Fatty Acid Oxidation Quiz

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 takes place in the mitochondria.
• FA oxidation is an aerobic process, requiring oxygen.
• NAD and FAD are used as co-enzymes, generating ATP.
• FAs are transported in the blood as free FAs.
• Longer-chain FAs are bound to albumin and then to a binding protein in cells.

Objectives

• Describe the processes of transporting FAs in the blood, activating them, and transporting them into mitochondria for breakdown.
• Outline the β-oxidation pathway for metabolizing FAs into acetyl-CoA.
• Explain how this pathway leads to ATP production.

Steps of FA Oxidation

• Activation: This is the only energy-requiring step in complete FA degradation, using ATP. Fatty acid + ATP + CoA → Acyl-CoA + AMP + PP_i. Several acyl-CoA synthetases (thiokinases) exist, each specific to FA chain lengths.
• Transport of long-chain FAs into mitochondria: Short-chain FAs can be oxidized directly inside the mitochondria, independent of carnitine. Long-chain acyl-CoA cannot penetrate the inner mitochondrial membrane unless it forms acyl carnitine.
• Long-chain FAs: These penetrate the inner mitochondrial membrane as carnitine derivatives. Carnitine (β-hydroxy-γ-trimethyl ammonium butyrate) is abundant in muscle and can be obtained from the diet or synthesized from lysine and methionine in the liver and kidney.

β-oxidation of Fatty Acids

• In β-oxidation, two carbons are activated at a time, starting from the carboxyl end of the acyl-CoA molecule.
• The chain is broken between α(2) and β(3) carbons.
• The resulting two-carbon units are acetyl-CoA molecules. For example, palmitoyl-CoA (16 carbons) forms 8 acetyl-CoA molecules.
• Several enzymes (collectively known as FA oxidase) catalyze the reaction in the mitochondrial matrix or inner membrane adjacent to the respiratory chain.
• These steps couple acyl-CoA oxidation with ADP phosphorylation to ATP.

Oxidation of Odd-Number FAs

• Odd-number FAs are also oxidized via β-oxidation, creating acetyl-CoA until a 3-carbon propionyl-CoA residue remains.
• Propionyl-CoA is converted to succinyl-CoA (a citric acid cycle constituent).
• The propionyl residue is the only glucogenic portion of the odd-number FA.

β-oxidation in Peroxisomes

• Very long-chain FAs (20 carbons or more) undergo preliminary β-oxidation in peroxisomes, yielding acetyl-CoA and H₂O₂.
• The initial step of dehydrogenation is catalyzed by an FAD-containing acyl-CoA oxidase, unique to peroxisomal β-oxidation.
• The produced FADH₂ is oxidized by molecular oxygen, generating H₂O₂. This H₂O₂ is then reduced to H₂O by catalase.
• Peroxisomal β-oxidation isn't directly linked to ATP production. However, its role includes shortening the side chain of cholesterol during bile acid formation and participation in plasmalogen, cholesterol, and dolichol synthesis.

α-oxidation of FAs

• α-oxidation involves removing one carbon from the carboxyl end of the FA molecule, primarily occurring in brain tissue.
• Branched-chain FAs (e.g., phytanic acid), due to their methyl group on the β-carbon, are not substrates for acyl-CoA dehydrogenase.
• Instead, these FAs are hydroxylated at the α-carbon by an α-hydroxylase and subsequently decarboxylated to generate a CoA derivative that enters the β-oxidation pathway.
• α-oxidation does not lead to high-energy phosphate production.

ω-oxidation of FAs

• ω-oxidation is a minor pathway that occurs in the endoplasmic reticulum (ER), involving cytochrome P450-dependent hydroxylases.
• The ω-carbon (the last carbon) of the FA is hydroxylated, followed by oxidation to form a carboxyl group. The final product is a dicarboxylic acid.

Oxidation of Unsaturated FAs

• Unsaturated FAs yield less energy compared to saturated FAs because they are less reduced and produce fewer reducing equivalents (NADH and FADH2).

Oxidation of Monounsaturated FAs

• Monounsaturated fatty acids (e.g. oleic acid), require 2,3-enoyl-CoA isomerase to convert a 3-cis derivative after several β-oxidation cycles to a 2-trans derivative to be used by the hydroxylase.

Oxidation of Polyunsaturated FAs

• The oxidation of polyunsaturated FAs (e.g., linoleic acid) necessitates NADPH-dependent reductase in addition to the isomerase.

Clinical Conditions

• Carnitine deficiency: Characterized by episodic hypoglycemia and muscle weakness. Causes include preterm infants, liver disease, malnutrition, vegetarianism, pregnancy, severe infections, burns, trauma, or hemodialysis, or organic aciduria. Treatment involves oral carnitine supplementation.

• Inherited defects in β-oxidation enzymes: lead to nonketotic hypoglycemia, coma, and fatty liver.

• Dicarboxylic aciduria: Excretion of C6-C10 ω-dicarboxylic acids and nonketotic hypoglycemia. Due to a lack of mitochondrial medium-chain acyl-CoA dehydrogenase, the oxidation of long and medium-chain FAs is impaired, leading to the buildup and excretion of dicarboxylic acids.

• Refsum disease: A rare, autosomal recessive disorder caused by a α-hydroxylase deficiency, resulting in phytanic acid accumulation. Symptoms are primarily neurological.

• Zellweger's syndrome: An inherited condition characterized by the absence of peroxisomes in all tissues. It leads to the accumulation of very long-chain FAs in the blood and tissues.

Test your knowledge on the oxidation of fatty acids and the biochemical processes involved. This quiz covers the transport of fatty acids in the blood, their activation, and the β-oxidation pathway that converts them into acetyl-CoA for ATP production. Dive into the details of this essential metabolic process!