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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.

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
ACS Chem Biol 11 2529-40 (2016)
Cited: 13 times
EuropePMC logo PMID: 27391855

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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Reviews citing this publication (4)

  1. Strategies for Tuning the Selectivity of Chemical Probes that Target Serine Hydrolases. Faucher F, Bennett JM, Bogyo M, Lovell S. Cell Chem Biol 27 937-952 (2020)
  2. Conformational control in structure-based drug design. Zheng Y, Tice CM, Singh SB. Bioorg Med Chem Lett 27 2825-2837 (2017)
  3. Reactive chemistry for covalent probe and therapeutic development. Grams RJ, Hsu KL. Trends Pharmacol Sci 43 249-262 (2022)
  4. The evolution of small molecule enzyme activators. Dow LF, Case AM, Paustian MP, Pinkerton BR, Simeon P, Trippier PC. RSC Med Chem 14 2206-2230 (2023)

Articles citing this publication (7)

  1. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects. Sliz E, Sebert S, Würtz P, Kangas AJ, Soininen P, Lehtimäki T, Kähönen M, Viikari J, Männikkö M, Ala-Korpela M, Raitakari OT, Kettunen J. Hum Mol Genet 27 2214-2223 (2018)
  2. Global targeting of functional tyrosines using sulfur-triazole exchange chemistry. Hahm HS, Toroitich EK, Borne AL, Brulet JW, Libby AH, Yuan K, Ware TB, McCloud RL, Ciancone AM, Hsu KL. Nat Chem Biol 16 150-159 (2020)
  3. Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes. Kathayat RS, Cao Y, Elvira PD, Sandoz PA, Zaballa ME, Springer MZ, Drake LE, Macleod KF, van der Goot FG, Dickinson BC. Nat Commun 9 334 (2018)
  4. Discovery of small-molecule enzyme activators by activity-based protein profiling. Kok BP, Ghimire S, Kim W, Chatterjee S, Johns T, Kitamura S, Eberhardt J, Ogasawara D, Xu J, Sukiasyan A, Kim SM, Godio C, Bittencourt JM, Cameron M, Galmozzi A, Forli S, Wolan DW, Cravatt BF, Boger DL, Saez E. Nat Chem Biol 16 997-1005 (2020)
  5. Development and biological applications of sulfur-triazole exchange (SuTEx) chemistry. Borne AL, Brulet JW, Yuan K, Hsu KL. RSC Chem Biol 2 322-337 (2021)
  6. Comparative analysis of the human serine hydrolase OVCA2 to the model serine hydrolase homolog FSH1 from S. cerevisiae. Bun JS, Slack MD, Schemenauer DE, Johnson RJ. PLoS One 15 e0230166 (2020)
  7. Lyplal1 is dispensable for normal fat deposition in mice. Watson RA, Gates AS, Wynn EH, Calvert FE, Girousse A, Lelliott CJ, Barroso I. Dis Model Mech 10 1481-1488 (2017)


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