Fatty acid oxidation | Anatomy2Medicine
Fatty Acid Oxidation

Fatty acid oxidation

 

  • Activation of fatty acids

 

      • In the cytosol, long-chain fatty acids are activated by ATP and CoA, forming fatty acyl CoA
      • Short-chain fatty acids are activated in mitochondria.
      • ATP is converted to AMP  and pyrophosphate (PPi) when a fatty acid is activated.

 

  • The PPi produced during the reaction is cleaved by pyrophosphatase to two inorganic phosphates (Pi). Thus, two high-energy bonds are required for fatty acid activation.

 

    • Transport of fatty acyl CoA from the cytosol into mitochondria
      • Cytosolic fatty acyl CoA reacts with carnitine in the outer mitochondrial membrane, forming fatty acyl carnitine via carnitine acyl transferase I (CAT I), also called carnitine palmitoyl trans-ferase I (CPT I).
      • Fatty acyl carnitine passes to the inner membrane, where it reacts with carnitine acyl transferase II (CAT II) to reform fatty acyl CoA, which enters the mitochondrial matrix.
      • CAT I
        • catalyzes the transfer of acyl groups from coenzyme A to carnitine,
        • inhibited by malonyl CoA, an intermediate in fatty acid synthesis.
        • Therefore, when fatty acids are synthesized in the cytosol, malonyl CoA inhibits their transport into mitochondria, preventing a futile cycle (synthesis followed by immediate degradation).
        • Inside the mitochondrion, fatty acyl CoA undergoes beta-oxidation.
    • Beta-Oxidation of even-chain fatty acids

 

  • Beta-Oxidation of a fatty acyl CoA is a four-step process.

 

      • The first three steps are similar to the TCA cycle reactions that convert succinate to OAA.
      • These steps are repeated until all carbons of even chain fatty acyl CoA are converted to acetyl CoA  
      • Step 1: FAD accepts hydrogens and electrons from fatty acyl CoA
        • A double bond is produced between the alpha-and beta-carbons,and an enoyl CoA is formed.
        • FADH2 produced interacts with the electron transport chain, generating ATP.
        • Enzyme for this reaction is acyl Co A dehydrogenase.
      • Step 2: H2O adds across the double bond, via enoyl CoA hydratase, and a beta-hydroxyacyl CoA is formed.
      • Step 3: beta-Hydroxyacyl CoA is oxidized by NAD+ to a b-ketoacyl CoA.
        • NADH produced interacts with the electron transport chain,generating ATP.
        • Enzyme for this reaction is  L-3-hydroxy acyl CoA dehydrogenase (specific for the L-isomer)
      • Step 4: Bond between the alpha- and beta-carbons of the beta-ketoacyl CoA is cleaved by a thiolase that requires coenzyme A.
        • Acetyl CoA is produced from the two carbons at the carboxyl end of the fatty acyl CoA, with remaining carbons forming a fatty acyl CoA that is two carbons shorter than the starting fatty acid.
        • The enzyme is beta-ketothiolase.
      • The shortened fatty acyl CoA repeats these four steps.
        • The spiral continues until all the carbons of the original fatty acyl CoA are converted to acetyl CoA.
        • The complete oxidation of the 16-carbon palmitoyl CoA undergoes seven repetitions of the oxidation spiral.

 

  • In the last repetition,a four-carbon fatty acyl CoA (butyryl CoA)is cleaved to 2 molecules of acetyl CoA.

 

    • Energy generated from beta-oxidation. (Very High yield area for MD Entrance)
      • When 1 mole of palmitoyl CoA is oxidized, 7 moles of FADH2, 7 moles of NADH, and 8 moles of acetyl CoA are formed.
      • Each of the 7 moles of FADH2 generates about 1.5 moles of ATP, for a total of about 10.5 moles of ATP.
      • Each of the 7 moles of NADH generates about 2.5 moles of ATP, for a total of about 17.5 moles of ATP.
      • Each of the 8 moles of acetyl CoA can enter the TCA cycle, each producing about 10 moles of ATP, for a total of about 80 moles of ATP.
      • With oxidation of one mole of palmitoyl CoA to CO2 and H2O, a total of about 108 moles of ATP are produced.
      • The net ATP produced from one mole of palmitate is about 106 moles because palmitate undergoes activation (requiring two high-energy bonds pre mole) before oxidation (108 ATP – 2 ATP [to represent the two high-energy bonds] = 106 ATP).
    • Oxidation of odd-chain
      • produce acetyl CoA and propionyl CoA.
      • These fatty acids repeat the four steps of the b-oxidation spiral, producing acetyl CoA until the last cleavage when the three remaining carbons are released as propionyl CoA. (MCQ)
      • Propionyl CoA,but not acetyl CoA,is converted to glucose.
    • omega-Oxidation of fatty acids
      • The (omega)-carbon (the terminal methyl carbon) of fatty acids is oxidized to a carboxyl group in the smooth endoplasmic reticulum. (MCQ)
      • -Oxidation then occurs in mitochondria at this end as well as from the original carboxyl end, assuming that -oxidation is functional.
    • Oxidation of very-long-chain fatty acids in peroxisomes (MCQ)
      • The process differs from -oxidation in that molecular O2 is used in the first oxidation step, which forms hydrogen peroxide (H2O2), without the generation of FADH2.

 

  • NADH is generated in the second oxidation step of peroxisomal fatty acid oxidation.

 

    • Shorter-chain fatty acids travel to mitochondria, where-oxidation occurs, generating ATP.
  • -Oxidation of fatty acids
    • Branched-chain fatty acids are oxidized at the -carbon in brain and nervous tissue
    • carboxyl carbon is released as CO2.
    • Once the carboxyl carbon is released, in most cases, normal -oxidation can degrade the rest of the branched-chain fatty acid.

 

    • Applied aspects :

 

  • Primary carnitine deficiency i

 

        • a deficiency of the plasma membrane carnitine transporter
        • leads to urinary wasting of carnitine
        • Subsequent depletion of intracellular carnitine impairs transport of long-chain fatty acids into mitochondria, limiting fatty acid availability for oxidation and energy production.
      • CAT I deficiency
        • results in intermittent ataxia, oculomotor palsy (cranial nerve [CN] III), hypotonia, mental confusion, and disturbance of consciousness.
      • Medium-chain acyl CoA dehydrogenase (MCAD) deficiency
        • a deficiency of one of the acyl CoA dehydrogenases, which oxidizes fatty acids between 6 and 10 carbons long
        • The defect is manifested when serum glucose levels are low (hypoglycemia) because of fasting, infection, or increased amount of time between feedings.
        • Fatty acids cannot be fully oxidized as an alternate form of energy in individuals with this disorder.

 

  • Zellweger syndrome

 

        • a peroxisomal disorder
        • result in accumulation of very-long-chain fatty acids
        • Clinical manifestations include congenital craniofacial dysmorphism, psychomotor retardation, and seizures
        • Death results in the first year of life.

 

  • Adrenoleukodystrophy

 

      • Very-long-chain fatty acids accumulate in the brain (causing demyelination) and in the adrenal cortex (causing degeneration)
      • inability to transport very-long-chain fatty acids into peroxisomes.

Clinical manifestations include psychomotor retardation and seizures