An enzyme known as stearoyl-CoA desaturase-1 (SCD-1) plays an important role in the accumulation of fat in the cell.
SCD-1 introduces the first double bond into saturated fatty acids, a key reaction in fatty acid metabolism. Since inhibition of SCD-1 reduces fat storage and increases fat consumption, the pharmaceutical industry has long attempted to target SCD-1 in the treatment of obesity and diabetes. However, efforts to develop efficient therapeutic reagents have been impeded by the lack of a more precise understanding of how the enzyme functions.
In a report that appears in the journal Nature, Dr. Ming Zhou, associate professor of biochemistry and molecular biology at Baylor College of Medicine, and his colleagues including those from Cornell University and the University of Wisconsin in Madison, sought to find out how SCD-1 works.
Using X-ray crystallography, they described the first three-dimensional structure of SCD-1. They found that the enzyme contains a cone-shaped domain embedded in the membrane capped by a hemisphere shaped domain residing in the cytosol (the liquid part of the cell), giving the protein an overall shape resembling an ice cream cone.
Findings provide first blueprint
“This structure provides the atomic details and tells us what the molecule looks like,” said Dr. Yonghong Bai, first author of the report. “It sheds light on how the enzyme is particularly selective in the reaction it catalyzes, a chemical property that has intrigued scientists ever since they first discovered the enzyme over 40 years ago.”
A tunnel buried in the cytosolic domain provides the clue. It is narrow and curved and locks the fatty acid involved in the reaction into a V-shape. This tunnel acts as a ruler that measures the precise position where the fatty acid is modified, he said. The structure also reveals how the protein binds the two metal atoms that catalyze the reaction. The findings provide the first blueprint of the enzyme for designing drugs that might reduce the negative effects of the enzyme, he said.
“SCD-1 does not do its job on its own,” he said. “It works with two other partners. Down the road, we hope to obtain a structure of the tripartite complex to get a more holistic picture of how SCD-1 works.”
Others who took part in this work include Jason G. McCoy and Elena J. Levin, of Baylor; Pablo Sobrado and Brian G. Fox of the University of Wisconsin, Madison; and Kanagalaghatta R. Rajashankar of Cornell University and the Argonne National Laboratory in Illinois.
Funding for this work came from the National Institutes of Health (Grants R01DK088057, R01GM098878, R01HL086392, U54GM095315, U54GM094584 and R01GM50853), the American Heart Association (Grant 12EIA8850017) and the Cancer Prevention and Research Institute of Texas (Grant R12MZ).