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Minor pathways of fatty acid oxidation (Alpha, omega and peroxisomal)- Subjective Questions
Answer- The β oxidation accounts for the bulk of the energy production from fatty acids in human. These reactions must be supplemented by other mechanisms, so that all types of ingested fatty acids can be oxidised.
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.
1) α- Oxidation
α- Oxidation- Takes place in the microsomes of brain and liver, involves decarboxylation process for the removal of single carbon atom at one time with the resultant production of an odd chain fatty acid that can be subsequently oxidized by beta oxidation for energy production. It is 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.
There are systems in many tissues for the hydroxylation of α –carbon of shorter chain fatty acids in order to start their oxidation.
Biological significance of alpha oxidation
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.
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-1)
Figure-1- Phytanic acid is oxidised by Phytanic acid α oxidase (α- hydroxylase enzyme) 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 can 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.
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. 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.
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.
Refsum disease is an Autosomal recessive disorder characterized by defective alpha-oxidation of phytanic acid.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. Symptoms develop progressively and slowly with neurologic and ophthalmic manifestations. 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.
- 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.
- 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 main indication for Plasmapheresis in patients with Refsum disease is a severe or rapidly worsening clinical condition.
- A minor indication is failure of dietary management to reduce a high plasma phytanic acid level.
Prognosis –in untreated patients generally is poor. Dysfunction of myelinated nerve fibers and the cardiac conduction system leads to central and peripheral neuropathic symptoms, impaired vision, and cardiac arrhythmias. The latter frequently are the cause of death.
In early diagnosed and treated cases, phytanic acid decreases slowly, followed by improvement of the skin scaling and, to a variable degree, reversal of recent neurological signs. Retention of vision and hearing are reported.
Pharmacological up regulation of the omega-oxidation of phytanic acid may form the basis of the new treatment strategy for adult Refsum disease in the near future.
2) Omega oxidation of fatty acids
Another minor pathway for the fatty acid oxidation also involves hydroxylation and occurs in the endoplasmic reticulum of many tissues. In this case hydroxylation takes place on the methyl carbon at the other end of the molecule from the carboxyl group or on the carbon next to the methyl end.
It uses the “mixed function oxidase” type of reaction requiring cytochrome P450, O2 and NADPH, as well as the necessary enzymes.
Hydroxy fatty acids can be further oxidised to a dicarboxylic acid via sequential reactions of Alcohol dehydrogenase and aldehyde dehydrogenases. The process occurs primarily with medium chain fatty acids.
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).
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 (Figure-2).
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. 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.
Fatty acid oxidation in these organelles, which halts at octanyl CoA, may serve to shorten long chains to make them better substrates of b-oxidation in mitochondria. Peroxisomal oxidation differs from beta oxidation in the initial dehydrogenation reaction (Figure–2). 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.
Figure-2- Initiation of Peroxisomal Fatty Acid Degradation, The first dehydration in the degradation of fatty acids in peroxisomes requires a flavoprotein dehydrogenase that transfers electrons to O2 to yield H2O2.
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. Given these diverse metabolic roles it is not surprising that the congenital absence of functional peroxisomes, an inherited defect , known as Zellwegar syndrome, has such devastating effects.
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. These are inherited conditions that damage the white matter of the brain and also affect how the body metabolizes particular substances in the blood and organ tissues. 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. Zellweger syndrome is the most severe of the PBDs. Infantile Refsum disease (IRD) is the mildest and neonatal adrenoleukodystrophy and rhizomelic chondrodysplasia have similar but less severe symptoms.
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. Of central diagnostic importance are the typical facial appearance (high forehead, unslanting palpebral fissures, hypo plastic supraorbital ridges, and epicanthal folds. 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!