Metabolism — fatty acid catabolism
Fatty acid β-oxidation cycle
How the Fatty acid β-oxidation cycle works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: Acyl-CoA, FAD, H₂O, NAD⁺, CoA-SH. Conditions: Mitochondrial matrix; acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, thiolase. Bonds formed: C=C; C–OH; C=O (β-keto); acetyl-CoA; FADH₂; NADH; bonds broken: α C–H and β C–H; C=C π; Cα–Cβ bond. Stereochemistry: trans-Δ² enoyl-CoA; L-3-hydroxyacyl-CoA. Rate and selectivity: Each turn shortens the chain by two carbons.
At a glance
Step 1: FAD dehydrogenation of Cα–Cβ
An acyl-CoA dehydrogenase removes two hydrogens from the alpha and beta carbons using FAD as the electron acceptor — the identical syn-dehydrogenation mechanism as succinate dehydrogenase — installing a new C=C double bond conjugated with the thioester.
Step 2: Hydration, then NAD⁺ oxidation
Water adds across that new double bond (enoyl-CoA hydratase, mechanistically the same conjugate addition as fumarase) to install a beta-hydroxyl group, which a second dehydrogenase then oxidizes with NAD⁺ (the same hydride-transfer chemistry as malate dehydrogenase) to a beta-ketothioester.
Step 3: Thiolytic cleavage (retro-Claisen)
A final thiolytic cleavage — a free CoA-SH molecule attacks the beta-ketothioester's carbonyl carbon in a retro-Claisen condensation, the reverse of citrate synthase's forward Claisen — releases acetyl-CoA and a fatty acyl-CoA shortened by two carbons, ready to re-enter the same four-step cycle.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- L
- Ligand. A Lewis-base group (often a phosphine) bound to a metal centre.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- Δ
- Heat. Reaction is run at elevated temperature.
- NAD+
- Nicotinamide adenine dinucleotide (oxidised). Hydride-accepting coenzyme in oxidations.
- NADH
- Nicotinamide adenine dinucleotide (reduced). Hydride-donating coenzyme.
- FAD
- Flavin adenine dinucleotide. Two-electron/one-electron redox coenzyme.
- CoA
- Coenzyme A. Thiol carrier that forms high-energy thioesters (acetyl-CoA).
How it compares with related reactions
| Fatty acid β-oxidation cycle | Glutamate dehydrogenase | Aconitase | |
|---|---|---|---|
| Reagents | Acyl-CoA, FAD, H₂O, NAD⁺, CoA-SH | L-Glutamate, NAD⁺ or NADP⁺, H₂O | Citrate, [4Fe-4S] cluster (Fe₄ binds OH), enzyme base (Ser) and acid |
| Conditions | Mitochondrial matrix; acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, thiolase | Mitochondrial matrix, glutamate dehydrogenase; reversible | Mitochondrial matrix, pH ≈ 7.4, 37 °C |
| Stereochemistry | trans-Δ² enoyl-CoA; L-3-hydroxyacyl-CoA | Hydride to one face of nicotinamide; planar iminium loses α-stereochemistry | Anti elimination; the intermediate flips so water adds to the opposite carbon |
| Rate / selectivity | Each turn shortens the chain by two carbons | Allosterically regulated: ADP/GDP activate, ATP/GTP inhibit | Near-equilibrium; citrate:isocitrate ≈ 90:10 at equilibrium |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Fatty acid β-oxidation cycle?
Acyl-CoA, FAD, H₂O, NAD⁺, CoA-SH. Conditions: Mitochondrial matrix; acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, thiolase.
Which bonds are formed and which are broken?
Formed: C=C; C–OH; C=O (β-keto); acetyl-CoA; FADH₂; NADH. Broken: α C–H and β C–H; C=C π; Cα–Cβ bond.
What is the stereochemical outcome?
trans-Δ² enoyl-CoA; L-3-hydroxyacyl-CoA
What controls the rate or the selectivity?
Each turn shortens the chain by two carbons
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- Curved-arrow notation: rules and the mistakes students make