29.4 Biosynthesis of Fatty Acids

Fatty Acid Biosynthesis

Process of fatty acid biosynthesis

Fatty acid biosynthesis constructs long-chain fatty acids from two-carbon and three-carbon building blocks. Understanding this pathway is essential because it connects carbohydrate metabolism to lipid storage, showing how excess glucose ultimately becomes fat.

The process takes place in the cytosol of cells, primarily in the liver, adipose tissue, and mammary glands. The two key substrates are:

• Acetyl CoA — a two-carbon unit derived from glucose oxidation or amino acid breakdown
• Malonyl CoA — a three-carbon molecule formed from acetyl CoA

Formation of malonyl CoA is the committed (rate-limiting) step. The enzyme acetyl CoA carboxylase (ACC) catalyzes the carboxylation of acetyl CoA, adding a $CO_2$ group to produce the three-carbon malonyl CoA. ACC requires biotin as a prosthetic group, which acts as a carrier for the $CO_2$ during this reaction.

Because acetyl CoA is produced inside the mitochondria but fatty acid synthesis happens in the cytosol, cells use the citrate shuttle to move acetyl CoA across the mitochondrial membrane. Inside the mitochondria, acetyl CoA condenses with oxaloacetate to form citrate, which is exported to the cytosol and then cleaved back into acetyl CoA and oxaloacetate by ATP-citrate lyase.

The fatty acid synthase (FAS) complex then does the heavy lifting. It's a large, multi-enzyme complex that catalyzes the sequential addition of two-carbon units to a growing fatty acid chain. Here's how the process begins:

1. An acetyl group from acetyl CoA is loaded onto the acyl carrier protein (ACP) domain of FAS. This serves as the "starter" unit.
2. A malonyl group from malonyl CoA is loaded onto a separate ACP site.
3. The elongation cycle (described below) then adds two carbons per round, repeating until the chain reaches 16 carbons (palmitate, $C_{16}$).
4. Thioesterase cleaves the finished palmitate from the FAS complex.

Key reactions in fatty acid synthesis

Each round of elongation adds two carbons and involves four sequential reactions. One full cycle looks like this:

1. Condensation — $\beta$-ketoacyl ACP synthase (KS) joins the malonyl group to the growing acyl chain, releasing $CO_2$. This forms a $\beta$-ketoacyl ACP intermediate. The $CO_2$ released here is the same one that was added by ACC, so the net carbon gain per cycle is two, not three.

2. First reduction — $\beta$-ketoacyl ACP reductase (KR) reduces the keto group at the $\beta$-carbon to a hydroxyl group, producing $\beta$-hydroxyacyl ACP. This step consumes one NADPH.

3. Dehydration — $\beta$-hydroxyacyl ACP dehydratase (DH) removes water ($H_2O$) across the $\alpha$- and $\beta$-carbons, forming a trans double bond and yielding enoyl ACP.

4. Second reduction — Enoyl ACP reductase (ER) reduces the double bond to a single bond using a second NADPH, producing a fully saturated acyl ACP.

The saturated acyl ACP then re-enters the cycle at step 1, where another malonyl ACP condenses onto it. After 7 rounds of this cycle (starting from the initial 2-carbon acetyl primer + 7 × 2 carbons from malonyl CoA), you get the 16-carbon palmitate.

Fatty acid biosynthesis vs. beta-oxidation

These two pathways are essentially opposites, but they differ in nearly every mechanistic detail. That's a common exam target.

The logic here: when energy is abundant (fed state, high insulin), cells store it by building fatty acids. When energy is scarce (fasted state, high glucagon), cells break fatty acids down for fuel.

Modifications and regulation of fatty acid synthesis

Once palmitate is released from FAS, it can be further modified:

• Elongases (located in the smooth ER) extend the chain beyond 16 carbons, producing longer fatty acids like stearate ($C_{18}$).
• Desaturases introduce cis double bonds at specific positions, converting saturated fatty acids into unsaturated ones. Humans can introduce double bonds at the $\Delta 9$, $\Delta 6$, and $\Delta 5$ positions but cannot desaturate beyond $\Delta 9$. This is why linoleic acid ($\omega$-6) and $\alpha$-linolenic acid ($\omega$-3) are essential fatty acids that must come from the diet.

Regulation of the overall pathway (lipogenesis) centers on ACC, since it catalyzes the committed step:

• Insulin activates ACC (via dephosphorylation), promoting fatty acid synthesis in the fed state.
• Glucagon and epinephrine inhibit ACC (via phosphorylation by AMPK), shutting down synthesis when energy is needed.
• Citrate allosterically activates ACC, signaling that acetyl CoA is abundant.
• Palmitoyl CoA (the end product) allosterically inhibits ACC, providing feedback inhibition.