'Getting into the groove' may block cancer, inflammation
When the enzyme fatty acid synthase sparks the production of long chain fatty acids, the cells have energy, can make membranes and carry out activities important to life. However, too much of the enzyme is associated with inflammation and cancer.
A new study by Baylor College of Medicine in the Proceedings of the National Academy of Sciences elucidates the crystal (x-ray) structure of a part (domain) of the enzyme. That study – which refined the structure to atomic level -- revealed that the thioesterase domain of the enzyme contains a long contiguous "groove-tunnel site," which binds part of the enzyme called a long chain polyunsaturated acyl chain. Further modeling studies showed that certain polyunsaturated fatty acids – and in particular one called dihomo-gamma-linolenic acid – also fit into that groove, blocking the action of synthase.
Many people take forms of polyunsaturated fatty acids – such as fish oil – as a way of warding off chronic disease, and the study's authors said that this finding has implications in that area.
No room for fatty acid synthase
"This part of the dihomo-gamma-linolenic acid fits in that groove very well and it inhibits the activity of the fatty acid synthase," said Dr. Salih Wakil, professor and chair emeritus of the department of biochemistry and molecular biology at BCM. "There is no room for the fatty acid synthase." Wakil is a senior author of the report.
In studies in breast tumor cells in the laboratory, this form of linolenic acid inhibited cell growth by blocking formation of the cell membrane and other structures.
Truth in the structure
"We solved the atomic structure," said Dr. Florante Quiocho, professor of biochemistry and molecular biology at BCM and one of the paper's senior authors. The effect of the polyunsaturated fat they tested was surprising, but "we saw it in the structure and the structure provides concrete evidence," said Quiocho.
Many studies have shown that certain fatty acids such as fish oil or the oils in the Mediterranean diet have health benefits, and this study shows how they act to block the negative effects of too much fatty acid synthase. Wakil, Quiocho and colleagues actually studied the effects of three polyunsaturated fatty acids, but they found that dihomo-gamma-linolenic acid worked best.
The authors said the findings provide "a tantalizing unique avenue approach in developing FAS (fatty acid synthase) TE (thioesterase) inhibitors with greater specificity and potency."
Others who took part in this study include Wei Zhang, Bornali Chakravarty, Fei Zheng, Ziwei Gu, Hongmei Wu and Jianqiang Mao, all of BCM.
Funding for this work came from the National Institutes of Health, the Welch Foundation, the Medallion Foundation and the Hefni Tech Training Foundation.
Dr. Wakil is a Distinguished Service Professor at Baylor College of Medicine. Dr. Quiocho is the Charles C. Bell Professor of Structural Biology at BCM.