Protein O-GlcNAcase (OGA) (OGA)

Protein O-GlcNAcase (OGA) is a specialized glycoside hydrolase that catalyzes the removal of O-linked beta-N-acetylglucosamine (O-GlcNAc) from serine and threonine residues of intracellular proteins (UniProt P54802). This enzyme works in opposition to O-GlcNAc transferase (OGT) to maintain the dynamic balance of O-GlcNAcylation, a post-translational modification that serves as a critical sensor for cellular nutrient and energy status (PubMed: PMC4545142). OGA is a primary therapeutic target in neurodegeneration, particularly tauopathies like Alzheimer's disease, because increasing O-GlcNAc levels on Tau protein has been shown to prevent its hyperphosphorylation and aggregation into neurofibrillary tangles (PubMed: 31034883). Small-molecule OGA inhibitors, such as MK-8719 and LY3372689, are designed to cross the blood-brain barrier and elevate O-GlcNAc levels to provide neuroprotection (ClinicalTrials.gov). Additionally, OGA's involvement in metabolic pathways and cell cycle regulation links it to the pathology of type 2 diabetes and various cancers, making it a versatile target for drug development (Nature Reviews Drug Discovery).

Other names

MGEA5Meningioma-expressed antigen 5N-acetyl-beta-D-glucosaminidaseHexosaminidase CO-GlcNAcaseO-linked beta-N-acetylglucosaminidase

Inhibition of the O-GlcNAcase enzyme to increase the levels of O-GlcNAc modification on intracellular proteins, which stabilizes Tau protein and prevents its pathological hyperphosphorylation and aggregation.