Biosynthesis — fatty acid chain extension
Decarboxylative Claisen condensation (fatty acid biosynthesis)
How the Decarboxylative Claisen condensation (fatty acid biosynthesis) 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: Malonyl-ACP, acyl-enzyme (KS, e.g. acetyl-KS), β-ketoacyl synthase (KS). Conditions: Aqueous, pH ~7, 37 °C, enzyme active site. Bonds formed: C–C (new Cα–acyl bond); CO₂; free KS–SH; bonds broken: C–CO₂⁻; C(acyl)–S(Enz). Stereochemistry: No new stereocentre at this step. Rate and selectivity: Irreversible: CO₂ loss pays for the otherwise uphill Claisen condensation.
At a glance
Step 1: Decarboxylation drives C–C bond formation
An enzyme-bound thioester (malonyl-ACP) loses CO₂, but instead of forming a simple carbanion, the departing CO₂'s electrons flow directly into forming a new carbon-carbon bond with an adjacent acyl-enzyme thioester — decarboxylation and nucleophilic attack happening as one concerted-feeling event.
Step 2: Tetrahedral intermediate + CO₂
This is mechanistically a Claisen condensation (the same addition-elimination logic covered early in this library) except that loss of CO₂, rather than an alkoxide leaving group, is what drives the reaction irreversibly forward — thermodynamically far more favorable than an ordinary reversible Claisen condensation.
Step 3: β-Ketothioester, chain +2 C
The product is a β-ketothioester, two carbons longer than the starting acyl chain — repeating this single decarboxylative Claisen step over and over, with reduction steps in between, is exactly how fatty acid synthase builds long fatty acid chains two carbons at a time.
How it compares with related reactions
| Decarboxylative Claisen condensation (fatty acid biosynthesis) | Cytochrome P450 | DNA glycosylase | |
|---|---|---|---|
| Reagents | Malonyl-ACP, acyl-enzyme (KS, e.g. acetyl-KS), β-ketoacyl synthase (KS) | Cytochrome P450 (heme-thiolate), O₂, NADPH (2 e⁻ via reductase), 2 H⁺, substrate R–H | DNA glycosylase (e.g. uracil-DNA glycosylase), H₂O |
| Conditions | Aqueous, pH ~7, 37 °C, enzyme active site | Aqueous, pH ~7.4, 37 °C, membrane-bound or soluble enzyme | Physiological pH, 37 °C |
| Stereochemistry | No new stereocentre at this step | Rebound is fast, so configuration is often largely retained | Inversion or retention at C1′ depending on enzyme |
| Rate / selectivity | Irreversible: CO₂ loss pays for the otherwise uphill Claisen condensation | Compound I formation fast; C–H abstraction is rate-limiting | Base flipping and oxocarbenium-like TS control rate |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Decarboxylative Claisen condensation (fatty acid biosynthesis)?
Malonyl-ACP, acyl-enzyme (KS, e.g. acetyl-KS), β-ketoacyl synthase (KS). Conditions: Aqueous, pH ~7, 37 °C, enzyme active site.
Which bonds are formed and which are broken?
Formed: C–C (new Cα–acyl bond); CO₂; free KS–SH. Broken: C–CO₂⁻; C(acyl)–S(Enz).
What is the stereochemical outcome?
No new stereocentre at this step
What controls the rate or the selectivity?
Irreversible: CO₂ loss pays for the otherwise uphill Claisen condensation
Study guides that help with this reaction
- Carbonyl chemistry: addition, acyl substitution and enolates
- How to learn reaction mechanisms (without memorising everything)
- Curved-arrow notation: rules and the mistakes students make