Knowledge of Fat-Making Complex Could Fight Obesity
In an advance that has implications for new anti-obesity and anti-cancer drugs, a “movie” has been made of how a molecular complex in the human cell performs a “dance” in which it dramatically changes shape to promote all of the stages of fat synthesis. The various enzymes that make fat are actually integrated into a rapidly metamorphosing unit called fatty acid synthase .
The pioneering study, which appeared in the journal Nature Structural and Molecular Biology, was done by Stuart Smith, at Children’s Hospital Oakland Research Institute, and Edward Brignole and Francisco Asturias from the Scripps Research Institute in La Jolla, Calif.
“Fatty acid synthase is a remarkably complex structure,” said Smith. “It contains all of the components needed to convert carbohydrates into fat. We have suspected for some time that the enzyme complex is extremely flexible, which makes it difficult to analyze using X-ray crystallography.
“Last year, the X-ray structure of the complex was solved by a group in Switzerland, but this structure provided only a snapshot of the complex in one of its many poses. We were able to use state-of-the-art electron microscopy to obtain images of the complex in many of its different conformations and assemble these images into a movie that displays the full range of motion of the components of the complex.”
The images show how fatty acid synthase folds, swings, swivels and rolls to bring distant parts of itself into contact, allowing a range of intracellular chemical reactions to be catalyzed. The extraordinary gyrations of the molecule complex are represented on the cover of the journal in the form of a flamenco dancer.
Because the micro-structure and function of fatty acid synthase has now been revealed through the detailed X-ray and electron-microscope images, investigators’ work on developing inhibitors of the molecular complex can be facilitated. Such inhibitors are expected to block conversion of carbohydrates into fat, suppressing appetite and slowing the growth of cancer cells. Scientists in Garmany showed that in 2007 increased fatty-acid synthase gene expression in fat tissue is linked to visceral fat accumulation and impaired insulin sensitivity, suggesting that impaired lipogenic pathways controlled by this enzyme may be linked to both obesity and Type 2 Diabetes.
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