4piv
Human Fatty Acid Synthase Psi/KR Tri-Domain with NADPH and GSK2194069Human Fatty Acid Synthase Psi/KR Tri-Domain with NADPH and GSK2194069
Structural highlights
FunctionFAS_HUMAN Fatty acid synthetase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein. Publication Abstract from PubMedHuman fatty acid synthase (hFAS) is a complex, multifunctional enzyme that is solely responsible for the de novo synthesis of long chain fatty acids. hFAS is highly expressed in a number of cancers, with low expression observed in most normal tissues. Although normal tissues tend to obtain fatty acids from the diet, tumor tissues rely on de novo fatty acid synthesis, making hFAS an attractive metabolic target for the treatment of cancer. We describe here the identification of GSK2194069, a potent and specific inhibitor of the beta-ketoacyl reductase (KR) activity of hFAS; the characterization of its enzymatic and cellular mechanism of action; and its inhibition of human tumor cell growth. We also present the design of a new protein construct suitable for crystallography, which resulted in what is to our knowledge the first co-crystal structure of the human KR domain and includes a bound inhibitor. A human fatty acid synthase inhibitor binds beta-ketoacyl reductase in the keto-substrate site.,Hardwicke MA, Rendina AR, Williams SP, Moore ML, Wang L, Krueger JA, Plant RN, Totoritis RD, Zhang G, Briand J, Burkhart WA, Brown KK, Parrish CA Nat Chem Biol. 2014 Sep;10(9):774-9. doi: 10.1038/nchembio.1603. Epub 2014 Aug 3. PMID:25086508[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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