Hedgehog acyltransferase (HHAT)

Hedgehog acyltransferase (HHAT) is a multi-pass transmembrane enzyme of the membrane-bound O-acyltransferase (MBOAT) family that catalyzes the N-palmitoylation of the N-terminal cysteine of Hedgehog family proteins, such as Sonic Hedgehog (SHH), via transfer of a palmitate group from palmitoyl-CoA[1][2][3]. This post-translational modification is essential for Hedgehog protein trafficking, secretion, and receptor activation, directly controlling Hedgehog pathway activity, which plays a key role in embryonic development, stem cell homeostasis, and several cancers[1][2][3]. Structurally, HHAT has 10–12 transmembrane domains and requires a heme cofactor for its enzymatic activity[3]. Aberrant HHAT activity or expression has been implicated in multiple tumor types, and small-molecule inhibitors such as IMP-1575 have shown promise in blocking HHAT function in preclinical signaling and cancer models[1][3]. HHAT is considered a high-interest target in cancer therapeutics, but its broad physiological importance necessitates careful modulation to avoid adverse systemic effects[2].

Other names

Protein-cysteine N-palmitoyltransferase HHATMART2SKI1MART-2FLJ10724SknskiraspsitGUP2Melanoma antigen recognized by T-cells 2Skinny hedgehog protein 1Central missingSightless

Inhibitors block HHAT-mediated N-palmitoylation of Hedgehog ligands, thereby suppressing Hedgehog pathway signaling