Which enzyme cleaves citrate in the cytosol to produce acetyl-CoA for fatty acid synthesis?

• A. Aconitase
• B. Citrate synthase
• C. ATP-citrate lyase
• D. Malate dehydrogenase

Answer: (C)

Acetyl-CoA for fatty acid synthesis in the cytosol comes from a shuttle: citrate is exported from mitochondria and cleaved in the cytosol to yield acetyl-CoA and oxaloacetate. The enzyme that performs this cleavage is ATP-citrate lyase, which uses ATP to split citrate into acetyl-CoA, the two-carbon building block needed for fatty acid chains, and oxaloacetate. This mechanism is essential because acetyl-CoA itself doesn’t cross the mitochondrial membrane efficiently, so citrate serves as the transport form into the cytosol.

Aconitase, by contrast, is part of the TCA cycle and converts citrate to isocitrate, not cleaving citrate to release acetyl-CoA. Citrate synthase catalyzes the formation of citrate from acetyl-CoA and oxaloacetate, the reverse direction of what’s needed for cytosolic acetyl-CoA production. Malate dehydrogenase interconverts malate and oxaloacetate and does not generate acetyl-CoA from citrate.

So, the enzyme that enables citrate to become cytosolic acetyl-CoA for fatty acid synthesis is ATP-citrate lyase.