Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT)

Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) is a lysosomal membrane enzyme required for the degradation of heparan sulfate, a highly sulfated glycosaminoglycan[1][2][3][5][7]. It catalyzes a unique transmembrane acetylation reaction in which the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and transferred to glucosamine residues on heparan sulfate[7]. This modification is a critical step in the sequential degradation of heparan sulfate sugar chains. Mutations in the HGSNAT gene result in loss or reduction of enzymatic activity, leading to accumulation of partially degraded heparan sulfate in lysosomes and causing mucopolysaccharidosis IIIC (Sanfilippo syndrome type C), a severe neurodegenerative disorder[1]. Structurally, HGSNAT is a dimeric transmembrane protein with 11 transmembrane helices per subunit, and recent studies have resolved its high-resolution structure in complex with acetyl-CoA, giving insight into its catalytic mechanism and the molecular impact of disease-causing mutations[2][3][7]. As of 2025, there are no approved drugs targeting this enzyme, but pharmacochaperone therapies are under investigation for treating certain mutant forms of HGSNAT that cause MPS IIIC[2][3].

Other names

TMEM76FLJ32731HGNATTransmembrane protein 76MPS3CRP73acetyl-CoA:heparan-alpha-D-glucosaminide N-acetyltransferaseacetyl-CoA:alpha-glucosaminide N-acetyltransferase

Pharmacochaperone therapy (investigational): small molecules act as chaperones to stabilize misfolded HGSNAT, thus restoring functional enzyme activity in certain mutants; Substrate reduction therapy (investigational): indirectly lowers substrate burden to alleviate pathophysiology (general for lysosomal disorders, not HGSNAT-specific)