PMID- 18445751 OWN - NLM STAT- MEDLINE DCOM- 20080828 LR - 20220309 IS - 0193-1849 (Print) IS - 1522-1555 (Electronic) IS - 0193-1849 (Linking) VI - 295 IP - 1 DP - 2008 Jul TI - Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity. PG - E17-28 LID - 10.1152/ajpendo.90281.2008 [doi] AB - O-linked beta-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that, analogous to phosphorylation, cycles on and off serine and/or threonine hydroxyl groups. Cycling of O-GlcNAc is regulated by the concerted actions of O-GlcNAc transferase and O-GlcNAcase. GlcNAcylation is a nutrient/stress-sensitive modification that regulates proteins involved in a wide array of biological processes, including transcription, signaling, and metabolism. GlcNAcylation is involved in the etiology of glucose toxicity and chronic hyperglycemia-induced insulin resistance, a major hallmark of type 2 diabetes. Several reports demonstrate a strong positive correlation between GlcNAcylation and the development of insulin resistance. However, recent studies suggest that inhibiting GlcNAcylation does not prevent hyperglycemia-induced insulin resistance, suggesting that other mechanisms must also be involved. To date, proteomic analyses have identified more than 600 GlcNAcylated proteins in diverse functional classes. However, O-GlcNAc sites have been mapped on only a small percentage (<15%) of these proteins, most of which were isolated from brain or spinal cord tissue and not from other metabolically relevant tissues. Mapping the sites of GlcNAcylation is not only necessary to elucidate the complex cross-talk between GlcNAcylation and phosphorylation but is also key to the design of site-specific mutational studies and necessary for the generation of site-specific antibodies, both of which will help further decipher O-GlcNAc's functional roles. Recent technical advances in O-GlcNAc site-mapping methods should now finally allow for a much-needed increase in site-specific analyses to address the functional significance of O-GlcNAc in insulin resistance and glucose toxicity as well as other major biological processes. FAU - Copeland, Ronald J AU - Copeland RJ AD - Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205-2185, USA. FAU - Bullen, John W AU - Bullen JW FAU - Hart, Gerald W AU - Hart GW LA - eng GR - R37-HD-13563/HD/NICHD NIH HHS/United States GR - N01-HV-28180/HV/NHLBI NIH HHS/United States GR - R01 CA042486/CA/NCI NIH HHS/United States GR - R33-DK-071280/DK/NIDDK NIH HHS/United States GR - R37 HD013563/HD/NICHD NIH HHS/United States GR - R01-DK-061671/DK/NIDDK NIH HHS/United States GR - R01 DK061671/DK/NIDDK NIH HHS/United States GR - R33 DK071280/DK/NIDDK NIH HHS/United States GR - R01-CA-42486/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20080429 PL - United States TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226 RN - 0 (Hexosamines) RN - EC 2.4.1.- (N-Acetylglucosaminyltransferases) RN - EC 3.2.1.52 (Acetylglucosaminidase) RN - V956696549 (Acetylglucosamine) SB - IM MH - Acetylglucosamine/*metabolism MH - Acetylglucosaminidase/*metabolism MH - Acylation MH - Amino Acid Sequence MH - Animals MH - Diabetes Mellitus, Type 2/enzymology/*metabolism MH - Hexosamines/*metabolism MH - Humans MH - Insulin Resistance/*physiology MH - Molecular Sequence Data MH - N-Acetylglucosaminyltransferases/*metabolism MH - Phosphorylation MH - Signal Transduction PMC - PMC3751035 EDAT- 2008/05/01 09:00 MHDA- 2008/08/30 09:00 PMCR- 2009/07/01 CRDT- 2008/05/01 09:00 PHST- 2008/05/01 09:00 [pubmed] PHST- 2008/08/30 09:00 [medline] PHST- 2008/05/01 09:00 [entrez] PHST- 2009/07/01 00:00 [pmc-release] AID - 90281.2008 [pii] AID - 10.1152/ajpendo.90281.2008 [doi] PST - ppublish SO - Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E17-28. doi: 10.1152/ajpendo.90281.2008. Epub 2008 Apr 29.