fatty acid degradation (b-oxidation)
Fatty‑Acid Degradation (β‑Oxidation) – Deep Dive
You’re preparing for a biochemistry quiz, so let’s break the pathway into four logical blocks and focus on the details that most exam questions love:
1⃣ Activation & Mitochondrial Entry
Step 1 – Activation (cytosol):
Fatty acid + ATP → Fatty‑acyl‑CoA + AMP + PPᵢ
Catalyzed by Acyl‑CoA synthetase (also called fatty‑acid‑CoA ligase).
Why AMP? The reaction effectively uses two high‑energy phosphates, “charging” the fatty acid for later oxidation.
Step 2 – Transport across the inner mitochondrial membrane:
Carnitine shuttle (essential for long‑chain FA > C12).
CPT‑I (outer membrane): transfers the acyl group from CoA to carnitine, forming acyl‑carnitine.
Translocase: swaps acyl‑carnitine for free carnitine across the inner membrane.
CPT‑II (inner membrane): re‑attaches CoA, regenerating acyl‑CoA inside the matrix.
Short‑chain/medium‑chain FA (≤ C8) can cross the membrane directly as CoA‑esters, bypassing the shuttle.
2⃣ The Repeating β‑Oxidation Cycle (in the matrix)
Each “round” shortens the fatty acyl‑CoA by two carbons, producing one acetyl‑CoA, one NADH, and one FADH₂. The four steps repeat until the entire chain is gone.
Step | Enzyme (location) | Reaction | Key Cofactor / Product |
|---|---|---|---|
1. Oxidation | Acyl‑CoA dehydrogenase | R‑CH₂‑CH₂‑CO‑SCoA → trans‑Δ²‑enoyl‑CoA + FADH₂ | FADH₂ → enters ETC (≈1.5 ATP) |
2. Hydration | Enoyl‑CoA hydratase | trans‑Δ²‑enoyl‑CoA + H₂O → L‑hydroxyacyl‑CoA | – |
3. Oxidation | 3‑Hydroxyacyl‑CoA dehydrogenase | L‑hydroxyacyl‑CoA → 3‑ketoacyl‑CoA + NADH | NADH → enters ETC (≈2.5 ATP) |
4. Thiolysis | β‑ketoacyl‑CoA thiolase | 3‑ketoacyl‑CoA + CoA‑SH → acetyl‑CoA + shortened acyl‑CoA (n‑2) | – |
Specificity: Different isoforms exist for short, medium, and long‑chain substrates (e.g., VLCAD, LCAD, MCAD).
Stereochemistry: The hydration step always yields the L‑hydroxy isomer; the dehydrogenase then oxidizes it to the keto form.
3⃣ End‑Products & Energy Yield
Acetyl‑CoA enters the TCA cycle → 3 NADH + 1 FADH₂ + 1 GTP per turn.
Total ATP from a saturated fatty acid (e.g., palmitate, C16):
Molecule | # of β‑oxidation rounds | NADH (β) | FADH₂ (β) | Acetyl‑CoA | ATP from NADH (2.5 ×) | ATP from FADH₂ (1.5 ×) | TCA ATP (per acetyl‑CoA) | Net ATP |
|---|---|---|---|---|---|---|---|---|
Palmitoyl‑CoA (C16) | 7 | 7 | 7 | 8 | 7 × 2.5 = 17.5 | 7 × 1.5 = 10.5 | 8 × 10 = 80 | ≈ 106 ATP (minus 2 ATP for activation) |
Odd‑chain fatty acids produce one propionyl‑CoA in the final round, which is converted to succinyl‑CoA (TCA intermediate) → yields ~ 0.5 ATP net.
4⃣ Regulation & Clinical Nuggets
Key regulatory point: CPT‑I (rate‑limiting) is inhibited by malonyl‑CoA (the first product of fatty‑acid synthesis). This prevents a futile cycle of synthesis ↔ degradation.
Hormonal control:
Insulin ↓ CPT‑I activity (via malonyl‑CoA ↑) → less β‑oxidation.
Glucagon/epinephrine ↑ fatty‑acid oxidation (activate hormone‑sensitive lipase → release FA; ↓ ACC → ↓ malonyl‑CoA).
Deficiencies:
Medium‑chain acyl‑CoA dehydrogenase deficiency (MCAD) → hypoketotic hypoglycemia after fasting.
Carnitine transport defects → accumulation of fatty acids, muscle weakness, cardiomyopathy.