By first probing the way primitive yeast make cholesterol, a team of scientists has discovered a long-sought protein whose human counterpart controls cholesterol production and potentially drug metabolism.

The collaborative study by investigators at Johns Hopkins University School of Medicine, Vanderbilt University, Indiana University and Eli Lilly Co., was published in the February issue of Cell Metabolism.

Dap1 controls the activity of a clinically important class of enzymes required for cholesterol synthesis and drug metabolism, says Peter Espenshade, Ph.D., assistant professor of cell biology at Johns Hopkins. Were excited because although we originally identified this protein in yeast, humans not only have the same protein, but it works the same way.

The search for Dap1 began with the hunt for factors that influence the actions of a large family of enzymes called cytochrome P450. These enzymes control many life-sustaining chemical reactions in humans and other animals.

Happily, Espenshade says, yeast have only two P450 enzymes, and both play roles in making cholesterol, narrowing down the territory for their search and giving them a telltale marker (the cholesterol) to track.

Reasoning that whatever controls the P450s likely would be turned on and off at roughly the same time as the P450 enzymes themselves, the researchers found that Dap1 does just that in the yeast cell.

To figure out what Dap1 does, Espenshade and colleagues genetically altered yeast cells to lack Dap1. Those cells predictably were unable to make cholesterol and instead contained a build-up of cholesterol precursors.

The research team then tracked Dap1s counterpart in humans by looking for similar proteins in a computer database and repeated their experiments in human kidney cells engineered to lack the human version of Dap1. As in yeast, the altered human cells accumulated cholesterol precursors and died because chole
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Contact: Audrey Huang
audrey@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
19-Feb-2007