4w82

Publication Abstract from PubMed

Human fatty acid synthase (FAS) is a large, multidomain protein that synthesizes long-chain fatty acids. Since these fatty acids are primarily provided by diet, FAS is normally expressed at low levels; however, it is highly upregulated in many cancers. Human enoyl-acyl carrier protein-reductase (hER) is one of the FAS catalytic domains and its inhibition by drugs like triclosan (TCL) can increase cytotoxicity and decrease drug resistance in cancer cells. We have determined the structure of hER in the presence and absence of TCL. TCL was not bound in the active site, as predicted, but rather at the protein-protein interface (PPI). TCL binding induces a dimer orientation change that causes downstream structural rearrangement in critical active site residues. Kinetics studies indicate that TCL is capable of inhibiting the isolated hER domain with an IC50 of approximately 55 muM. Given the hER-TCL structure and the inhibition observed in the hER domain, it seems likely that TCL is observed in the physiologically relevant binding site and that it acts as an allosteric PPI inhibitor. TCL may be a viable scaffold for the development of anti-cancer PPI FAS inhibitors.

Crystal Structure of the Human Fatty Acid Synthase Enoyl-Acyl Carrier Protein-Reductase Domain Complexed with Triclosan Reveals Allosteric Protein-Protein Interface Inhibition.,Sippel KH, Vyas NK, Zhang W, Sankaran B, Quiocho FA J Biol Chem. 2014 Oct 9. pii: jbc.M114.608547. PMID:25301948^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.