Fatty Acid Oxidation Processes

Oxidation of Fatty Acids

• Fatty acids (FAs) are oxidized to acetyl-CoA and synthesized from acetyl-CoA.
• FA oxidation is a different process than FA biosynthesis, occurring in a separate cellular compartment.
• FA oxidation occurs in the mitochondria.
• FA oxidation is an aerobic process, requiring oxygen.
• NAD and FAD are used as coenzymes, generating ATP.
• FAs are transported in the blood as free FAs.
• Longer-chain FAs combine with albumin and are attached to a FA binding protein in cells.

Steps of FA Oxidation

• Activation: This is the only step in FA degradation requiring energy from ATP.
  • FA + ATP + CoA → Acyl-CoA + AMP + PPi.
  • Several acyl-CoA synthases are specific to different chain lengths.
• Transport of long-chain FAs into mitochondria
  • Activation of short-chain fatty acids and their oxidation in mitochondria can occur independently of carnitine.
  • Long-chain acyl-CoAs cannot penetrate the inner mitochondrial membrane and become oxidized unless they first form acylcarnitine.
  • Long-chain FAs penetrate the inner mitochondrial membrane as carnitine derivatives.
  • Carnitine (β-hydroxy y-trimethyl ammonium butyrate) is abundant in muscle.

β-oxidation of Fatty Acids

• In β-oxidation, two carbons are activated at a time from acyl-CoA molecules starting at the carboxyl end.
• The chain is broken between α(2) and β(3) carbon atoms.
• The two-carbon units formed are acetyl-CoA.
• For example, palmitoyl-CoA forms 8 acetyl-CoA molecules.
• Several enzymes, collectively called FA oxidase, catalyze the reaction in the mitochondrial matrix or inner membrane adjacent to the respiratory chain.
• This system is coupled with ADP phosphorylation to ATP.

β-Oxidation in Peroxisomes

• Very long-chain FAs (20 carbons or longer) undergo preliminary β-oxidation in peroxisomes, leading to acetyl-CoA and H₂O₂ formation.
• The initial dehydrogenation in peroxisomes is catalyzed by an FAD-containing acyl-CoA oxidase.
• The FADH₂ produced is oxidized by molecular oxygen, which is reduced to H₂O₂.
• H₂O₂ is reduced to H₂O by catalase.
• Peroxisomal β-oxidation helps shorten the side chain of cholesterol in bile acid formation.

α-Oxidation of FAs

• Removal of one carbon at a time from the carboxyl end of the fatty acid molecule (in brain tissue).
• Branched-chain FAs (like phytanic acid) are not substrates for acyl-CoA dehydrogenase, due to a methyl group on the β-carbon.
• Instead, they are hydroxylated at the α-carbon by an α-hydroxylase, then decarboxylated, and activated to their CoA derivative.
• This derivative is then a substrate for the enzymes of β-oxidation.
• α-oxidation doesn't produce high-energy phosphate.

ω-Oxidation of FAs

• A minor pathway involving hydroxylase enzymes and cytochrome P450 in the endoplasmic reticulum (ER).
• The -CH₃ group is converted to -CH₂OH, and subsequently oxidized to -COOH, forming a dicarboxylic acid.

Oxidation of Unsaturated FAs

• Oxidation of unsaturated FAs produces less energy than that of saturated FAs because they are less reduced.
• Fewer reducing equivalents are produced.

Oxidation of Monounsaturated FAs

• Oxidation of monounsaturated FAs (e.g., oleic acid) requires additional enzyme 2,3-enoyl-CoA isomerase, converting the 3-cis derivative to the 2-trans derivative, used as a substrate for hydroxylase.

Oxidation of Polyunsaturated FAs

• Oxidation of polyunsaturated FAs (e.g., linoleic acid) needs NADPH-dependent reductase in addition to isomerase.

Clinical Conditions

• Carnitine deficiency: Characterized by episodic hypoglycemia and muscular weakness. Caused by conditions like preterm infants, liver diseases, malnutrition, vegetarians, pregnancy, severe infections, burns, trauma, hemodialysis, or organic aciduria patients.
• Treatment with oral carnitine supplementation.
• Inherited defects in β-oxidation enzymes: lead to nonketotic hypoglycemia, coma and fatty liver
• Dicarboxylic aciduria: Characterized by the excretion of C6-C10 ω-dicarboxylic acids and nonketotic hypoglycemia. It's caused by a lack of mitochondrial medium-chain acyl-CoA dehydrogenase, which impairs β-oxidation but increases ω-oxidation, ultimately producing medium-chain dicarboxylic acids.

Additional Conditions

• Refsum disease: A rare autosomal recessive disorder caused by a deficiency of α-hydroxylase, leading to phytanic acid accumulation in plasma and tissues; mainly neurologic symptoms.
• Zellweger's syndrome: Inherited absence of peroxisomes in all tissues leading to accumulation of very long-chain FAs in blood and tissues.