Structure Report for: 5KRE

N1-substituted triazole urea previously disclosed as an inhibitor of ABHD6 KT195 was modified as N2-substituted isomer and shown to inhibit LYPLAL1. The compound 2 inhibited also other alpha/beta hydrolases and some SGNH hydrolase-type esterase (PAFAH1B2-3), but compound 11 and 12 are specific. The adduct in the structure is the small (R)-2-phenylpiperidine-1-carbonyl

Title: Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism
Ahn K, Boehm M, Brown MF, Calloway J, Che Y, Chen J, Fennell KF, Geoghegan KF, Gilbert AM and Yan J <19 more author(s)> Ahn K, Boehm M, Brown MF, Calloway J, Che Y, Chen J, Fennell KF, Geoghegan KF, Gilbert AM, Gutierrez JA, Kalgutkar AS, Lanba A, Limberakis C, Magee TV, O'Doherty I, Oliver R, Pabst B, Pandit J, Parris K, Pfefferkorn JA, Rolph TP, Patel R, Schuff B, Shanmugasundaram V, Starr JT, Varghese AH, Vera NB, Vernochet C, Yan J (- 19)
Ref: ACS Chemical Biology, 11:2529, 2016 : PubMed
Abstract


ESTHER: Ahn_2016_ACS.Chem.Biol_11_2529
PubMedSearch: Ahn 2016 ACS.Chem.Biol 11 2529
PubMedID: 27391855
Gene_locus related to this paper: human-LYPLAL1
Inhibitor(s) related to this paper: Piperidinyl-1,2,3-triazole-urea-inhibitor-11, Piperidinyl-1,2,3-triazole-urea-inhibitor-12, Piperidinyl-1,2,3-triazole-urea-inhibitor-2

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.