Y1S2 005 II Biochem Fatty Acid Nomenclature

Clinical Significance of Fatty Acid Deficiencies

• Inherited diseases that impair β-oxidation result from deficiencies in acyl-CoA dehydrogenases.
• Medium Chain Acyl CoA Dehydrogenase Deficiency is the most common form of acyl-CoA dehydrogenase deficiency.
• Symptoms of this deficiency include vomiting, lethargy, and frequently coma, and can be diagnosed by excessive urinary excretion of medium-chain dicarboxylic acids and their glycine and carnitine esters.
• Avoiding prolonged fasting is sufficient to prevent clinical problems in this deficiency.

Refsum's Disease

• Refsum's disease is a rare inherited disorder in which patients lack the mitochondrial α-oxidizing enzyme.
• Patients accumulate large quantities of phytanic acid in their tissues and serum, leading to severe symptoms such as cerebellar ataxia, retinitis pigmentosa, nerve deafness, and peripheral neuropathy.
• Restricting dairy products and ruminant meat from the diet can ameliorate the symptoms of this disease.

Hormones and Release of Metabolic Energy

• Glucagon, epinephrine, or β-corticotropin stimulate the activation of hormonesensitive lipase.
• Hormones bind cell-surface receptors that are coupled to the activation of adenylate cyclase upon ligand binding.
• The resultant increase in cAMP leads to activation of PKA, which in turn phosphorylates and activates hormonesensitive lipase.

Generation of Fatty Acids from Triacylglycerols for β-Oxidation

• Hormone-sensitive lipase hydrolyzes fatty acids from triacylglycerols.
• The resulting diacylglycerols are substrates for either hormonesensitive lipase or for the non-inducible enzyme diacylglycerol lipase.
• Finally, the monoacylglycerols are substrates for monoacylglycerol lipase.
• The net result of the action of these enzymes is three moles of free fatty acid and one mole of glycerol.

Inhibition of Mobilization of Fatty Acids

• Insulin inhibits the mobilization of fat from adipose tissue.
• This inhibition is exerted upon adenylate cyclase, preventing the inappropriate mobilization of stored fat when an individual is in a well-fed state.

Activation of Fatty Acids in the Cytoplasm

• Fatty acids are activated in the cytoplasm before oxidation in the mitochondria.
• Activation is catalyzed by fatty acyl-CoA ligase (also called acyl-CoA synthetase or thiokinase).
• The net result of this activation process is the consumption of 2 molar equivalents of ATP.

Fatty Acid Transport to Mitochondria

• The transport of fatty acyl-CoA into the mitochondria is via an acyl-carnitine intermediate, generated by the action of carnitine acyltransferase I.
• The acyl-carnitine molecule is then transported into the mitochondria where carnitine acyltransferase II catalyzes the regeneration of the fatty acyl-CoA molecule.

Fatty Acid Oxidation (β-Oxidation of Fatty Acids)

• Beta oxidation is the process by which fatty acid molecules are broken down in the mitochondria and/or peroxisomes to generate acetyl-CoA for the Krebs cycle.

Mobilization of Fatty Acids for β-Oxidation

• The primary sources of fatty acids for oxidation are dietary and mobilization from cellular stores.
• Fatty acids from the diet can be delivered from the gut to cells via transport in the blood.
• Fatty acids are stored in the form of triacylglycerols primarily within adipocytes of adipose tissue.

β-Oxidation of Lipids with Odd Number of Carbons

• Fatty acids with an odd number of carbon atoms yield acetyl-CoA units + 1 mole of propionyl-CoA upon complete β-oxidation.
• The propionyl-CoA is converted, in an ATP-dependent pathway, to succinyl-CoA, which then enters the TCA cycle for further oxidation.

β-Oxidation of Lipids with Odd Number of Carbons (Additional Enzymes)

• Carboxylation by the biotin-dependent propionyl CoA carboxylase in an ATP-requiring reaction is the first step.
• The D- isomer is converted to the L- isomer by methylmalonyl CoA racemase in the intermediate step.
• In the final step, the L- isomer is converted to succinyl CoA by methylmalonyl CoA mutase.

Cis Double Bond Conversion

• The action of enoyl CoA isomerase is required to handle double bonds at odd-numbered carbons because β-oxidation generates or requires pre-existing double bonds at even-numbered carbons.