This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The enzyme fatty acid synthase (FAS) is responsible for the synthesis of long chain fatty acids. The expression and activity of human FAS are highly correlated with the occurrence of many diseases such as malignancy, obesity and diabetes. It is an important drug target for combating obesity, and a leading marker for poor prognosis in certain cancers, including breast cancer. Human FAS is a supermolecular homodimeric enzyme (~0.55 million Da) with seven domains on each single polypeptide chain. Each subunit contains six enzymes and a carrier peptide. The sequential organization is beta-ketosynthase (KS), acetyl/malonyl transacylases (A/MT), beta-hydroxyacyl dehydratase (DH), enoyl reductase (ER), beta-ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE). There are two identical active centers of fatty acid synthesis using acetyl-CoA, malonyl-CoA, and NADPH as substrates. The active center is assembled by the participation of KS-AT/MT-DH of one subunit and ER-KR-ACP-TE of the second subunit. To obtain the final products of palmitate, nearly 50 reactions have to occur coordinately in the catalytic center with seven reactions repeatedly in order to insert two-carbon units to the growing acyl group. The particle has a height of 185.0 ?, a length of 130.0 ? and a width of 75.0 ?. Due to its huge size and complexity, the development of potent and efficacious drugs targeting FAS has been hampered by the lack of detailed structure knowledge of FAS, even though a wealth of biochemical and molecular biological information has been available. Elucidation of the mechanism of this gigantic enzyme will help us to understand this metabolic process and the development of FAS related diseases. This cryoEM structure will provide a basis for potential future development of therapeutic agents for treatment of these diseases
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