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Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum.

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Zhao Y, Ren J, Hillier J, Jones M, Lu W, Jones EY
OpenAccess logo J Pineal Res 68 e12630 (2020)
Related entries: 6tr6, 6tr7

Cited: 14 times
EuropePMC logo PMID: 31876313

Abstract

The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high-resolution structures (≤1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid, and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 µmol/L), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which upregulation of Wnt signalling may be beneficial.

Articles - 6tr5 mentioned but not cited (2)

  1. Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum. Zhao Y, Ren J, Hillier J, Jones M, Lu W, Jones EY. J Pineal Res 68 e12630 (2020)
  2. Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling. Bayle ED, Svensson F, Atkinson BN, Steadman D, Willis NJ, Woodward HL, Whiting P, Vincent JP, Fish PV. J Med Chem 64 4289-4311 (2021)


Reviews citing this publication (3)

  1. A systematic summary of survival and death signalling during the life of hair follicle stem cells. Hu XM, Li ZX, Zhang DY, Yang YC, Fu SA, Zhang ZQ, Yang RH, Xiong K. Stem Cell Res Ther 12 453 (2021)
  2. Small-molecule inhibitors of carboxylesterase Notum. Zhao Y, Jolly S, Benvegnu S, Jones EY, Fish PV. Future Med Chem 13 1001-1015 (2021)
  3. Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects. Samec M, Liskova A, Koklesova L, Zhai K, Varghese E, Samuel SM, Šudomová M, Lucansky V, Kassayova M, Pec M, Biringer K, Brockmueller A, Kajo K, Hassan STS, Shakibaei M, Golubnitschaja O, Büsselberg D, Kubatka P. Cancers (Basel) 13 3018 (2021)

Articles citing this publication (9)

  1. Notum deacylates octanoylated ghrelin. Zhao Y, Schuhmacher LN, Roberts M, Kakugawa S, Bineva-Todd G, Howell S, O'Reilly N, Perret C, Snijders AP, Vincent JP, Jones EY. Mol Metab 49 101201 (2021)
  2. Caffeine inhibits Notum activity by binding at the catalytic pocket. Zhao Y, Ren J, Hillier J, Lu W, Jones EY. Commun Biol 3 555 (2020)
  3. Structural Insights into Notum Covalent Inhibition. Zhao Y, Svensson F, Steadman D, Frew S, Monaghan A, Bictash M, Moreira T, Chalk R, Lu W, Fish PV, Jones EY. J Med Chem 64 11354-11363 (2021)
  4. Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit. Willis NJ, Mahy W, Sipthorp J, Zhao Y, Woodward HL, Atkinson BN, Bayle ED, Svensson F, Frew S, Jeganathan F, Monaghan A, Benvegnù S, Jolly S, Vecchia L, Ruza RR, Kjær S, Howell S, Snijders AP, Bictash M, Salinas PC, Vincent JP, Jones EY, Whiting P, Fish PV. J Med Chem 65 7212-7230 (2022)
  5. Lower Plasma Melatonin in the Intervertebral Disk Degeneration Patients Was Associated with Increased Proinflammatory Cytokines. Tian Y, Ji Y, Mei X, Pan J, He W, Sun J, Wan K, Yang H. Clin Interv Aging 16 215-224 (2021)
  6. Notum palmitoleoyl-protein carboxylesterase regulates Fas cell surface death receptor-mediated apoptosis via the Wnt signaling pathway in colon adenocarcinoma. Gong H, Niu Q, Zhou Y, Wang YX, Xu XF, Hou KZ. Bioengineered 12 5241-5252 (2021)
  7. Antiviral effect of melatonin on Japanese encephalitis virus infection involves inhibition of neuronal apoptosis and neuroinflammation in SH-SY5Y cells. Kitidee K, Samutpong A, Pakpian N, Wisitponchai T, Govitrapong P, Reiter RJ, Wongchitrat P. Sci Rep 13 6063 (2023)
  8. Structural Analysis and Development of Notum Fragment Screening Hits. Zhao Y, Mahy W, Willis NJ, Woodward HL, Steadman D, Bayle ED, Atkinson BN, Sipthorp J, Vecchia L, Ruza RR, Harlos K, Jeganathan F, Constantinou S, Costa A, Kjær S, Bictash M, Salinas PC, Whiting P, Vincent JP, Fish PV, Jones EY. ACS Chem Neurosci 13 2060-2077 (2022)
  9. Notum enhances gastric cancer stem-like cell properties through upregulation of Sox2 by PI3K/AKT signaling pathway. Liu Y, Chen H, Xiao L, Dong P, Ma Y, Zhou Y, Yang J, Bian B, Xie G, Chen L, Shen L. Cell Oncol (Dordr) (2023)


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