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. 2016 Sep 16;11(9):2529-40.
doi: 10.1021/acschembio.6b00266. Epub 2016 Jul 19.

Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism

Kay Ahn  1   2 , Markus Boehm  1   2 , Matthew F Brown  1   2 , Jessica Calloway  1   2 , Ye Che  1   2 , Jinshan Chen  1   2 , Kimberly F Fennell  1   2 , Kieran F Geoghegan  1   2 , Adam M Gilbert  1   2 , Jemy A Gutierrez  1   2 , Amit S Kalgutkar  1   2 , Adhiraj Lanba  1   2 , Chris Limberakis  1   2 , Thomas V Magee  1   2 , Inish O'Doherty  1   2 , Robert Oliver  1   2 , Brandon Pabst  1   2 , Jayvardhan Pandit  1   2 , Kevin Parris  1   2 , Jeffrey A Pfefferkorn  1   2 , Timothy P Rolph  1   2 , Rushi Patel  1   2 , Brandon Schuff  1   2 , Veerabahu Shanmugasundaram  1   2 , Jeremy T Starr  1   2 , Alison H Varghese  1   2 , Nicholas B Vera  1   2 , Cecile Vernochet  1   2 , Jiangli Yan  1   2
Affiliations

Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism

Kay Ahn et al. ACS Chem Biol. .

Abstract

Lysophospholipase-like 1 (LYPLAL1) is an uncharacterized metabolic serine hydrolase. Human genome-wide association studies link variants of the gene encoding this enzyme to fat distribution, waist-to-hip ratio, and nonalcoholic fatty liver disease. We describe the discovery of potent and selective covalent small-molecule inhibitors of LYPLAL1 and their use to investigate its role in hepatic metabolism. In hepatocytes, selective inhibition of LYPLAL1 increased glucose production supporting the inference that LYPLAL1 is a significant actor in hepatic metabolism. The results provide an example of how a selective chemical tool can contribute to evaluating a hypothetical target for therapeutic intervention, even in the absence of complete biochemical characterization.

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