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Wang J, Cao W, Zhang W, Dou B, Zeng X, Su S, Cao H, Ding X, Ma J, Li X. Ac(3)4FGlcNAz is an effective metabolic chemical reporter for O-GlcNAcylated proteins with decreased S-glyco-modification. Bioorganic chemistry 2023 131 36610251
O-GlcNAcylation is a ubiquitous post-translational modification governing vital biological processes in cancer, diabetes and neurodegeneration. Metabolic chemical reporters (MCRs) containing bio-orthogonal groups such as azido or alkyne, are widely used for labeling of interested proteins. However, most MCRs developed for O-GlcNAc modification are not specific and always lead to unexpected side reactions termed S-glyco-modification. Here, we attempt to develop a new MCR of Ac34FGlcNAz that replacing the 4-OH of Ac4GlcNAz with fluorine, which is supposed to abolish the epimerization of GALE and enhance the selectivity. The discoveries demonstrate that Ac34FGlcNAz is a powerful MCR for O-GlcNAcylation with high efficiency and the process of this labeling is conducted by the two enzymes of OGT and OGA. Most importantly, Ac34FGlcNAz is predominantly incorporated intracellular proteins in the form of O-linkage and leads to negligible S-glyco-modification, indicating it is a selective MCR for O-GlcNAcylation. Therefore, we reason that Ac34FGlcNAz developed here is a well characterized MCR of O-GlcNAcylation, which provides more choice for label and enrichment of O-GlcNAc associated proteins.
O-GlcNAc proteins:
Species: Mus musculus
Papanicolaou KN, Jung J, Ashok D, Zhang W, Modaressanavi A, Avila E, Foster DB, Zachara NE, O'Rourke B. Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy. The Journal of biological chemistry 2023 299(3) 36642184
The dynamic cycling of O-linked GlcNAc (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase. O-GlcNAc cycling is important in homeostatic and stress responses, and its perturbation sensitizes the heart to ischemic and other injuries. Despite considerable progress, many molecular pathways impacted by O-GlcNAcylation in the heart remain unclear. The mitogen-activated protein kinase (MAPK) pathway is a central signaling cascade that coordinates developmental, physiological, and pathological responses in the heart. The developmental or adaptive arm of MAPK signaling is primarily mediated by Erk kinases, while the pathophysiologic arm is mediated by p38 and Jnk kinases. Here, we examine whether O-GlcNAcylation affects MAPK signaling in cardiac myocytes, focusing on Erk1/2 and p38 in basal and hypertrophic conditions induced by phenylephrine. Using metabolic labeling of glycans coupled with alkyne-azide "click" chemistry, we found that Erk1/2 and p38 are O-GlcNAcylated. Supporting the regulation of p38 by O-GlcNAcylation, the OGT inhibitor, OSMI-1, triggers the phosphorylation of p38, an event that involves the NOX2-Ask1-MKK3/6 signaling axis and also the noncanonical activator Tab1. Additionally, OGT inhibition blocks the phenylephrine-induced phosphorylation of Erk1/2. Consistent with perturbed MAPK signaling, OSMI-1-treated cardiomyocytes have a blunted hypertrophic response to phenylephrine, decreased expression of cTnT (key component of the contractile apparatus), and increased expression of maladaptive natriuretic factors Anp and Bnp. Collectively, these studies highlight new roles for O-GlcNAcylation in maintaining a balanced activity of Erk1/2 and p38 MAPKs during hypertrophic growth responses in cardiomyocytes.
O-GlcNAc proteins:
M3K7, CREB1, MK03, MP2K2, HSPB1, MK01, MK14, MP2K1, CDC37
He J, Fan Z, Tian Y, Yang W, Zhou Y, Zhu Q, Zhang W, Qin W, Yi W. Spatiotemporal Activation of Protein O-GlcNAcylation in Living Cells. Journal of the American Chemical Society 2022 144(10) 35138101
O-linked N-acetylglucosamine (O-GlcNAc) is a prevalent protein modification that plays fundamental roles in both cell physiology and pathology. O-GlcNAc is catalyzed solely by O-GlcNAc transferase (OGT). The study of protein O-GlcNAc function is limited by the lack of tools to control OGT activity with spatiotemporal resolution in cells. Here, we report light control of OGT activity in cells by replacing a catalytically essential lysine residue with a genetically encoded photocaged lysine. This enables the expression of a transiently inactivated form of OGT, which can be rapidly reactivated by photo-decaging. We demonstrate the activation of OGT activity by monitoring the time-dependent increase of cellular O-GlcNAc and profile glycoproteins using mass-spectrometry-based quantitative proteomics. We further apply this activation strategy to control the morphological contraction of fibroblasts. Furthermore, we achieved spatial activation of OGT activity predominantly in the cytosol. Thus, our approach provides a valuable chemical tool to control cellular O-GlcNAc with much needed spatiotemporal precision, which aids in a better understanding of O-GlcNAc function.