ATOMIC MAP REVEALS CLUES TO HOW CHOLESTEROL IS MADE
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.
"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) inNature.
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."
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