7 min readPathway sheetOften a 10-mark answer

Biosynthesis of fatty acids

In the cytoplasm, acetyl-CoA is built up two carbons at a time into palmitate (16 C), using malonyl-CoA, ATP and NADPH.

WhereCytoplasm of liver, adipose tissue, lactating mammary gland

Start → EndAcetyl-CoA → Palmitate (16:0)

Control pointAcetyl-CoA carboxylase (biotin), rate-limiting

Cost per palmitate8 acetyl-CoA, 7 ATP, 14 NADPH

The steps

Acetyl-CoA is made in the mitochondria, but fat is built in the cytoplasm. Steps 1–2 move and activate it. Steps 3–8 run on the fatty acid synthase complex, a large multi-enzyme protein that carries the growing chain on its acyl carrier protein (ACP). Starred steps are key.

1
Acetyl-CoA + oxaloacetate → citrate (mitochondria); citrate → acetyl-CoA + oxaloacetate (cytoplasm)
Citrate synthase; ATP-citrate lyase · citrate shuttle · the lyase uses ATP
2★
Acetyl-CoA + CO2 + ATP → Malonyl-CoA
Acetyl-CoA carboxylase (biotin) · rate-limiting, committed step
3
Acetyl and malonyl groups load onto the synthase
Acetyl transacylase, malonyl transacylase · ACP holds the chain
4
Acetyl + Malonyl → Acetoacetyl (4 C) + CO2
β-Ketoacyl synthase (condensing enzyme) · the CO2 added in step 2 is released
5
β-Ketoacyl → β-Hydroxyacyl
β-Ketoacyl reductase · uses NADPH
6
β-Hydroxyacyl → Enoyl (has a double bond)
Dehydratase · removes water
7
Enoyl → Acyl (butyryl, 4 C)
Enoyl reductase · uses NADPH
8★
Steps 4–7 repeat (7 rounds in all) → Palmitoyl → free Palmitate
Thioesterase · releases palmitate (16 C)

★ one-way, controls the pace

Cost of one palmitate

Acetyl-CoA (1 primer + 7 as malonyl-CoA)8

ATP (to make 7 malonyl-CoA)7

NADPH (2 per round × 7 rounds)14

Overall8 acetyl-CoA + 7 ATP + 14 NADPH → palmitate

Synthesis vs beta-oxidation

Fatty acid synthesisCytoplasm. Carrier is ACP. Uses NADPH. Adds 2 carbons from malonyl-CoA. Key enzyme: acetyl-CoA carboxylase. Runs in the fed state (insulin).

Beta-oxidationMitochondria. Carrier is CoA. Makes FADH2 and NADH. Removes 2 carbons as acetyl-CoA. Key enzyme: CPT-I. Runs in fasting (glucagon).

Malonyl-CoA blocks CPT-I, so the cell does not make and burn fat at the same time.

NADPH supply and control

HMP shunt (pentose phosphate pathway): the main source of NADPH.
Malic enzyme (malate → pyruvate) supplies some more NADPH.
Citrate switches acetyl-CoA carboxylase on; palmitoyl-CoA switches it off.
Insulin activates the enzyme; glucagon and adrenaline inactivate it.

Nutrition link

Acetyl-CoA carboxylase needs biotin. Raw egg white contains avidin, which binds biotin, so eating many raw eggs can cause biotin deficiency. ACP and CoA carry pantothenic acid (B5), and NADPH comes from niacin (B3). This pathway is how excess carbohydrate becomes body fat.

Exam angle

10 marks: “Describe the biosynthesis of fatty acids.” Cover the citrate shuttle, acetyl-CoA carboxylase, the 4 repeated reactions on fatty acid synthase, the overall equation and regulation.

5 marks: “Distinguish fatty acid synthesis from beta-oxidation.” Compare site, carrier, coenzyme, 2-carbon unit, key enzyme and hormonal state in a table.

2 marks: “Name the rate-limiting enzyme of fatty acid synthesis and its coenzyme.” Acetyl-CoA carboxylase; biotin.

Remember it

The synthase repeats Condense, Reduce, Dehydrate, Reduce: roughly beta-oxidation run backwards.