Atomic model for core modifying region of human fatty acid synthase in complex with Denifanstat

by Selleckchem | Sep 21 2023

Fatty acid synthase (FASN) catalyzes the de novo synthesis of palmitate, a 16-carbon chain fatty acid that is the primary precursor of lipid metabolism and an important intracellular signaling molecule. FASN is an attractive drug target in diabetes, cancer, fatty liver diseases, and viral infections. Here, we develop an engineered full-length human FASN (hFASN) that enables isolation of the condensing and modifying regions of the protein post-translation. The engineered protein enables electron cryo-microscopy (cryoEM) structure determination of the core modifying region of hFASN to 2.7 Å resolution. Examination of the dehydratase dimer within this region reveals that unlike its close homolog, porcine FASN, the catalytic cavity is close-ended and is accessible only through one opening in the vicinity of the active site. The core modifying region exhibits two major global conformational variabilities that describe long-range bending and twisting motions of the complex in solution. Finally, we solved the structure of this region bound to an anti-cancer drug, Denifanstat (i.e., TVB-2640), demonstrating the utility of our approach as a platform for structure guided design of future hFASN small molecule inhibitors.

Comments:

That's an interesting development! The information you provided describes the development of an engineered full-length human Fatty Acid Synthase (hFASN) protein that allows for the isolation and study of specific regions involved in the modification of fatty acids. By utilizing electron cryo-microscopy (cryoEM), researchers were able to determine the structure of the core modifying region of hFASN at a resolution of 2.7 Å.

The study focused on the dehydratase dimer within this region and found that, unlike a closely related homolog, porcine FASN, the catalytic cavity of hFASN is closed at one end and can only be accessed through a single opening near the active site. This structural information provides insights into the functional characteristics of hFASN and how it differs from other related enzymes.

Furthermore, the researchers investigated the dynamic behavior of the core modifying region and identified two significant conformational variabilities. These variations describe bending and twisting motions of the complex in solution, indicating flexibility in the protein structure.

Additionally, the researchers successfully determined the structure of the core modifying region bound to an anti-cancer drug called Denifanstat (TVB-2640). This finding demonstrates the potential of their approach as a platform for designing small molecule inhibitors targeting hFASN, which could have implications in the treatment of various conditions such as diabetes, cancer, fatty liver diseases, and viral infections.

Overall, this research provides valuable structural insights into the functioning of hFASN and highlights the potential for developing targeted therapeutics against this enzyme in various disease contexts.