbon atom at one time
- An odd chain fatty acid is produced by decarboxylation
- Subsequent process involves beta oxidation for energy production
- Strictly an aerobic process.
- No prior activation of the fatty acid is required.
- The process involves hydroxylation of the alpha carbon with a specific α-hydroxylase enzyme that requires Fe++ and vitamin C/FH4 as cofactors.
A) Biological significance of alpha oxidation
1) Oxidation of methylated fatty acids- Although the use of the α- Oxidation scheme is relatively less in terms of total energy production, but it is significant in the metabolism of dietary fatty acids that are methylated. A principal example of these is Phytanic acid (Figure-1) α- Oxidation is most suited for the oxidation of phytanic acid, produced from dietary phytol, a constituent of chlorophyll of plants. Phytanic acid is a significant constituent of milk lipids and animal fats and normally it is metabolized by an initial α- hydroxylation followed by dehydrogenation and decarboxylation. Beta oxidation can not occur initially because of the presence of 3- methyl groups, but it can proceed after decarboxylation. The whole reaction produces three molecules of propionyl co A, three molecules of Acetyl co A, and one molecule of iso butyryl co A (Figure-2).
Figure-1-Phytanic acid -3, 7, 11, 15-tetramethylhexadecanoic acid
Figure-2- Phytanic acid is oxidized by Phytanic acid α oxidase to yield CO2 and odd chain fatty acid Pristanic acid that can be subsequently oxidised by beta oxidation. This process involves hydroxylation of the alpha carbon, removal of the terminal carboxyl group and concomitant conversion of the alpha hydroxyl group to a terminal carboxyl group, and linkage of CoA to the terminal carboxyl group. This branched substrate will function in the beta-oxidation process, ultimately yielding propionyl-CoA, acetyl Co As and, in the case of phytanic acid, 2-methyl propionyl CoA (Iso butyryl Co A)
2) The hydroxy fatty acids produced as intermediates of this pathway like Cerebronic acid can be used for the synthesis of cerebrosides and sulfatides
3) Odd chain fatty acid produced upon decarboxylation in this pathway, can be used for the synthesis of sphingolipids and also undergo beta oxidation to form propionyl co A and Acetyl co A .The number of acetyl co A depend upon the chain length. Propionyl co A is converted to Succinyl co A to gain entry in to TCA cycle for further oxidation.
B) Clinical significance of alpha oxidation of fatty acids
Refsum disease (RD)
Refsum disease (RD) is a neurocutaneous syndrome that is characterized biochemically by the accumulation of phytanic acid in plasma and tissues. Refsum first described this disease.
Refsum disease is an autosomal recessive disorder. Patients with Refsum disease are unable to degrade phytanic acid because of a deficient activity of Phytanic acid oxidase enzyme catalyzing the first step of phytanic acid alpha-oxidation (Figure-2)
Consequently, this unusual, exogenous C20-branched-chain (3, 7, 11, 15-tetramethylhexadecanoic acid) fatty acid accumulates in brain, blood and other tissues. It is almost exclusively of exogenous origin and is delivered mainly from dietary plant chlorophyll and, to a lesser extent, from animal sources. Blood levels of phytanic acid are increased in patients with Refsum disease. These levels are 10-50 mg/dL, whereas normal values are less than or equal to 0.2 mg/dL, and account for 5-30% of serum lipids. Phytanic acid replaces other fatty acids, including such essential ones as Linoleic and Arachidonic acids, in lipid moieties of various tissues. This situation leads to an essential fatty acid deficiency, which is associated with the development of ichthyosis.
Refsum disease is rare, with just 60 cases observed so far.
Classic Refsum disease manifests in children aged 2-7 years; however, diagnosis usually is delayed until early adulthood. Infantile Refsum disease makes its appearance in early infancy. Peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, and Ichthyosis (rough, dry and scaly skin) are the major clinical components. The symptoms evolve slowly and insidiously from childhood through adolescence and early adulthood.
The disease is characterized by
- Night blindness due to degeneration of the retina (retinitis pigmentosum)
- Loss of the sense of smell (anosmia)
- Concentric constriction of the visual fields
- Signs resulting from cerebellar ataxia –Cardiac arrhythmias
- Progressive weakness
- Foot drop
- Loss of balance
- Some individuals will have shortened bones in their fingers or toes.
- The children usually have moderately dysmorphic features that may include epicanthal folds, a flat bridge of the nose, and low-set ears.
- Levels of plasma cholesterol and high- and low-density lipoprotein are often moderately reduced.
- Blood phytanic acid levels are elevated.
- Cerebrospinal fluid (CSF) shows a protein level of 100-600 mg/dL.
- Routine laboratory investigations of blood and urine do not reveal any consistent diagnostic abnormalities.
- Phytanic oxidase activity estimation in skin fibroblast cultures is important
Skeletal radiography is required to estimate bone changes.
- Eliminate all sources of chlorophyll from the diet.
- Plasmapheresis – Patients may also require plasma exchange (Plasmapheresis) in which blood is drawn, filtered, and reinfused back into the body, to control the buildup of phytanic acid.
- The major dietary exclusions are green vegetables (source of phytanic acid) and animal fat (phytol).
- The aim of such dietary treatment is to reduce daily intake of phytanic acid from the usual level of 50 mg/d to less than 5 mg/d.
