Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Primitive yeast yields secrets of human cholesterol and drug metabolism

22.02.2007
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. “We’re 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.

... more about:
»Dap1 »Espenshade »P450 »cholesterol »metabolism

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 Dap1’s 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 cholesterol is essential for cell survival.

To show that Dap1 directly works with P450s and not through some other biochemical steps, Espenshade’s team tested the ability of human Dap1 protein to bind to four of the 57 known human P450 enzymes, essentially challenging Dap1 to bind to P450s that perform totally different functions in different cells as a way to see how far-reaching its control might be.

Dap1 locked on to all four P450s, including one required for clearing half of all known drugs from the body, another involved in making bile and one required for making natural steroid hormones in the adrenal glands.

“Collectively, our experiments suggest that Dap1 acts as a common regulator of cytochrome P450s in mammals,” says Espenshade.

Because Dap1 affects one particular P450 responsible for drug metabolism, Espenshade suspects that genetic variations in the genetic blueprint coding for Dap1 may provide clues to how and why different people react differently to certain drugs.

“Understanding the molecular underpinnings of so-called pharmacogenetic variation will have a big impact on the future of medicine,” he says.

The research was funded by the National Institutes of Health, American Heart Association and Burroughs Wellcome Fund.

Authors on the paper are Adam Hughes and Espenshade of Hopkins; David Powell and Andrew Link of Vanderbilt University School of Medicine; Martin Bard of Indiana University-Purdue University Indianapolis; James Eckstein and Robert Barbuch of Eli Lilly and Company.

Audrey Huang | EurekAlert!
Further information:
http://www.cellmetabolism.org
http://www.hopkinsmedicine.org/cellbio/profiles/profdisplay.cfm?senduserID=177&sendpage=directory
http://www.jhmi.edu

Further reports about: Dap1 Espenshade P450 cholesterol metabolism

More articles from Life Sciences:

nachricht Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Chemists at FAU successfully demonstrate imine hydrogenation with inexpensive main group metal
22.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

Im Focus: Computer-Designed Customized Regenerative Heart Valves

Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.

Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...

Im Focus: Light-induced superconductivity under high pressure

A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.

Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Supersonic waves may help electronics beat the heat

18.05.2018 | Power and Electrical Engineering

Keeping a Close Eye on Ice Loss

18.05.2018 | Information Technology

CrowdWater: An App for Flood Research

18.05.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>