Chemical Approaches to Study O-GlcNAcylation

Overview

Journal Chem Soc Rev

Specialty Chemistry

Date 2012 Dec 19

PMID 23247267

Citations 28

Authors

Partha S Banerjee

Gerald W Hart

Jin Won Cho

Affiliations

Soon will be listed here.

Abstract

The enzymatic addition of a single β-D-N-acetylglucosamine sugar molecule on serine and/or threonine residues of protein chains is referred to as O-GlcNAcylation. This novel form of post-translational modification, first reported in 1984, is extremely abundant on nuclear and cytoplasmic proteins and has site specific cycling dynamics comparable to that of protein-phosphorylation. A nutrient and stress sensor, O-GlcNAc abnormalities underlie insulin resistance and glucose toxicity in diabetes, neurodegenerative disorders and dysregulation of tumor suppressors and oncogenic proteins in cancer. Recent advances have helped understand the biochemical mechanisms of GlcNAc addition and removal and have opened the door to developing key inhibitors towards this type of protein modification. Advanced methods in detecting and measuring O-GlcNAcylation have assisted in delineating its biological roles in a variety of cellular processes and diseased states. Availability of facile glycomic techniques are allowing for the exponential growth in the study of protein O-GlcNAcylation and are helping to elucidate key biological roles of this novel PTM.

Citing Articles

Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation.

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O-GlcNAcylation in ischemic diseases.

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O-GlcNAcylation: cellular physiology and therapeutic target for human diseases.

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A fluorescent probe to simultaneously detect both O-GlcNAcase and phosphatase.

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Emerging Role of Protein O-GlcNAcylation in Liver Metabolism: Implications for Diabetes and NAFLD.

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References

Yuzwa S, Macauley M, Heinonen J, Shan X, Dennis R, He Y . A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol. 2008; 4(8):483-90. DOI: 10.1038/nchembio.96. View

Yang W, Kim J, Nam H, Ju J, Kim H, Kim Y . Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol. 2006; 8(10):1074-83. DOI: 10.1038/ncb1470. View

Tarrant M, Rho H, Xie Z, Jiang Y, Gross C, Culhane J . Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis. Nat Chem Biol. 2012; 8(3):262-9. PMC: 3288285. DOI: 10.1038/nchembio.771. View

Rao F, Dorfmueller H, Villa F, Allwood M, Eggleston I, van Aalten D . Structural insights into the mechanism and inhibition of eukaryotic O-GlcNAc hydrolysis. EMBO J. 2006; 25(7):1569-78. PMC: 1440316. DOI: 10.1038/sj.emboj.7601026. View

Khidekel N, Ficarro S, Clark P, Bryan M, Swaney D, Rexach J . Probing the dynamics of O-GlcNAc glycosylation in the brain using quantitative proteomics. Nat Chem Biol. 2007; 3(6):339-48. DOI: 10.1038/nchembio881. View

Klein A, Berkaw M, Buse M, Ball L . O-linked N-acetylglucosamine modification of insulin receptor substrate-1 occurs in close proximity to multiple SH2 domain binding motifs. Mol Cell Proteomics. 2009; 8(12):2733-45. PMC: 2816021. DOI: 10.1074/mcp.M900207-MCP200. View

ODonnell N, Zachara N, Hart G, Marth J . Ogt-dependent X-chromosome-linked protein glycosylation is a requisite modification in somatic cell function and embryo viability. Mol Cell Biol. 2004; 24(4):1680-90. PMC: 344186. DOI: 10.1128/MCB.24.4.1680-1690.2004. View

Cetinbas N, Macauley M, Stubbs K, Drapala R, Vocadlo D . Identification of Asp174 and Asp175 as the key catalytic residues of human O-GlcNAcase by functional analysis of site-directed mutants. Biochemistry. 2006; 45(11):3835-44. DOI: 10.1021/bi052370b. View

Chen Y, Du J, Zhou L, Liu X, Zhao Y, Nakanishi H . Alternative O-GlcNAcylation/O-phosphorylation of Ser16 induce different conformational disturbances to the N terminus of murine estrogen receptor beta. Chem Biol. 2006; 13(9):937-44. DOI: 10.1016/j.chembiol.2006.06.017. View

10.

Martinez-Fleites C, Macauley M, He Y, Shen D, Vocadlo D, Davies G . Structure of an O-GlcNAc transferase homolog provides insight into intracellular glycosylation. Nat Struct Mol Biol. 2008; 15(7):764-5. DOI: 10.1038/nsmb.1443. View

11.

Iyer S, Hart G . Roles of the tetratricopeptide repeat domain in O-GlcNAc transferase targeting and protein substrate specificity. J Biol Chem. 2003; 278(27):24608-16. DOI: 10.1074/jbc.M300036200. View

12.

Kim E . Chemical arsenal for the study of O-GlcNAc. Molecules. 2011; 16(3):1987-2022. PMC: 6259741. DOI: 10.3390/molecules16031987. View

13.

Lameira J, Alves C, Moliner V, Marti S, Castillo R, Tunon I . Quantum mechanical/molecular mechanical molecular dynamics simulation of wild-type and seven mutants of CpNagJ in complex with PUGNAc. J Phys Chem B. 2010; 114(20):7029-36. DOI: 10.1021/jp9115673. View

14.

Whitworth G, Macauley M, Stubbs K, Dennis R, Taylor E, Davies G . Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: mechanistic and structural insights into inhibitor selectivity and transition state poise. J Am Chem Soc. 2007; 129(3):635-44. DOI: 10.1021/ja065697o. View

15.

Slawson C, Zachara N, Vosseller K, Cheung W, Lane M, Hart G . Perturbations in O-linked beta-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J Biol Chem. 2005; 280(38):32944-56. DOI: 10.1074/jbc.M503396200. View

16.

Clarke A, Hurtado-Guerrero R, Pathak S, Schuttelkopf A, Borodkin V, Shepherd S . Structural insights into mechanism and specificity of O-GlcNAc transferase. EMBO J. 2008; 27(20):2780-8. PMC: 2556091. DOI: 10.1038/emboj.2008.186. View

17.

Wang Z, Park K, Comer F, Hsieh-Wilson L, Saudek C, Hart G . Site-specific GlcNAcylation of human erythrocyte proteins: potential biomarker(s) for diabetes. Diabetes. 2008; 58(2):309-17. PMC: 2628603. DOI: 10.2337/db08-0994. View

18.

Nandi A, Sprung R, Barma D, Zhao Y, Kim S, Falck J . Global identification of O-GlcNAc-modified proteins. Anal Chem. 2006; 78(2):452-8. DOI: 10.1021/ac051207j. View

19.

Boyce M, Carrico I, Ganguli A, Yu S, Hangauer M, Hubbard S . Metabolic cross-talk allows labeling of O-linked beta-N-acetylglucosamine-modified proteins via the N-acetylgalactosamine salvage pathway. Proc Natl Acad Sci U S A. 2011; 108(8):3141-6. PMC: 3044403. DOI: 10.1073/pnas.1010045108. View

20.

Khidekel N, Arndt S, Lamarre-Vincent N, Lippert A, Poulin-Kerstien K, Ramakrishnan B . A chemoenzymatic approach toward the rapid and sensitive detection of O-GlcNAc posttranslational modifications. J Am Chem Soc. 2003; 125(52):16162-3. DOI: 10.1021/ja038545r. View