Prognosis – in untreated patients generally is poor.
2) Omega oxidation of fatty acids
- Another minor pathway for the fatty acid oxidation
- Involves hydroxylation of omega carbon (the methyl carbon at the other end of the molecule from the carboxyl group or on the carbon next to the methyl end).
- Occurs in the endoplasmic reticulum of many tissues.
- Hydroxylation involves the “mixed function oxidase” type of reaction requiring cytochrome P450, O2 and NADPH, as well as the necessary enzymes (Figure-3)
Figure-3- The methyl end of the fatty acid is hydroxylated by a specialized hydroxylase, called Mixed function oxidase, that uses molecular oxygen and NADPH for hydroxylation.
- Hydroxy fatty acids can be further oxidised to a dicarboxylic acid via sequential reactions of Alcohol dehydrogenase and aldehyde dehydrogenases (Figure-4 and 5)
Figure-4- Omega hydroxy fatty acid is oxidized by alcohol dehydrogenase to form Omega aldo acid.
- The process occurs primarily for medium chain fatty acids.
Figure-5- Omega aldo acid is further oxidized by aldehyde dehydrogenase to form Dicarboxylic acid
- The dicarboxylic acids so formed can be activated at either end of molecule to form a Co A ester, which can undergo beta oxidation to produce shorter chain dicarboxylic acids such as Adipic acids(C6) and succinic acid (C4).
Clinical significance of Omega oxidation
The microsomal (endoplasmic reticulum, ER) pathway of fatty acid ω-oxidation represents a minor pathway of overall fatty acid oxidation.
However, in certain pathophysiological states, such as diabetes, chronic alcohol consumption, and starvation, the ω-oxidation pathway may provide an effective means for the elimination of toxic levels of free fatty acids.
3) Peroxisomal oxidation of very long chain fatty acids
- Although most fatty acid oxidation takes place in mitochondria, some oxidation takes place in cellular organelles called peroxisomes.
- Peroxisomes are a class of sub cellular organelles with distinctive morphological and chemical characteristics.
- These organelles are characterized by high concentrations of the enzyme catalase, which catalyzes the dismutation of hydrogen peroxide into water and molecular oxygen
- Fatty acid oxidation in these organelles, which halts at octanoyl CoA, may serve to shorten long chains to make them better substrates of beta-oxidation in mitochondria.
- Peroxisomal oxidation differs from beta oxidation in the initial dehydrogenation reaction (Figure-6).
Figure-6- The first reaction is catalyzed by acyl co A dehydrogenase same as Beta oxidation but the reduced FADH2 is not oxidized in the electron transport chain instead it is oxidized using direct molecular oxygen to form H2O2 which is subsequently decomposed by catalase to form water and oxygen.
- In peroxisomes, a flavoprotein dehydrogenase transfers electrons to O2 to yield H2O2 instead of capturing the high-energy electrons as FADH2, as occurs in mitochondrial beta oxidation.
- Catalase is needed to convert the hydrogen peroxide produced in the initial reaction into water and oxygen.
- Subsequent steps are identical with their mitochondrial counterparts, although they are carried out by different isoforms of the enzymes.
- The specificity of the peroxisomal enzymes is for somewhat longer chain fatty acids. Thus peroxisomal enzymes function to shorten the chain length of relatively long chain fatty acids to a point at which beta oxidation can be completed in mitochondria.
- Other peroxisomal reactions include chain shortening of dicarboxylic acids, conversion of cholesterol to bile acids and formation of ether lipids.
- It has been suggested that peroxisomes may function in a protective role against oxygen toxicity.
- Several lines of evidence suggest that they are also involved in the lipid catabolism. A number of drugs used clinically to decrease triglyceride levels in patients cause a marked increase in peroxisomes.
Zellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder (present at birth), characterized by the reduction or absence of Peroxisomes in the cells of the liver, kidneys, and brain.
Zellweger syndrome is one of a group of four related diseases called peroxisome biogenesis disorders (PBD), which are part of a larger group of diseases known as the leukodystrophies. It is characterized by an individual’s inability to beta-oxidize very-long chain fatty acids in the Peroxisomes of the cell, due to a genetic disorder in one of the several genes involved with peroxisome biogenesis.
The most common features of Zellweger syndrome include-
- Enlarged liver
- High levels of iron and copper in the blood stream, and
- Vision disturbances.
- Some affected infants may show prenatal growth failure.
- Symptoms at birth may include a lack of muscle tone, an inability to move and glaucoma.
- Other symptoms may include unusual facial characteristics, mental retardation, seizures, and an inability to suck and/or swallow.
- Jaundice and gastrointestinal bleeding may also occur.
- More than 90% show postnatal growth failure.
There are several noninvasive laboratory tests that permit precise and early diagnosis of peroxisomal disorders. The abnormally high levels of VLCFA ( Very long chain fatty acids ), are most diagnostic .
There is no cure for Zellweger syndrome, nor is there a standard course of treatment. Since the metabolic and neurological abnormalities that cause the symptoms of Zellweger syndrome are caused during fetal development, treatments to correct these abnormalities after birth are limited. Most treatments are symptomatic and supportive.
The prognosis for infants with Zellweger syndrome is poor. Most infants do not survive past the first 6 months, and usually succumb to respiratory distress, gastrointestinal bleeding, or liver failure.Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!