Michigan University. US: With the aid of X-ray crystallography, researchers at the University
of Michigan have revealed the structures of two closely related enzymes
that play essential roles in the body's ability to metabolize excess
lipids, including cholesterol.
The findings are an important step toward understanding and being
able to therapeutically target disorders and drug side effects that
cause lipids, including cholesterol, to build up in the body—leading to
heart and kidney failure and other problems.
Investigators in John Tesmer's lab at the U-M Life Sciences Institute
obtained a high-resolution picture of the atomic structure of lysosomal
phospholipase A2, which is known as LPLA2, and a lower-resolution image
of the structure of lecithin-cholesterol acyltransferase, which is
known as LCAT. The enzymes share many structural similarities but
perform different functions within the body.
Being able to see the structures for the first time gives scientists a
better understanding of the role the two enzymes play in helping the
body to break down and remove cholesterol and other lipids. The findings
are scheduled for publication in Nature Communications on March 2.
In healthy people, LCAT facilitates the removal of cholesterol from
the body. But LCAT doesn't function properly in people with genetic
disorders that cause plaques to build up in the blood vessels of the
heart and kidneys, and in the corneas.
Meanwhile, LPLA2 helps cells break down excess lipids. Side effects
of certain drugs lead to inhibition of LPLA2, which in turn leads to a
buildup of lipids within cells. Recent studies suggest LPLA2 may also
play a role in lupus, a chronic autoimmune disease.
"The structures reveal how the catalytic machinery of these enzymes
is organized and how they interact with membranes and HDL particles,"
said the study's first author, Alisa Glukhova, who received a doctorate
from U-M's Program in Chemical Biology last fall and who is now working
as a research fellow at Monash University in Melbourne, Australia.
The high-resolution snapshot of LPLA2 can also help illuminate the impact of mutations within the enzyme.
"By knowing the architecture of these key enzymes, we can further
understand how more than 55 known mutations of LCAT lead to dysfunction
and disease," said study senior author John Tesmer, a research professor
at the Life Sciences Institute, where his laboratory is located, and a
professor of biological chemistry and pharmacology in the U-M Medical
School. "These structures also suggest new approaches to develop better
biotherapeutics to treat LCAT deficiency."
The researchers are now working on obtaining a higher resolution
image of the LCAT structure to get a more refined understanding of how
it functions.
Co-authors on the paper include Vania Hinkovska-Galcheva, Robert
Kelly and James Shayman of the Department of Internal Medicine in the
U-M Medical School and Akira Abe of the Department of Internal Medicine
in the U-M Medical School and Sapporo Medical University in Japan.
Support for the research was provided by grants from the National
Institutes of Health, an American Heart Association Predoctoral
Fellowship, a Rackham Graduate Student Research Grant and a Merit Review
Award from the Department of Veterans Affairs.