Beta-Oxidation and Ketone Bodies: Fatty Acid Breakdown for the MCAT

Beta-oxidation breaks a fatty acid into acetyl-CoA two carbons at a time. It runs in the mitochondrial matrix. Synthesis is the opposite: cytosol, with malonyl-CoA and NADPH.

Getting in: the carnitine shuttle

1. Acyl-CoA synthetase activates the fatty acid in the cytosol (uses 2 ATP equivalents, ATP to AMP).
2. Carnitine acyltransferase I (CPT-I) on the outer membrane swaps CoA for carnitine. This is the rate-limiting step, inhibited by malonyl-CoA.
3. The acyl-carnitine crosses the inner membrane and CPT-II restores acyl-CoA in the matrix.

The four steps (each cycle)

Counting ATP

Each cycle gives 1 FADH₂ (1.5 ATP), 1 NADH (2.5 ATP) and 1 acetyl-CoA (about 10 ATP through the citric acid cycle), so about 14 ATP per cycle.

Palmitate (16 carbons): 7 cycles and 8 acetyl-CoA.

• 7 x 4 = 28 from FADH₂ and NADH
• 8 x 10 = 80 from acetyl-CoA
• Minus 2 for activation
• Total about 106 ATP (older ratios: 129 or 131)

An n-carbon fatty acid needs (n/2) - 1 cycles.

Special cases

• Odd-chain: the last cycle leaves 3-carbon propionyl-CoA, which becomes succinyl-CoA (needs biotin and B12) and can make glucose.
• Unsaturated: extra isomerase (and reductase) steps; fewer FADH₂ because the first oxidation is already done at the double bond.

Ketone bodies

During fasting the liver makes more acetyl-CoA than the citric acid cycle can use, because oxaloacetate is diverted to gluconeogenesis. The liver converts the excess to acetoacetate and beta-hydroxybutyrate (and acetone). The brain, heart and muscle use them. The liver lacks thiophorase, so it cannot use ketones itself.

Common traps

• Putting beta-oxidation in the cytosol. It is in the matrix.
• Forgetting the activation cost.
• Saying fatty acids make net glucose. Only the glycerol and propionyl-CoA parts can.

One-minute recap

• Carnitine shuttle, CPT-I is rate-limiting, malonyl-CoA inhibits.
• Each cycle: FADH₂, NADH, acetyl-CoA.
• Palmitate gives about 106 ATP; ketones form when acetyl-CoA accumulates.