Researchers found the structure of activated lecithin:cholesterol acyltransferase (LCAT) enzyme and how it helps to return excess cholesterol to the liver.
Scientists determined the mechanism of an enzyme and its reaction in association with a drug-like chemical. The findings were published in the online journal eLIfe on November 26, 2018. The researchers suggests that future drugs could use the same mechanism to restore LCAT function in people with familial LCAT deficiency (FLD), a rare inherited disease that puts them at risk of eye problems, anaemia and kidney failure.
LCAT helps high-density lipoprotein to converts the lipid from blood into a form that is easier to package and transport. Mutations in LCAT could lead to the occurrence of rare diseases, scientists have found over 90 mutations that are causes of some diseases such as fish eye disease and coronary heart diseases.
Kelly Manthei, a Postdoctoral Fellow at the University of Michigan Life Sciences Institute and lead author of the sudy, said: â€œIn this study, we used structural biology to understand how a patented LCAT activator binds to LCAT and how it promotes cholesterol transport. We also asked if the compound could help recover activity of LCAT enzymes that have commonly observed mutations seen in FLD.â€
Using X-ray crystallography, the researchers stabilized LCAT enzyme in its active state with two different chemicalsâ€”the activator molecule, and a second compound that mimics a substrate bound to the enzyme. The researchers concluded that both the compounds bind to the enzyme in different places
"Our results will help scientists design compounds that can better target LCAT so they might be of therapeutic benefit for heart disease and FLD patients," concludes senior author John Tesmer, Walther Professor in Cancer Structural Biology at Purdue University, US.
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