Ammonia is then spontaneously released from the 1-amino GlcNAc at physiological pH (<8), giving rise to a free oligosaccharide with an N,N’-diacetylchitobiose structure at the reducing end.

[15][16] NGLY1, when compared with the yeast orthologues, possesses extended N-terminal and C-terminal sequences in addition to the transglutaminase domain.

Regarding the function of NGLY1, it has been shown that the enzyme is involved in the ER-associated degradation (ERAD), one of the ER quality control/homeostasis systems for newly synthesized glycoproteins.

[29][30][31] The Ngly1-mediated (glycosylated) Asn-to-Asp deamidation constitutes, together with other reactions such as transpeptidation, unconventional post-translational modifications for antigenic peptides that are presented by MHC class I molecules.

Details of the mechanism responsible for the pathogenesis of the NGLY1-deficiency remain unknown, while the intracellular accumulation of N-GlcNAc proteins, due to the excess action of cytosolic endo-b-N-acetylglucosaminidase[46] to misfolded glycoproteins, in Ngly1-deficient cells has been hypothesized as a potential cause.

[47][48][49][50] Studies have been carried out to discover small molecules that can bind to the transglutaminase domain of the protein to stabilize it as a potential therapeutic in the treatment of disorder caused by NGLY1 defects.