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

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Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2016-07-19 00:00:00 , DOI: 10.1021/acschembio.6b00266
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}

Affiliation

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.

中文翻译：

溶血磷脂酶样1（LYPLAL1）的选择性共价抑制剂的发现，以评估该丝氨酸水解酶在代谢中的作用的工具。

类溶血磷脂酶1（LYPLAL1）是一种未表征的代谢丝氨酸水解酶。人类全基因组关联研究将编码该酶的基因变异与脂肪分布，腰臀比和非酒精性脂肪肝相关联。我们描述了LYPLAL1的有效和选择性共价小分子抑制剂的发现及其用于研究其在肝代谢中的作用。在肝细胞中，LYPLAL1的选择性抑制增加了葡萄糖的产生，从而支持了LYPLAL1在肝代谢中的重要作用。结果提供了一个示例，说明即使没有完整的生化特征，选择性化学工具也可以如何有助于评估假设的治疗干预目标。

更新日期：2016-07-19

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