O-GlcNAcase: promiscuous hexosaminidase or key regulator of O-GlcNAc signaling?
Bottom Line: O-GlcNAc signaling is regulated by an opposing pair of enzymes: O-GlcNAc transferase installs and O-GlcNAcase (OGA) removes the modification from proteins.The dynamics and regulation of this process are only beginning to be understood as the physiological functions of both enzymes are being probed using genetic and pharmacological approaches.We identify several areas of "known unknowns" that would benefit from future research, such as the enigmatic C-terminal domain of OGA.
Affiliation: From the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit and.Show MeSH
Mentions: The elucidation of the OGA catalytic mechanism has enabled the development of potent and selective inhibitors that have subsequently been used to study O-GlcNAcylation in cells and organisms. The available inhibitors have been the subject of multiple recent reviews (35, 49–51). Ostrowski and van Aalten (51) focused on their use as probes to study O-GlcNAc signaling and covered significant problems with some of the early OGA inhibitors, PUGNAc and streptozotocin, which are unsuitable for cell biological studies due to their off-target effects (35). Here, we will give a brief overview of the two main classes of mechanism-inspired, potent, and selective OGA inhibitors. The catalytic mechanism of O-GlcNAc hydrolysis proceeds via an oxazoline reaction intermediate. Stable mimics of reaction intermediates can act as selective enzyme inhibitors, and consequently, thiazoline derivatives of GlcNAc have been explored as OGA inhibitors (Fig. 3). Modifications of the 1,2-dideoxy-2′-methyl-α-d-glucopyranoso[2,1-d]-Δ2′-thiazoline (NAG-thiazoline) acyl side chain (39, 52–54) led to improved selectivity over GH18, GH20, and GH56 enzymes that employ the same reaction mechanism. NAG-thiazolines are water-soluble and synthetically accessible OGA inhibitors with potencies in the nanomolar-to-micromolar range, with Thiamet-G being the most selective representative. This family of OGA inhibitors has been described to possess cardioprotective effects: NAG-thiazolines protect against ischemia/reperfusion injury, improving contractile function through preservation of the striated muscle structure (55), and Thiamet-G counteracts TNF-α-induced vascular dysfunction (56). Thiamet-G has also been proposed as a potential therapeutic for Alzheimer disease, as discussed in detail in an accompanying minireview (83). Alzheimer disease and other tauopathies are associated with phosphorylation-dependent oligomerization of tau protein, resulting in neurofibrillary tangles. O-GlcNAcylation has been suggested to negatively regulate tau phosphorylation in a site-specific manner (57, 58). Oral administration of Thiamet-G in mice causes an increase in tau S400 O-GlcNAcylation and a reduction in neurofibrillary tangles in the brainstem, hypothalamus, and cortex (59). Transgenic mice overexpressing a human tau mutant (JNPL3(P301L)) subjected to long-term administration of Thiamet-G display an increase in motor neurons and body weight paired with a decreased neurogenic atrophy of skeletal muscle (60). Similarly, in a recent study in rTg(tauP301L)4510 mice, Thiamet-G administration caused a remarkable reduction in pathological 64-kDa tau in brain homogenates (61).
Affiliation: From the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit and.