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Recent Progress in the Field of Neoglycoconjugate Chemistry See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/247838044 Recent progress in the field of neoglycoconjugate chemistry Article in Biomolecular concepts · May 2010 DOI: 10.1515/BMC.2010.007 CITATIONS READS 0 29 4 authors, including: Carmen Jiménez-Castells David Andreu University Pompeu Fabra University Pompeu Fabra 7 PUBLICATIONS 61 CITATIONS 318 PUBLICATIONS 8,765 CITATIONS SEE PROFILE SEE PROFILE Ricardo Gutiérrez Gallego University Pompeu Fabra 99 PUBLICATIONS 1,541 CITATIONS SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, Available from: David Andreu letting you access and read them immediately. Retrieved on: 29 August 2016 Article in press - uncorrected proof BioMol Concepts, Vol. 1 (2010), pp. 85–96 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/BMC.2010.007 Review Recent progress in the field of neoglycoconjugate chemistry Carmen Jime´nez-Castells1, Sira Defaus1, David type N-glycans) in recombinant human erythropoietin (EPO) Andreu1 and Ricardo Gutie´rrez-Gallego1,2,* (2) (Figure 1). Carbohydrate attachment to the backbone, usually occur- 1 Department of Experimental and Health Sciences, ring at the protein surface, entails not only modest-to-sub- Pompeu Fabra University, Barcelona Biomedical Research stantial structure alteration but also often the generation of Park, Dr. Aiguader 88, 08003 Barcelona, Spain differently glycosylated variants of a single gene product. 2 Pharmacology Research Unit, Bio-analysis group, Glycosylation has been extensively studied in eukaryotes Neuropsychopharmacology program, Municipal Institute of (3–6) and evidence is growing that in prokaryotes it is also Medical Research IMIM-Hospital del Mar, Barcelona more common than hitherto supposed (7, 8). Glycans have Biomedical Research Park, Dr. Aiguader 88, 08003 been associated with many biological events such as fertili- Barcelona, Spain zation (9, 10), cell growth (11), tumor growth/metastasis * Corresponding author (12), immune reactions (13, 14), cell communication e-mail: [email protected]; [email protected] (15–17), or infections (18, 19). Glycosylation, as opposed to glycation, is an enzymatic process that can occur in the endo- plasmic reticulum (ER) as a cotranslational event or in the Golgi apparatus as the newly synthesized protein passes Abstract through. It should be stressed that glycosylation is a contingent cel- Glycosylation is probably the most complex secondary gene lular process, resulting from non-template-directed, second- event that affects the vast majority of proteins in nature ary gene events. Different types of glycosylation exist and resulting in the occurrence of a heterogeneous mixture of the two most frequently occurring are N-glycosylation and glycoforms for a single protein. Many functions are exerted O-glycosylation (Figure 2). A particular feature of N-gly- by single monosaccharides, well-defined oligosaccharides, or cosylation is that initiation requires a consensus sequon larger glycans present in these glycoproteins. To unravel (Asn-Xxx-Thr/Ser; Xxx/Pro). If this motif occurs a preas- these functions it is of the utmost importance to prepare well- sembled 14-sugar precursor (Figure 2) can be transferred to defined single glycans conjugated to the underlying aglycon. Asn while the protein is still being synthesized in the ER. In this review, the most recent developments are described Upon completion of protein translation in the ER, the three to address the preparation of carbohydrate-amino acid (glyco- terminal glucose units are removed by glucosidases and the conjugates). Naturally occurring N- and O-linked glycosy- resulting oligomannose glycan can be trimmed by manno- lation are described and the preparation of non-natural sidases before the glycoprotein is passed onto the Golgi. This sugar-amino acid linkages are also included. trimming is not always quantitative and thus gives rise to structural heterogeneity wranging from, e.g., Man (20) to Keywords: biomolecular interactions; glycosylation; 3 Man Glc sugars (21)x. In the Golgi several glycosyltrans- neoglycopeptides; synthesis. 