Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Atomic map reveals clues to how cholesterol is made

13.10.2014

In spite of its dangerous reputation, cholesterol is in fact an essential component of human cells.

Manufactured by the cells themselves, it serves to stiffen the cell's membrane, helping to shape the cell and protect it. By mapping the structure of a key enzyme involved in cholesterol production, Rockefeller University researchers and a colleague in Italy have gained new insight into this complex molecular process.


An enzyme responsible for a crucial step in the production of cholesterol has ten segments that span the cell membrane in which it is embedded. These contain two pockets the enzyme uses to bring the reactants together.

Credit: Laboratory of Cell Biology at The Rockefeller University/Nature

"This is the first report to pinpoint the location of every atom — in this case nearly 3,000 of them — in one of the membrane-embedded enzymes cells use to make cholesterol. With the structure of this enzyme, we can better understand how the body synthesizes it," says Günter Blobel, John D. Rockefeller Jr., Professor and head of the Laboratory of Cell Biology. "This accomplishment offers new insight on genetic disorders as well as the possibility of new approaches to lowering blood cholesterol when it becomes dangerously high." The findings were published today (October 12) in Nature.

Cells aren't the only source of cholesterol; cheeseburgers, lobsters, whipped cream and other rich foods can raise levels. Eat a lot of them, and the body compensates by making less of its own cholesterol and by becoming less receptive to cholesterol in the blood. (It's when traveling in the blood that cholesterol can become a hazard, leading to the formation of potentially blood-vessel blocking plaques.)

Healthy cholesterol requires balance: Too much can cause problems, but a certain amount is necessary. Not only do cholesterol molecules make cells' membranes more resistant to wear and tear, the health of the human body as a whole depends on it. This waxy substance serves as a precursor to some hormones, such as testosterone, as well as vitamin D and bile.

The cholesterol-making process in cells requires about 30 chemical reactions and 20 enzymes, seven of which are embedded in the cellular membrane. The mapping project focused on one of these, known as a sterol reductase, which helps two electrons travel from a molecule known as NADPH to another molecule that will eventually become cholesterol. This type of reaction is known as a reduction.

"Our images revealed two pockets within the enzyme's architecture. One contains the NADPH, and the other provides access to the cholesterol precursor. When in place, these molecules are close enough to spark this important step in the synthesis of cholesterol," says first author Xiaochun Li, a postdoc.

Li's interest began with a molecule known as the lamin B receptor (LBR), a sterol reductase in human cells. "Although LBR was discovered 26 years ago, and we know it contributes to cholesterol synthesis, no one knew what it looked like, or how it works," Li says.

Biologists interested in the structure of molecules crystallize them, and then bounce X-rays off the crystals. Based on the pattern produced by the X-rays, the scientists then infer the structure of the molecule. But LBR did not crystallize well, so Li had to find a more accommodating molecule. He found a good candidate in the maSR1 protein from a methane-eating bacterium, then tests at the University of Perugia in Italy revealed that maSR1 could perform the same reducing work as LBR, the human protein.

The X-ray diffraction of maSR1 crystals revealed a protein with 10 segments spanning the membrane. One half of the molecule contains two pockets that bring the reactants together. The researchers think the other half interacts with other enzymes involved in making cholesterol synthesis, as part of a relay system for ferrying the evolving molecule along.

Mutations in sterol reductase genes, including those for LBR, are associated with several disorders, including Pelger-Huet Anomaly, which causes defects in certain white blood cells, and Smith-Lemli-Opitz syndrome, associated with behavioral, physical and mental disabilities. To get a better idea of how these mutations alter the enzymes, Li and colleagues pinpointed the locations of the defects they caused in models of the molecule.

The research also has implications for the treatment of high cholesterol, Blobel says. "Many of the pills currently available interfere with early steps in the complex series of reactions that generates cholesterol. Our reaction occurs later, and may offer a new target worth investigating."

Wynne Parry | Eurek Alert!

Further reports about: Atomic NADPH X-rays cholesterol clues crystallize crystals defects disorders enzymes reactions structure synthesis

More articles from Health and Medicine:

nachricht Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania

nachricht The strange double life of Dab2
10.01.2017 | University of Miami Miller School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

Im Focus: Repairing defects in fiber-reinforced plastics more efficiently

Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.

Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

New technology enables 5-D imaging in live animals, humans

16.01.2017 | Information Technology

Researchers develop environmentally friendly soy air filter

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>