Fatty Acid Synthesis

Step 1 When energy charge is high, citrate accumulates in the mitochondria and is exported to the cytoplasm via the citrate transport protein. ATP-citrate lyase cleaves it → acetyl-CoA + OAA. OAA is reduced to malate (using NADH), then decarboxylated by malic enzyme → pyruvate + NADPH. Pyruvate re-enters the mitochondria.

Citrate accumulates in mitochondria and is exported to the cytoplasm. ATP-citrate lyase cleaves citrate into acetyl-CoA and OAA. OAA is reduced to malate, then decarboxylated to pyruvate + NADPH. Pyruvate re-enters the mitochondria.

Step 2 ACC (acetyl-CoA carboxylase) carboxylates acetyl-CoA → malonyl-CoA using biotin and ATP. This is the committed, rate-limiting step. ACC is activated allosterically by citrate and by insulin-driven dephosphorylation; inhibited by palmitoyl-CoA and by AMPK phosphorylation (high AMP/ATP). High malonyl-CoA also inhibits CPT-I, blocking β-oxidation simultaneously.

ACC carboxylates acetyl-CoA into malonyl-CoA using biotin and ATP. This is the committed, rate-limiting step, activated by citrate and insulin, inhibited by palmitoyl-CoA and AMPK phosphorylation.

Step 3 FAS is loaded: acetyl-CoA transfers to the Cys residue of the KS domain; malonyl-CoA transfers to the ACP domain via MAT. FAS is a homodimer with 7 functional components (transferase, KS, KR, DH, ER, TE, ACP).

FAS is loaded with acetyl-CoA transferring to the Cys residue of the KS domain and malonyl-CoA transferring to the ACP domain. FAS has 7 functional components.

Step 4 Condensation (KS): malonyl-ACP is decarboxylated and the resulting 2C fragment attacks acetyl-Cys → acetoacetyl-ACP (4C) + CO₂. Loss of CO₂ drives the reaction forward.

Condensation occurs where malonyl-ACP is decarboxylated, and the 2C fragment attacks acetyl-Cys, forming acetoacetyl-ACP (4C) + CO₂.

Step 5 Reduction (KR): the β-keto group of acetoacetyl-ACP is reduced using NADPH → hydroxybutyryl-ACP.

Reduction of the β-keto group of acetoacetyl-ACP using NADPH results in hydroxybutyryl-ACP.

Step 6 Dehydration (DH): H₂O is removed → butenoyl-ACP (2,3 trans double bond).

Dehydration removes H₂O to form butenoyl-ACP (with a 2,3 trans double bond).

Step 7 Reduction (ER): the double bond is reduced using NADPH → butyryl-ACP. The cycle (steps 4–7) repeats 7 times total. After 7 rounds, palmitoyl-ACP (16C) is formed. Thioesterase hydrolyzes the thioester bond → free palmitate. Total cost: 7 ATP + 14 NADPH ≈ 42 ATP per palmitate. Elongation beyond 16C occurs in the ER using CoA instead of ACP, same 4-step chemistry.

Reduction of the double bond using NADPH yields butyryl-ACP. The cycle (steps 4–7) repeats 7 times to produce palmitoyl-ACP (16C). Afterward, thioesterase hydrolyzes the thioester bond to release free palmitate.