Notum Function and Modulation in Wnt Signaling
Summary
Notum is a secreted carboxylesterase that acts as a key negative regulator of Wnt signalling by catalysing the removal of an essential palmitoleate lipid from Wnt ligands. This lipid modification is critical for Wnt receptor engagement and downstream pathway activation. By deacylating Wnt proteins, Notum finetunes gradients of Wnt activity during embryonic development, tissue homeostasis and regeneration. Dysregulated Notum activity has been implicated in diverse pathologies, including osteoporosis, neurodegeneration and tumour progression, making it a compelling target for therapeutic intervention. Advances in structural biology and chemical biology have enabled the design of selective Notum inhibitors, which restore Wnt signalling in models of disease where excessive Notum activity undermines tissue repair or cell survival. These inhibitors encompass both covalent warheads that form irreversible adducts with the active site serine and non-covalent scaffolds that occupy the palmitoleate pocket, offering complementary tools for probing Notum function and exploring clinical opportunities in bone, brain and cancer biology.
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Notum Function and Modulation in Wnt Signaling publication trend
The graph below shows the total number of articles in notum function and modulation in wnt signaling across all publications each year (not limited to Nature Index journals).
Technical terms
Wnt signalling: A conserved cell-to-cell communication pathway regulated by lipid-modified glycoproteins that control development, stem cell maintenance and regeneration.
Notum: A secreted carboxylesterase enzyme that deacylates Wnt ligands, antagonising Wnt receptor activation and attenuating downstream signalling.
Palmitoleoylation: The post-translational attachment of a palmitoleate lipid to a conserved serine residue on Wnt proteins, essential for their biological activity.
Carboxylesterase: An enzyme class that hydrolyses ester bonds, here referring to Notum’s deacylating action on Wnt palmitoleate.
Covalent inhibitor: A molecule designed to form a stable, often irreversible, bond with a target enzyme’s active site residue, enhancing potency and duration of action.
Non-covalent inhibitor: A molecule that binds reversibly to a target enzyme through non-covalent interactions such as hydrogen bonds and hydrophobic contacts, allowing for adjustable modulation of activity.
References
- Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity. European Journal of Medicinal Chemistry (2023).
- Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen. RSC Medicinal Chemistry (2019).
- Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling. Journal of Medicinal Chemistry (2021).
- Small-molecule inhibitors of carboxylesterase Notum. Future Medicinal Chemistry (2021).
- Structural Insights into Notum Covalent Inhibition. Journal of Medicinal Chemistry (2021).
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