Notum, palmitoleoyl-protein carboxylesterase (NOTUM)

Notum, palmitoleoyl-protein carboxylesterase (NOTUM), is a secreted enzyme of the alpha/β-hydrolase superfamily that functions primarily as a carboxylesterase removing the palmitoleate group from Wnt proteins, thereby inactivating Wnt signaling[3][4][5][6]. This reaction is a central mechanism of extracellular negative regulation for the Wnt signaling pathway, essential in embryonic development, tissue homeostasis, and diseases including cancer and osteoporosis[3][5]. NOTUM's enzymatic activity relies on a hydrophobic active site pocket that accommodates the lipid moiety of its substrates and is mechanistically similar to other serine hydrolases[2][6][8]. Inhibition of NOTUM enhances Wnt signaling and is being explored in various disease models, particularly osteoporosis and cancers with suppressed Wnt activity, while excessive NOTUM activity is linked to pathological downregulation of Wnt responses[3][5][6]. NOTUM is also capable of removing lipid modifications from other proteins, such as the octanoyl group from ghrelin, suggesting additional physiological roles beyond Wnt regulation[6].

Other names

Palmitoleoyl-protein carboxylesterase NOTUMOK/SW-CL.30hNOTUMWnt protein O-palmitoleoyl-L-serine hydrolasenotum pectinacetylesterase homologprotein notum homolog

Inhibitors of NOTUM increase Wnt signaling by preventing deacylation of Wnt ligands, maintaining their activity. Covalent Notum inhibitors occupy and irreversibly modify the enzyme's active site, blocking its function[2][3][8].