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JournalofProteom e Research • Vol. 1, No. 4, 2002
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[email protected] editorial
EDITOR-IN-CHIEF
William S. Hancock Thermo Finnigan 390 Robinwood Lane Hillsborough, CA 94010 650-348-0204; fax: 650-348-0204
[email protected] ASSOCIATE EDITORS
Joshua LaBaer Harvard Medical School
György Marko-Varga AstraZeneca and Lund University EDITORIAL ADVISORY BOARD
Ruedi H. Aebersold Institute for Systems Biology
Leigh Anderson Large Scale Biology
Ettore Appella National Cancer Institute
Ronald Beavis Proteomic Solutions
Walter Blackstock Cellzome
Brian Chait The Rockefeller University
Patrick L. Coleman 3M
Catherine Fenselau University of Maryland
Daniel Figeys MDS Proteomics
Stanley Hefta Bristol-Myers Squibb
Donald F. Hunt University of Virginia
Barry L. Karger Northeastern University
Daniel C. Liebler University of Arizona
Matthias Mann University of Southern Denmark
Stephen A. Martin Applied Biosystems
Jeremy Nicholson Imperial College of London
J. Michael Ramsey Oak Ridge National Laboratory
Pier Giorgio Righetti University of Verona
John T. Stults Genentech, Inc.
Glycosylation, Who Cares? key part of proteomics research is examining the more than 100 different types of posttranslational modifications (PTMs) that can occur to proteins, of which two of the most important are phosphorylation and glycosylation. An observer of proteomic meetings would be struck by the strong focus on phosphorylation with an occasional, if any, mention of glycosylation. This is unfortunate since glycosylation would seem to be a rich and important area for proteomic exploration. In 2-D gel analyses, there are often a complex pattern of spots that can be related back to the charge variants that arise when proteins are phosphorylated, glycosylated, or otherwise modified. For instance, in the comparison of diseased versus normal tissue, one often sees a change in spots caused by differential incorporation of sialic acid. There is considerable evidence that such variations, called microheterogeneity, are important, for example, sialic acid is associated with clearance of circulating proteins through the asialo-receptor present in the liver. Interestingly, cancer is often associated with changes in glycosylation. For example, several studies have noted changes in the degree of fucosylation of cancer-associated proteins. In such studies, it is difficult to determine whether one is observing cause or effect, but there is no question that changes in glycosylation are strongly associated with many different types of cancer, as well as other diseases such as rheumatoid arthritis. Within the biotechnology industry, the importance of glycosylation is well known and has resulted in the characterization of major carbohydrate structures in recombinant-DNA produced protein pharmaceuticals. Examples include the blockbuster drugs tissue plasminogen activator and erythropoietin, each of which contains two or more carbohydrate residues associated with protein activity. In both cases, the FDA required substantial characterization of the protein glycosylation and demonstration of consistency of this modification in replicate manufacturing batches before these drugs were approved for therapeutic use. One must recognize, however, that the characterization of changes of glycosylation (particularly in minute samples) is a challenging exercise. At this stage, it’s difficult to see how global methods of proteomic analysis can be applied routinely to such detailed characterization efforts, particularly because glycopeptides produced by tryptic digestion are present at extremely low levels due to the heterogeneity of the modifications. In the analytical biotechnology lab, analysts usually separate major isoforms by HPLC or capillary electrophoresis, followed by the development of a peptide map on each of the separated components. Protein chips are not ideal for measuring such modifications because the antibody or other binding ligand on the chip will probably not recognize subtle changes in glycosylation, unless the ligand is specifically tailored to recognize such a change. It is certainly an area where 2-D gels will remain a key technology for providing global views of changes in PTMs. One can hope that the integration of these other approaches (such as new MS systems and protein arrays) with the 2-D gel format will allow detection and then characterization of PTMs in a global way. In addition, development of new chemistries and use of biological reagents such as lectins and glycosidases will also be key parts. Finally, development of improved databases to give a global view of possible glycosylation structures will be important when we start looking at the characterization of the proteome in a wide range of species. So I trust that the response to this editorial is a resounding “Yes, we care”, that the proteomics community believes that glycosylation is an essential part of future proteomic studies. If so, the community will surely make a sufficient investment in technology to allow the development of adequate methods for these challenging studies.
A
Peter Wagner Zyomyx
Keith Williams Proteome Systems
John R.Yates, III The Scripps Research Institute © 2002 American Chemical Society
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