PHARC is a rare genetic human neurological disorder caused by mutations to the Abhd12 gene, which encodes the integral membrane serine hydrolase enzyme ABHD12.
Recent studies have shown that mice without ABHD12, murine model of PHARC, show increased concentrations of lyso-phosphatidylserine (lyso-PS) lipids in brains. Now Indian researchers, using mice model, have found the biochemical explanation for such very long chain lipids accumulation in the brain.
Dr. Siddhesh S. Kamat’s team at Indian Institute of Science Education and Research (IISER), Pune - have shown that the enzyme ABHD12 has a strong substrate preference for very long chain lipids which contains ≥ C22 atoms.
Researchers found the location of this enzyme (ABHD12) in the membrane of the endoplasmic reticulum, a cellular compartment, where virtually, all of the very long chain lipids are biosynthesized. The results of this study were published in ‘The Journal of Biological Chemistry.’
“We first chemically synthesized a library of lipid substrates ranging from fatty acids C10 – C24 with different degrees of un-saturations. Next, we performed enzyme kinetics studies for this lipid library against recombinant human, and endogenous mouse brain ABHD12, and found in both cases that there is a preference for very long chain lipids,” said Dr. Siddhesh S. Kamat.
“Our study will help to better understand the pathology of PHARC and it might enable development of much-needed biomarkers (very long chain lipids) for better diagnostics for this condition,” he added.
“This work is a classic illustration of the value of a biochemical approach in understanding what a clinically important protein actually does in cells. This biochemical characterization reveals a very broad substrate choice for this important protein, and also explains how cells can maintain an appropriate balance of long-chain lipid substrates. This can now be used to identify activators or inhibitors of this enzyme,” commented Dr. Sunil Laxman from InStem, Bangalore, who was not associated with this study.
The research team included Alaumy Joshi, Minhaj Shaikh, Shubham Singh, Abinaya Rajendran, Amol Mhetre and Siddhesh S. Kamat from IISER Pune. This study was supported by Wellcome Trust DBT India Alliance and DST-FIST infrastructure development grant.
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