Fatty acid synthase

Fatty acid synthase
Name	Fatty acid synthase
Uniprot	P49327
Organism	Homo sapiens

Fatty acid synthase is a multi-enzyme complex that catalyzes de novo synthesis of long-chain fatty acids in Homo sapiens and many other taxa, operating as a dimeric homomer or multifunctional polypeptide in animals and fungi. It plays central roles in lipogenesis, integrates with pathways regulated by insulin, glucagon, and nutrient-sensing kinases such as AMP-activated protein kinase, and is implicated in physiologic processes from adipogenesis to neurogenesis. Studies of synthase biochemistry have informed fields including metabolic engineering, cancer biology, and antibiotic development.

Structure and domains

The mammalian enzyme is a large ~270 kDa polypeptide encoded by the FASN gene that assembles into a homodimer with two reaction chambers analogous to chambers in bacterial type I fatty acid synthase systems described in Escherichia coli and Mycobacterium tuberculosis. Each monomer contains discrete catalytic domains: an acyl carrier protein domain tethering intermediates via a phosphopantetheine prosthetic group; a beta-ketoacyl synthase domain that mediates condensation; a beta-ketoacyl reductase domain; a dehydratase domain; an enoyl reductase domain; and a thioesterase domain that releases final products—arranged in an architecture similar to multifunctional enzymes characterized in Saccharomyces cerevisiae and Aspergillus nidulans. High-resolution structural studies using X-ray crystallography and cryo-electron microscopy have resolved conformations related to substrate shuttling, revealing interdomain linkers and a central dimer interface comparable to oligomers studied by researchers at institutions such as The Scripps Research Institute and Max Planck Institute for Molecular Physiology.

Catalytic mechanism and reaction cycle

The reaction cycle proceeds through iterative rounds of condensation, reduction, dehydration, and reduction, beginning with loading of acetyl and malonyl substrates by acetyl-CoA carboxylase and transfer onto the acyl carrier protein via a phosphopantetheinyl transferase mechanism analogous to that characterized in Streptomyces coelicolor. Each cycle extends the acyl chain by two carbon units through a decarboxylative Claisen condensation mediated by the beta-ketoacyl synthase domain; subsequent beta-keto reduction uses NADPH supplied by pentose phosphate pathway enzymes and cytosolic malic enzyme activity, with further steps resembling mechanisms studied in Mycobacterium smegmatis and Pseudomonas aeruginosa. Termination occurs when the thioesterase domain hydrolyzes or cyclizes the acyl-ACP intermediate to yield primarily palmitate, a process that has parallels with polyketide synthase release mechanisms elucidated by teams at California Institute of Technology and University of Oxford.

Regulation and expression

Expression of the synthase is transcriptionally regulated by nutrient- and hormone-responsive transcription factors including sterol regulatory element-binding protein 1 (SREBP1), carbohydrate-responsive element-binding protein (ChREBP), and nuclear receptors such as peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR), with post-translational control exerted by phosphorylation via AMPK and ubiquitin-mediated turnover involving E3 ligases identified in studies from Massachusetts General Hospital and Dana-Farber Cancer Institute. Levels rise in response to feeding, insulin signaling, and activation of growth factor pathways such as PI3K–AKT–mTOR, whereas fasting signals mediated by glucagon and catecholamines suppress expression. Tissue distribution is highest in lipogenic organs including the liver, adipose tissue, and lactating mammary gland, while inducible expression occurs in proliferating cells investigated in laboratories at Johns Hopkins University and Memorial Sloan Kettering Cancer Center.

Biological roles and metabolism

The enzyme supplies saturated fatty acids for membrane biogenesis, energy storage, and lipid-modified signaling molecules in processes ranging from embryogenesis to immune cell activation described in research from National Institutes of Health groups. Its product palmitate is substrate for elongases and desaturases such as stearoyl-CoA desaturase-1 (SCD1) and elongases encoded by ELOVL genes, integrating with lipid trafficking pathways mediated by apolipoprotein B and microsomal triglyceride transfer protein. In rapidly proliferating cells, elevated synthase activity supports membrane phospholipid synthesis, a phenomenon reported in studies on glioblastoma, breast cancer, and prostate cancer tissues analyzed by investigators at University of Texas MD Anderson Cancer Center. In microorganisms and plants, homologous synthases contribute to pathogen virulence and seed oil production, intersecting with work at Rothamsted Research and Iowa State University.

Clinical significance and therapeutic targeting

Overexpression and increased activity are associated with metabolic diseases and cancer; elevated expression has prognostic implications in malignancies studied at Harvard Medical School and University College London. Small-molecule inhibitors such as cerulenin and C75 were foundational tools, while later clinical candidates including TVB-2640 and related compounds have progressed through trials coordinated by pharmaceutical companies and consortia including Novartis and Threshold Pharmaceuticals. Inhibitors can induce apoptosis, limit proliferation, and alter lipid composition in tumor models from Dana-Farber Cancer Institute and Fred Hutchinson Cancer Research Center, but present challenges of toxicity and metabolic compensation mediated by upregulation of lipid uptake via CD36 and scavenger pathways elucidated by researchers at Weill Cornell Medicine. Targeting mycobacterial homologs has yielded antibiotic leads against tuberculosis, with structural insights guiding drug design at London School of Hygiene & Tropical Medicine.

Evolution and homologs

Fatty acid synthase systems diverged into type I multifunctional enzymes in animals and fungi and type II dissociated systems in bacteria and plant plastids, a split explored in comparative genomics at European Molecular Biology Laboratory and Stanford University. Homologs include mammalian synthase encoded by FASN, fungal complexes in Candida albicans and Aspergillus fumigatus, and bacterial enzymes such as FabF and FabH in Escherichia coli and Bacillus subtilis. Evolutionary adaptations produced polyketide synthases in Streptomyces that share catalytic modules, informing synthetic biology efforts at ETH Zurich and Massachusetts Institute of Technology to engineer novel lipid and secondary metabolite pathways.

Category:Enzymes