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Beta-oxidation Fatty Acids

Big picture

  • Fatty acids (FA) are turned into energy in muscle and into triacylglycerol in fat cells .
  • FA are not used by brain and RBC for energy, and not used by the majority of liver .

Lipolysis (mobilizing fatty acids)

Triggers :

  • low glucose level
  • low ATP
  • hormone-sensitive control

Hormone-sensitive lipase control

  • controlled by hormone-sensitive lipase

  • activated by epinephrine / glucagon (phosphorylated)

  • inhibited by insulin
  • PKA phosphorylates triacylglycerol lipase and activates it.
  • converts triacylglycerol (TG) → fatty acids + glycerol (glycerol goes back to liver)

Transport in blood

  • FA binds to albumin and moves to target tissue in the blood.
  • albumin releases FA into the cytoplasm of the target cell.

Fatty acid activation (forming fatty acyl-CoA)

Occurs on the mitochondrial outer membrane .

Steps:

  1. ATP binds to FA with fatty acyl-CoA synthase (outer mitochondrial membrane)
  2. fatty acyl-CoA synthase kicks off AMP and attaches CoA-SH
  3. formed FA–CoA (activated fatty acid)

Carnitine shuttle (long-chain FA transport)

  • Long-chain FA require transport into the mitochondrial matrix.
  • Small-chain FA with < 12 carbons do not need transport .

Steps

  1. CPT-1 (outer membrane): converts FA–CoA + carnitine → fatty acylcarnitine + CoA
  2. fatty acylcarnitine enters via TIM while carnitine leaves matrix
  3. CPT-2 (inner membrane): converts fatty acylcarnitine + CoA → FA–CoA + carnitine

Regulation

  • CPT-1 is inhibited by malonyl-CoA (from the fatty acid synthase pathway).

Beta-oxidation spiral (activated fatty acid)

  • cuts between C2 and C3
  • uses repeated “spirals” (cycles)

One cycle

  1. alpha and beta carbon (C2 and C3) form a double bond via acyl-CoA dehydrogenase, converting FAD → FADH\(_2\)
  2. add –OH to beta carbon and –H to alpha carbon via enoyl-CoA hydratase
  3. beta-hydroxyacyl-CoA dehydrogenase forms a double bond of the C and –OH, converting NAD\(^+\) → NADH + H\(^+\)
  4. cleavage via beta-keto-thiolase between alpha–beta carbon with CoA-SH, leaving acetyl-CoA

Then restart with the new shortened acyl-CoA.

Energy yield: palmitoyl-CoA (16C)

Beta-oxidation outputs

  • 7 FADH\(_2\)
  • 7 NADH
  • 8 acetyl-CoA

TCA outputs (from acetyl-CoA)

  • 8 GTP
  • 8 FADH\(_2\)
  • 2 NADH

Grand total

  • 15 FADH\(_2\)
  • 31 NADH
  • 8 GTP
  • 108 ATP

Energy yield of palmitoyl (16C):

  • \(108 - 2 = 106\) ATP

Isoenzymes

  • first three enzymes of beta-oxidation have isoenzymes for different chain lengths.

Special cases

Unsaturated fatty acids

  • only when there is a double bond at \(C_3=C_4\):

  • use enoyl-CoA isomerase to convert to a double bond at \(C_2=C_3\)

Odd-chain fatty acids

  • last five carbon yields:

  • acetyl-CoA (2C) and propionyl-CoA (3C)

Propionyl-CoA → succinyl-CoA

  1. propionyl-CoA carboxylase (biotin):

  2. input: ATP + HCO\(_3^-\)

  3. output: ADP
  4. forms D-methylmalonyl-CoA
  5. epimerized and isomerized
  6. forms succinyl-CoA

Clinical / toxicology notes

MCAD deficiency (MCADD)

  • medium-chain acyl-CoA dehydrogenase deficiency (autosomal recessive)
  • affects isoenzyme for medium chain
  • unable to harvest energy from fatty acids → causes inability to gluconeogenesis in liver

Jamaican vomiting sickness

  • ackee fruit contains hypoglycin (if prepared improperly)
  • hypoglycin binds to carnitine and affects carnitine shuttle (lysine analog)

  • metabolized into methylene cyclopropyl acetic acid (MCPA)

  • inhibits acyl-CoA dehydrogenase (short-chain and medium-chain)

Ketogenesis (liver production of ketone bodies)

Sequence :

  • fatty oxidation → beta-oxidation → acetyl-CoA

  • 2 acetyl-CoA

  • beta-ketothiolase (CoA release) → acetoacetyl-CoA

  • HMG-CoA synthase (takes acetyl-CoA, releases CoA) → HMG-CoA

  • HMG-CoA lyase (releases acetyl-CoA) → acetoacetate

  • acetoacetate can be released into blood as a ketone body

  • D-beta-hydroxybutyrate dehydrogenase (NADH + H\(^+\) → NAD\(^+\)) → D-beta-hydroxybutyrate

  • can be released into blood as a ketone body

  • acetoacetate can spontaneously form acetone

Key note:

  • ketone bodies can power the brain and the muscle.

Ketone body utilization

  1. D-beta-hydroxybutyrate → acetoacetate (NAD\(^+\) → NADH + H\(^+\))

  2. acetoacetate → acetoacetyl-CoA using succinyl-CoA: acetoacetate CoA transferase

  3. succinyl-CoA → succinate

  4. liver has minimal activity of this enzyme
  5. acetoacetyl-CoA → 2 acetyl-CoA via thiolase (uses CoA)

Energy content

  • acetoacetate yields 19 ATP

  • D-beta-hydroxybutyrate is produced in a higher ratio and has more energy:

  • 21.5 ATP