Sandbox Reserved 381: Difference between revisions

<Structure load='3pe3' size='400' frame='true' align='right' caption='Ternary complex O-GlcNAc transferase with UDP' scene='Insert optional scene name here' />

== ''O-GlcNAc transferase'' ==

O-linked β-N-acetylglucosamine transferase (O-GlcNAc transferase) is an essential mammalian enzyme that acts as a nutrient sensor, coupling metabolic status to the regulation of a wide variety of cellular signaling pathways.<ref> Hart GW, Housley MP, Slawson C. Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins. Nature.2007;446:1017-22.[http://www.nature.com/nature/journal/v446/n7139/abs/nature05815.html]</ref> OGT catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to serines and threonines of cytoplasmic, nuclear and mitochondrial proteins, including numerous transcription factors, tumour suppressors, kinases, phospahateses and histone-modifying proteins.<ref>PMID:21240259</ref> Two crystal structures of human OGT are reported here as a ternary complex with UDP and a <scene name='Sandbox_Reserved_381/Binary_complex_with_udp/1'>binary complex</scene> with UDP and a peptide substrate.

Faulty regulation of O-GlcNAc midifications has been suggested to be involved in neurodegenerative diseases, diabetes mellitus and cancer. Biochemical details of these processes are still unclear.<ref>PMID:16051707</ref> Proteins modified by O-GlcNAc have been directly shown to have a role in the pathology of human diseases. For instance, the Ser/The kinase AKT,PI₍₃₎K,insulin receptor substrate 1, glycogen synthase and endothelial nitric oxide synthase,all of which are enzymes that have a crucial role in insulin signalling,are reversibly modified by OGT. A recent study showed that recruitment of OGT to the plasma membrane specifically prevents the phosphorylation of AKT and possibly other proteins, thereby terminating insulin signalling.<ref>PMID:18288188</ref> This adds evidence to the view that increasing the level of O-GlcNAc modifications correlates with the development of insulin resistance, which is a characteristic of type II diabetes.<ref>PMID:16317114</ref><ref>PMID:16781888</ref> Some indications suggest that O-GlcNAc modifications have a role in Alzheimer disease. Higher levels of O-GlcNAc can be detected in the brain tissue, and several proteins involved in neuronal signaling are modified with O-GlcNAc. Among them are the β-amyloid precursor protein, clathrin-assembly proteins and neurofilaments. In the brains of patients with Alzheimer disease, hyperphosphorylated Tau protein was modified by O-GlcNAc to a lesser extent than in healthy individuals.<ref>PMID:17940659</ref> Studies have shown that some oncogenes and tumour suppressors are targets of O-glycosylation, including the SV40 T antigen and c-MYC.<ref>PMID:14533811</ref> Tumour cells have an altered glucose metabolism that is expected to produce changes in O-GlcNAc levels and to affect different signaling pathways.