Key enzyme involved in cholesterol production mapped

Researchers have mapped the structure of a key enzyme involved in cholesterol production in an effort to better understand the complex molecular process.
"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," said Gunter Blobel, head of the Laboratory of Cell Biology at Rockefeller University.
"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," Blobel said.
The cholesterol-making process in cells requires about 30 chemical reactions and 20 enzymes, seven of which are embedded in the cellular membrane.

Researchers 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," said first author Xiaochun Li, a postdoc.

"When in place, these molecules are close enough to spark this important step in the synthesis of cholesterol," Li said.
Li's interest began with a molecule known as the lamin B receptor (LBR), a sterol reductase in human cells.

Biologists interested in the structure of molecules crystallise 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.
However, LBR did not crystallise 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 showed that maSR1 could perform the same reducing work as LBR, the human protein.
The X-ray diffraction of maSR1 crystals showed a protein with 10 segments spanning the membrane. One half of the molecule contains two pockets that bring the reactants together.

The researchers believe 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 behavioural, 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 findings were published in the journal Nature.