Minor pathways of oxidation of fatty acids- Lecture-2 (omega and peroxisomal oxidation)

Omega oxidation of fatty acids

Another minor pathway for 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.

Figure-1-Showing hydroxylation of omega carbon to form omega hydroxy acids.

Hydroxy fatty acids can be further oxidized to a dicarboxylic acid via sequential reactions of Alcohol dehydrogenase (figure-2) and aldehyde dehydrogenases (figure-3). The process occurs primarily with medium-chain fatty acids.

 Figure-2- dehydrogenation of omega hydroxy acid to form omega aldoacid.

The dicarboxylic acids so formed can be activated at either end of the 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).

Figure-3- Formation of dicarboxylic acid by dehydrogenation of Omega Aldo acid

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. 

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-4).

Peroxisomes are a class of subcellular 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 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 octenyl 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-4- 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 Zellweger syndrome, has such devastating effects.

Zellweger syndrome

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.

Biochemical defect

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.

Clinical Manifestations

The most common features of Zellweger syndrome include enlarged liver, high levels of iron and copper in the bloodstream, 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, hypoplastic supraorbital ridges, and epicanthal folds. More than 90% show postnatal growth failure.

Laboratory diagnosis

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.

Treatment

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.

Prognosis

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.