Beta Oxidation

• “Carnitine shuttle”


  1. Penetration of active fatty acids through the inner mitochondrial membrane via carnitine shuttle

  2. Enzyme – Carnitine palmitoyltransferase I (outer mitochondrial membrane) – regulatory enzyme

  3. Carnitine palmitoyltransferase II (inner mitochondrial membrane)

  4. Transport protein (translocase) – Carnitin/acylcarnitine translocase

  5. Regulation – inhibition of Carnitine palmitoyltransferase I by malonyl-CoA
• During the oxidation reduced equivalents (NADH and FADH2) are formed, which are oxidized in the Electron-transport chain
• Deficiencies in Acyl-CoA Dehydrogenases can lead to non-ketonic hypoglycemia, coma, and fatty liver
• Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency symptoms include vomiting, lethargy, coma, and excessive urinary excretion of medium-chain dicarboxylic acids
• Acyl-CoA dehydrogenases – set of isoenzymes (3) catalyzing the oxidation of active fatty acids (Acyl-CoA) with different length chains – long-, middle- and short-chain FA
• Oxidation of Very Long Chain Fatty Acids in Peroxisomes leads to the formation of acetyl-CoA molecules and H2O2, which is broken down by catalase
• In “b-oxidation” Acetyl-CoA molecules are released, which can enter the Citric acid cycle and produce ATP
• Regulatory step in b-oxidation is catalyzed by Carnitine palmitoyltransferase I (CPT I)
• Oxidation of Fatty Acids

  1. The main source of fatty acids for oxidation are dietary lipids and TAG in adipose tissues

  2. In response to energy demands or other stimulus, TAG deposits are mobilized and they release FFA

  3. In plasma longer-chain FFA are transported combined with albumin (VHDL)

  4. Shorter-chain FFA are more water-soluble and are free in the blood

  5. In cells FFA are attached to a fatty acid-binding protein

  6. The oxidation of FFA, called b-oxidation, is a catabolic pathway for oxidation of fatty acids with even and odd number of C atoms, saturated, mono- or polyunsaturated

  7. It is called “b-oxidation” due to the fact that there is oxidation of the 3rd (b) C atom of active fatty acid (Acyl-CoA), followed by cleavage between the a(2)- and b(3)-carbon atoms — releasing two-carbon units (Acetyl-CoA)
• Oxidation of unsaturated FA is essentially the same process as for saturated FA, except when a double bond is encountered
• Activation of fatty acids

  1. Activation via binding of -COOH group of the fatty acids with CoA-SH – thioester macroergic bond

  2. Two macroergic bonds are cleaved in this reaction (pyrophosphate bond of ATP between a and b phosphate moieties and the bond of pyrophosphoryl acid)

  3. Enzymes – Acyl-CoA synthetases (thiokinases) – in endoplasmic reticulum, peroxisomes, and outer mitochondrial membrane

  4. There are different enzymes catalyzing the reaction of fatty acids with chains with a different number of C atoms
• The “b-oxidation” is an aerobic mitochondrial process
• Oxidation of odd-chain length FA proceeds regularly till obtaining Propionyl-CoA, which is converted into Succinyl-CoA (metabolite of Citric Acid Cycle)
• Clinical Significance: Carnitine deficiency could lead to episodic hypoglycemia, muscle pain, severe muscle weakness, and even death
• Deficiency of hepatic Carnitine Palmitoyltransferase I (CPT I) results in decreased oxidation of FA in the liver and hypoglycemia
• The biological role of “b-oxidation” is ENERGETIC, providing a great amount of free energy accumulated in ATP
• Deficiency of muscle Carnitine Palmitoyltransferase II (CPT II) results in recurrent muscle pain, fatigue, and myoglobinuria following intensive exercise
• Fatty acid with n C-atoms undergoes (n/2-1) turnovers of b-oxidation and releases n/2 molecules Acetyl-CoA