SEARCH

SEARCH BY CITATION

image

image

The most complex post-translational modification of proteins, glycosylation, is controlled by diverse regulatory mechanisms that include the 3D structure of the protein, the complement of glycosyltransferases and glycosidases that are expressed, the transport of substrates into the endoplasmic reticulum and the Golgi, and the topographical transit of the proteins through these compartments during biosynthesis. It is not surprising, therefore, that the glycans expressed on a particular protein reflect the state of the cell that has synthesized it, be it normalcy or that of pathology. Difficulties in our ability to focus on protein glycosylation as a means to develop diagnostic and prognostic assays for particular disorders and diseases are beginning to be overcome, however, as Glycomic technologies are developed. The collection of studies published in this issue demonstrates progress in developing several tools and methodologies to analyze tissues and fluids for altered protein glycosylation, as well as for identifying particular protein glycosylation markers that are associated with the disease state.

The first three contributions are largely focused on describing state-of-the-art technologies and reagents to perform glycoproteomics and identify potential biomarkers. The first, from G. Hart's laboratory [1], summarizes current glycoproteomics and mass spectrometric approaches to identify site-specific glycosylation with the monosaccharide O-GlcNAc. This post-translational modification is as ubiquitous and its functions as diverse as phosphorylation, and there are indications that it may be able to identify the pre-diabetic state. Next, K. Ueda presents an overview of strategies for identification of potential cancer glycan markers using glycoproteomic strategies [2]. R. Cummings’ laboratory [3] then presents a comprehensive review of the utility of the Tn and sialyl-Tn antigens in identifying various cancers and other diseases and disorders, such as IgA nephropathy, concentrating on the mechanism that causes loss of the T-synthase and production of these antigens, namely, mutations in the molecular chaperone, Cosmc.

The next three papers describe progress using lectin-based analyses to discover novel biomarkers. B. Haab's laboratory [4] discusses a novel methodology to predict O-glycan motifs by analyzing the binding of multi-lectins to the Consortium for Functional Glycomics glycan array, and applying this method to identify and distinguish motifs on MUC1 synthesized and secreted by eight cultured pancreatic cancer cell lines. Narimatsu's laboratory [5] discusses a lectin/antibody-based assay to quantify a specific glycoform of Mac-2 binding protein (galectin-3) in serum as a marker for liver fibrosis. Next, Miyoshi's laboratory [6] has developed an assay for serum Mac-2 binding protein that can assist diagnosis of nonalcoholic fatty liver disease and, predicting severity of this disease and distinguishing between this disease and simple steatosis.

The final four contributions describe somewhat more advanced glycan markers for particular diseases. Kitazume and Taniguchi, et al. [7] describe a glycoform of amyloid b peptide secreted by vascular endothelial cells that is O-glycosylated. This glycoform has the potential to be a biomarker for acute coronary syndrome. Miyamoto and Lebrilla [8] have evaluated to protein enrichment techniques to evaluate glycan differences in serum and on IgG to demonstrate differences in serum from non-diseased and lung cancer patients. Drake's laboratory [9] has developed glycoproteomic methods to analyze expressed prostatic secretions on total glycoproteins and prostatic acid phosphatase and showed an association of an increase in bisected N-linked glycans, and loss of highly branched N-linked glycans, with prostatic carcinoma severity. Finally, Mehta and colleagues [10] demonstrated that N-linked glycan analysis of total serum glycoproteins could distinguish well hepatocellular carcinoma from cirrhosis. When combined with alpha-fetoprotein levels, the sensitivity of the method increased to 95% with a specificity of 90%, which is very impressive.

It is clear from these contributions that significant progress has been made in the identification of glycan biomarkers for several diseases, as well as development of assays to quantify them. These diseases and disorders range from hepatocellular and epithelial cancers, to acute coronary syndrome, prediabetes, and various liver diseases. There is no doubt that as advances in glycomic technologies and assays continue to be developed, we will soon be able to see past the tip of the “iceberg”, where we are now, and dive deep into the treasure of glycobiomarkers with clinical applications that we will assuredly discover.

image

image

References

  1. Top of page
  2. References
  • 1
    Copeland, R. J., Han, G., Hart, G. W., O-GlcNAcomics—Revealing roles of O-GlcNAcylation in disease mechanisms and development of potential diagnostics. Proteomics Clin. Appl. 2013, 7, 597606.
  • 2
    Ueda, K., Glycoproteomic strategies: From discovery to clinical application of cancer carbohydrate biomarkers. Proteomics Clin. Appl. 2013, 7, 607617.
  • 3
    Ju, T., Wang, Y., Aryal, R. P., Lehoux, S. D. et al., Tn and sialyl-Tn antigens, aberrant O-glycomics as human disease markers. Proteomics Clin. Appl. 2013, 7, 618631.
  • 4
    Haab, B., McCarter, C., Kletter, D., Tang, H. et al., Prediction of glycan motifs using quantitative analysis of multi-lectin binding: motifs on MUC1 produced by cultured pancreatic cancer cells. Proteomics Clin. Appl. 2013, 7, 632641.
  • 5
    Kuno, A., Sato, T., Shimazaki, H., Unno, S. et al., Reconstruction of a robust glycodiagnostic agent supported by multiple lectin-assisted glycan profiling. Proteomics Clin. Appl. 2013, 7, 642647.
  • 6
    Miyoshi, E., Kamada, Y., Fujii, H., Fujii, H. et al., Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis. Proteomics Clin. Appl. 2013, 7, 648656.
  • 7
    Kitazume, S., Yoshihisa, A., Yamaki, T., Oikawa, M. et al., Soluble amyloid precursor protein 770 is a novel biomarker candidate for acute coronary syndrome. Proteomics Clin. Appl. 2013, 7, 657663.
  • 8
    Ruhaak, L. R., Nguyen, U. T., Stroble, C., Taylor, S. L. et al., Enrichment strategies in glycomics-based lung cancer biomarker development. Proteomics Clin. Appl. 2013, 7, 664676.
  • 9
    Drake, R., Nyalwidhe, J., Betesh, L., Powers, T. et al., Increased bisecting N-acetylglucosamine and decreased branched chain glycans of N-linked glycoproteins in expressed prostatic secretions associated with prostate cancer progression. Proteomics Clin. Appl. 2013, 7, 677689.
  • 10
    Mehta, A., Comunale, M. A., Wang, M., Anbarasan, N. et al., Total serum glycan analysis is superior to lectin-FLISA for the early detection of hepatocellular carcinoma. Proteomics Clin. Appl. 2013, 7, 690700.