9 ferases are involved in the elongation, and the nature of the resulting glycotope largely depends on the protein migration rate, the availability of donor/acceptor substrate and appro- Introduction priate enzymes, environmental factors and, last but not least, the preceding enzymatic reaction (22, 23). It is also in the With the sequencing of an ever-increasing number of Golgi where the other most abundant type of glycosylation, genomes, and the number of genes encountered, it has i.e., O-glycosylation, is initiated. In contrast to N-glycosy- become very clear that the primary gene products are mostly lation, O-glycosylation builds from the initial addition of an unique structural scaffolds and that post-translational modi- a-linked GalNAc to Ser or Thr and no consensus sequon is fications (PTMs) of the encoded proteins actually provide known for the initial addition, making this type of glycosy- the structural diversity required for function. In this context, lation less predictable. This feature is enhanced through the glycosylation represents the most extended and complex type existence of at least 21 polypeptide-N-acetylgalactosamine- of PTM, ranging from the attachment of a single monosac- transferases (ppGalNAcT-1 to -21) (24) that are encoded by charide we.g., fucose to Thr61 in human tissue plasminogen different genes, differ in their amino acid sequences, and activator (1)x to far more complex structural arrangements catalyze the same reaction. It has be shown that these pp- (e.g., tetrasialylated tetraantennary core-fucosylated complex GalNAcTs act in either stand-alone or concerted reaction 2010/003 Article in press - uncorrected proof 86 C. Jime´ nez-Castells et al. Figure 1 Glycosylation as post-translational modification ranges from a single fucose residue (top) to an N-acetyllactosamine repeat containing tetrasialylated tetraantennary core-fucosylated complex type N-glycan (bottom). modes (25), which suggests that the O-glycosylation is not building block during peptide synthesis) or convergent (gly- random at all and that its fine-tuning is not yet understood. cosylation carried out on a full-length peptide end product), Similarly, the other glycosylation steps can be coordinated tend to be as diverse as the structures they target, and to rely by several homologous glycosyltransferases, some of which on purely chemical, purely enzymatic approaches, or on are truly tissue-specific, generating the inherent structural combinations of both. heterogeneity of glycoproteins. The way in which glycans In this review, an update of the field is provided in the are synthesized, added to the lack of proof-reading mecha- different areas of glycopeptide and neoglycopeptide synthe- nisms, has long obscured the understanding of the crucial sis, focusing primarily on chemistries that yield the sugar- role played by these entities in the biological phenomena amino acid moiety. For simplicity the subject matter is indicated above. divided between natural and non-natural linkages between To further unravel the functions that particular glycotopes the glycan and the non-glycan moieties, and subclassifica- exert, it is of the utmost importance that chemically well- tions are made according to the type of linkage or the chem- defined glycans are available, not only as free entities but istry applied during the synthesis. Non-glycosidic linkages also as particular glycoconjugates, so that the combined between sugars are not included in this review. Further rec- effect of carbohydrate epitope and the underlying structural ommended readings in this area can be found elsewhere entity can be evaluated. Much effort has been put into the (28–31). development of different chemical and enzymatic strategies to generate such glycotope targets in sufficient amounts for structural and functional studies. Unlike DNA, proteins or Natural glycosidic linkages peptides, where PCR amplification, recombinant DNA tech- nology, and Merrifield solid-phase peptide synthesis (SPPS), N-linked glycosylation respectively, allow for amplification and/or efficient produc- tion, carbohydrate synthesis is a technology still under develop- Evidently, the optimal mimic of a particular glycoprotein part ment, relying on non-routine, chemically non-straightforward would be the peptide sequence containing the natural linkage protocols. Several attempts are being made, particularly by to the peptide-bound monosaccharide and the subsequent the Seeberger group (26–28), to develop automated synthetic glycan epitope. The most frequently occurring glycan types procedures, but despite encouraging results they have not yet have been addressed by different groups. Thus, Crich et al. reached the universal applicability of their peptide counter- (32) employed N-benzyloxycarbonyl-L-aspartic cyclic mono- part. In general, glycan synthetic strategies, either linear thioanhydrides and unprotected glycosyl primary amines and (glycan incorporated as a preformed glycosyl amino acid N-sulfonyl amino acid derivatives in a one-pot synthetic Article in press - uncorrected proof Developments in neoglycoconjugate chemistry 87 Figure 2 Short-hand notation for the two most frequently occurring types of glycosylation. The top panel depicts N-type glycans, with the 14-residue dolichol pyrophosphate precursor above the dashed line. Below the dashed
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