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

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 c...

Full description

Saved in:
Bibliographic Details
Published in:ACS chemical biology 2016-09, Vol.11 (9), p.2529-2540
Main Authors: Ahn, Kay, Boehm, Markus, Brown, Matthew F, Calloway, Jessica, Che, Ye, Chen, Jinshan, Fennell, Kimberly F, Geoghegan, Kieran F, Gilbert, Adam M, Gutierrez, Jemy A, Kalgutkar, Amit S, Lanba, Adhiraj, Limberakis, Chris, Magee, Thomas V, O’Doherty, Inish, Oliver, Robert, Pabst, Brandon, Pandit, Jayvardhan, Parris, Kevin, Pfefferkorn, Jeffrey A, Rolph, Timothy P, Patel, Rushi, Schuff, Brandon, Shanmugasundaram, Veerabahu, Starr, Jeremy T, Varghese, Alison H, Vera, Nicholas B, Vernochet, Cecile, Yan, Jiangli
Format: Article
Language:English
Subjects:
Anatomy
Animals
BASIC BIOLOGICAL SCIENCES
Crystallization
Crystallography, X-Ray
Enzyme Inhibitors - pharmacology
Humans
Hydrolases - metabolism
Inhibitors
INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Lysophospholipase - antagonists & inhibitors
Lysophospholipase - chemistry
Monomers
Peptides and proteins
Rodent models
Serine - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.6b00266