Fatty Acid-Oxidation ( Beta oxidation of fatty acids ) Biochemistry Animation – Usmle step 1
In the cytosol, long chain free fatty acids are converted to fatty acyl-CoA by fatty acyl CoA synthetase. This step activates the fatty acid for transport into the mitochondria.
Because the inner mitochondrial membrane is impermeable to CoA, the carnitine shuttle system is required to transport the fatty acyl CoA into the mitochondrial matrix.
Enzyme: CAT-I ie carnitine acyl transferase I on the outer mitochondrial membrane
Reaction: Fatty acyl-CoA + carnitine → fatty acyl carnitine + free CoA
CoA remains in the cytosol, and fatty acyl carnitine can now pass through the inner mitochondrial membrane.
Enzyme: CAT-II on the inner surface of the inner mitochondrial membrane
Reaction: Fatty acyl carnitine + CoA which is already in the mitochondrial matrix → fatty acyl CoA + free carnitine
Fatty acyl CoA stays in the mitochondrial matrix for further metabolism, and carnitine leaves the matrix to be used again in the shuttle.
Carnitine deficiency → decreased ability to utilize long chain fatty acids as a fuel source. Can be due to environmental (e.g. malnutrition) or genetic factors (e.g. CAT-I deficiency).
Symptoms: Muscle aches and fatigue following exercise, ↑ free fatty acid levels in the blood, hypoketotic hypoglycemia.
Treatment: Diet high in carbohydrates and medium and short chain fatty acids, low in long chain fatty acids.
Malonyl-CoA, an intermediate in fatty acid biosynthesis, inhibits this shuttle system to prevent newly synthesized fatty acids from entering the degradation pathway, and thus prevent a futile synthesis-degradation cycle
Medium and short chain fatty acids directly enter the mitochondrial matrix without need for a special transport.
In the mitochondrial matrix, fatty acyl-CoA synthetase activates short/medium chain fatty acids to fatty acyl-CoA molecules.
MCADD (medium-chain acyl-CoA dehydrogenase deficiency):
MCAD is a enzyme required for complete oxidation of medium length fatty acids. Deficiency → inability to oxidize fatty acids with less thn 12 carbons.
Presents with symptoms of hypoglycemia.
Treatment: Avoid prolonged fasting, ↑ carbohydrate and protein intake, ↓ fat intake.
Inside the mitochondria, fatty acyl-CoA with an even number of carbons undergo successive rounds of β oxidation, yielding acetyl-CoA, and NADH & FADH2.
Acetyl-CoA enters the citric acid cycle.
NADH and FADH~2~ are used in the electron transport chain.
Oxidation of fatty acids containing an odd number of carbons → Acetyl-CoA and Propionyl-CoA
Because Propionyl-CoA → Succinyl-CoA, it is the only part of fatty acids that is gluconeogenic.
Ketogenesis occurs when there is a high rate of fatty acid oxidation forming Acetyl-CoA
When the liver is overloaded with Acetyl-CoA → ketone bodies form
The 2 main ketone bodies are acetoacetate and β-hydroxybutyrate
Acetoacetate undergoes spontaneous decarboxylation to form acetone
Ketones are generally used in 2 ways:
1) Extrahepatic tissues can convert ketone bodies → Acetyl-CoA
2) Because ketone bodies are volatile, they are readily exhaled by the lungs (Note: This is why diabetics in DKA have “fruity” smelling breath)