Fatty Acid Degradation

• Lipids encompass more than just fatty acids (FA) and are categorized into five classes.
• Fatty acids (FA) consist of a carboxyl group at one end and a linear alkyl chain, which may include one or more cis double bonds.
• The systematic symbolic representation for FA indicates the number of carbons and the position of double bonds (e.g., 18:4 Δ6,9,12,15 signifies 18 carbons and four double bonds at positions 6-7, 9-10, 12-13, and 15-16).
• Polyunsaturated FA have weaker interactions due to less tight packing, resulting in lower melting points compared to saturated FA.
• Fatty acids are stored as triacylglycerol (TAG) in adipose tissue.

FA Degradation

• FA degradation occurs in the mitochondrial matrix, requiring initial activation and transport.
• FA is adenylated by expending ATP, creating fatty acyl-AMP; AMP is then replaced by CoA, forming acyl CoA, a reaction catalyzed by acyl CoA synthetase.
• Acyl CoA is converted to acyl carnitine via carnitine acyltransferase I, replacing CoA with carnitine.
• Acyl carnitine is transported across the inner mitochondrial membrane by an antiporter, which simultaneously transports carnitine out of the matrix.
• In the matrix, acyl carnitine is converted back to acyl CoA by carnitine acyltransferase II.

β-Oxidation

• β-Oxidation is the main pathway for degrading FA into acetyl CoA.
• Acyl CoA dehydrogenase introduces a trans double bond between carbons 2 and 3 (α-β, Δ2), reducing FAD to FADH2 with the released electrons.
• Enoyl CoA hydratase adds a water molecule to the trans double bond, forming L-3-hydroxyacyl CoA.
• L-3-hydroxyacyl CoA dehydrogenase oxidizes the hydroxyl group on carbon 3 (β) into a ketone, producing NADH from NAD+ with the liberated electrons.
• Thiolase cleaves 3-ketoacyl CoA to produce acetyl CoA and a shortened acyl CoA (by two carbons).
• The cycle repeats until the acyl chain is completely converted to acetyl CoA.

Degradation of cis-Δ3-enoyl CoA

• cis-Δ3-enoyl CoA isomerase replaces the first step of β-oxidation (acyl CoA dehydrogenase), converting cis-Δ3-enoyl CoA to trans-Δ2-enoyl CoA.
• β-oxidation follows the conversion.

Degradation of cis-Δ4-enoyl CoA

• After the first step of β-oxidation (acyl CoA dehydrogenase), produces a 2,4-dienoyl CoA intermediate, the following two steps are inserted:
• 2,4-dienoyl CoA reductase uses NADPH to reduce the 2,4-dienoyl CoA intermediate to trans-Δ3-enoyl CoA.
• cis-Δ3-enoyl CoA isomerase converts trans-Δ3-enoyl CoA to trans-Δ2-enoyl CoA.
• β-oxidation follows.

Degradation of FAs containing cis-Δ3,6-dienoyl CoA

• cis-Δ3-enoyl CoA isomerase converts the cis-Δ3 bond to trans-Δ2.
• One round of β-oxidation removes the first two carbons, yielding cis-Δ4-enoyl CoA.
• Further degradation proceeds similarly to the cis-Δ4-enoyl CoA degradation pathway.

Degradation of FAs containing cis-Δ4,7-dienoyl CoA

• cis-Δ4 is converted to trans-Δ2.
• Two rounds of β-oxidation are performed.
• The resulting product, cis-Δ3-enoyl CoA, is processed.

Degradation of odd-chain fatty acid (Propionyl CoA)

• Propionyl CoA carboxylase carboxylates propionyl CoA to produce methylmalonyl CoA, a four-carbon fragment.
• Methylmalonyl CoA is converted to succinyl CoA, which is then incorporated into the TCA cycle.

Ketone Bodies

• Ketone bodies are synthesized in the liver from acetyl CoA derived from FA degradation.
• Acetyl CoAs combine to form acetoacetate initially.
• Acetoacetate is reduced by NADH to produce 3-hydroxybutyrate or spontaneously decarboxylated to form acetone.
• 3-hydroxybutyrate is transported to other tissues and converted back to acetyl CoA.
• 3-hydroxybutyrate is oxidized back to acetoacetate, which is then attached to CoA by CoA transferase.
• Thiolase converts acetoacetate CoA to acetyl CoA.

Regulation of Fatty Acid Degradation

• The release of free fatty acids from adipose tissue primarily regulates fatty acid degradation.
• Glucagon and epinephrine activate PKA in adipocytes.
• PKA activation leads to the activation of lipases, which release fatty acids from triacylglycerol (TAG).
• Fatty acids are then transported to other cells for metabolism.