DEVELOPMENT OF BISUBSTRATE COVALENT INHIBITORS OF PROTEIN O-GLCNAC TRANSFERASE (OGT)

摘要

Reversible posttranslational modification of certain serine and threonine residues in nucleocytoplasmic proteins by attachment of a single ss-N-acetylglucosamine (O-GlcNAc) is highly conserved in higher eukaryotes and is essential for proper development of the animal embryo [1, 2]. The protein O-GlcNAc transferase (OGT; EC 2.4.1.255) uses the donor substrate UDP-GlcNAc to transfer the sugar moiety onto target proteins, while deglycosylation reaction is carried out by O-GlcNAc hydrolase (OGA). Substantial substrate promiscuity enables this single pair of enzymes to control the proteome linked to the regulation of a range of cellular processes [3]. Dysregulation of the O-GlcNAc cycle is manifested in multiple metabolic pathologies, such as diabetes [4] and cancer [5], as well as neurological diseases such as Alzheimer's and Parkinson's [6]. Elucidation of the precise biological role(s) of protein O-GlcNAcylation is hampered by the lack of functional inhibitors of OGT. The known drug-like small molecules originated from fragment screening are yet to be improved to reach useful level of selectivity and potency [7]. The metabolic OGT inhibitor, i.e. per-acetylated derivative of 5-thio-GlcNAc is a priori non-selective when considered in the context of several other families of essential UDP-GlcNAc processing glycosyl transferases present in the cell [8].