Journal of Molecular Biology
CommunicationAn Evolving Hierarchical Family Classification for Glycosyltransferases
Section snippets
The problems of current nomenclature
A vast number of glycosyltransferase sequences are unveiled by the sequencing of genomes. Current estimates suggest that about 1% of the ORFs of each genome is dedicated to the task of glycosidic bond synthesis (P.M.C. & B.H., unpublished results). Furthermore, protein glycosylation, a glycosyltransferase-catalysed process, massively expands the functional proteome of higher organisms. It is a huge drawback, and not merely to glycobiology, that glycosyltransferases have often proved extremely
Sequence families: historical perspectives
In order to overcome the limitations of the IUBMB system and to reflect the likely increase in sequence data, Campbell and colleagues had proposed the classification of glycosyltransferases into families on the basis of similarities in amino acid sequence,8 a scheme inspired by the analogous and widely accepted classification of glycoside hydrolases.9., 10., 11. In 1997, 27 families of glycosyltransferases were described based on the analysis of the 600 sequences available at that time.8., 12.
Enzymes not included in the classification
The IUBMB classification features one class of glycosyltransferase not considered here: the enzymes that utilise disaccharides, oligosaccharides or polysaccharides as sugar donors, such as cyclodextrin glucanotransferases (EC 2.4.1.19), dextransucrase (EC 2.4.1.5), xyloglucan endotransferases (EC 2.4.1.207), etc. Unlike the glycosyltransferases discussed here, these enzymes are transglycosidases which are structurally, mechanistically and evolutionarily related to glycosidases.
An updated and evolving sequence classification for glycosyltransferases
Table 1 shows a summary of the content of the 65 glycosyltransferase families identified so far, including families GT1–GT27 described previously.8., 12. These continuously updated families, together with their links to appropriate databases (including GenBank, SwissProt, Enzyme, Taxonomy, Protein DataBank, etc.) are available from the Carbohydrate-Active enZymes (CAZy) database† . Our classification is probably incomplete, as it is likely that some
Genomic annotation
A feature of the sequence-based classification is that given families contain enzymes that display the same stereochemical outcome (Figure 1). Even in the most general case, instead of annotating an ORF as putative glycosyltransferase (now commonplace), one may annotate it as putative retaining (or inverting) glycosyltransferase from family GTxx. Whilst a superficially small improvement, such annotations would massively improve our ability to dissect diverse cellular processes such as
Glycosyltransferases: fold, clans, families, stereochemistry and specificities
As already noted,8., 12., 16. distant similarities between some families are revealed with sensitive sequence-similarity detection methods such as hydrophobic cluster analysis17 or PSI-BLAST.18 These distant similarities indicate interfamily relatedness, presumably as a result of evolutionary divergence. 3-D structure comparison is, arguably, the most powerful means to establish relatedness of proteins, even in the absence of detectable sequence similarity, and the recent elucidation of the
The CAZy classification highlights sequence “pitfalls” including so-called “conserved” motifs and modularity
One benefit of the sequence family classification is that it allows one to assess other potential diagnostics of glycosyltransferase activity. For example, it has been observed that a number of glycosyltransferases contain a so-called DxD motif,30., 31., 32., 33. although, confusingly, none of the elements of this conserved motif is invariant. In the GT-A fold structures, this motif binds one of the ribose hydroxyl groups and a divalent metal ion coordinated to the phosphate groups.19., 21., 34.
Concluding remarks
Structurally, glycosyltransferases could be mistaken as “dull”, as they seem to adopt either one of only two folds. Given the large number of nucleotide-sugar donors, the huge variety of acceptors (almost any class of molecule can be glycosylated: proteins, sugars, lipids, steroids, nucleic acids, antibiotics, etc.) and the resulting astronomical number of products, the two structural templates prove to be amongst the most ingenious and versatile scaffolds in nature. The almost infinite variety
Acknowledgements
We thank Chris Whitfield (Guelph, Ontario, Canada), Warren Wakarchuk (Ottawa, Ontario, Canada), Chris West (Gainesville, FL, USA), Rafael Oriol (Villejuif, France) for useful discussions and/or for sharing unpublished observations with us. This work was funded by grant QLK5-CT2001-00443 (EDEN) of the European Commission and by the Wellcome Trust. G.J.D is a Royal Society University Research Fellow.
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