FattySäureSynthase

FattySäureSynthase (FAS) is a multifunctional enzyme complex that catalyzes de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA, using NADPH as a reducing agent. In animals and fungi, FAS typically refers to a type I system—a single polypeptide harboring all catalytic activities. In bacteria and plants, fatty acid synthesis more often uses a type II system with discrete enzymes.

Type I FAS is a homodimer with multiple catalytic domains organized in modules, including ketoacyl synthase (KS), malonyl/acetyl transferase (MAT), acyl carrier protein (ACP), ketoacyl reductase (KR), dehydratase (DH), enoyl reductase (ER), and a terminal thioesterase (TE). Type II FAS uses separate enzymes for each step. The cycle begins with an acetyl starter unit and proceeds by iterative condensations with malonyl-CoA, performing two-carbon elongations through condensation, reduction, dehydration, and a second reduction, with the growing chain tethered to ACP. Release by TE yields a fatty acid, commonly palmitate (C16:0) in many organisms.

Regulation and metabolism: FAS operates in the cytosol, powered by NADPH. Its activity depends on the supply of acetyl-CoA and malonyl-CoA, produced by acetyl-CoA carboxylase. Hormonal and transcriptional control (e.g., insulin signaling and SREBP factors) modulate expression and activity. Malonyl-CoA also inhibits fatty acid entry into mitochondria by inhibiting CPT1, linking synthesis and oxidation.

Biological and clinical relevance: de novo lipogenesis via FAS contributes to membrane synthesis and energy storage. FAS is often upregulated in cancer and metabolic diseases. Inhibitors studied include cerulenin, C75, and clinical candidates such as TVB-2640 (denifanstat). Beyond medicine, engineered FAS pathways are used to produce tailored fatty acids in microbes and plants.