title: Three monophyletic superfamilies account for the majority of the known glycosyltransferases.
abstract: Sixty-five families of glycosyltransferases (EC 2.4.x.y) have been recognized on the basis of high-sequence similarity to a founding member with experimentally demonstrated enzymatic activity. Although distant sequence relationships between some of these families have been reported, the natural history of glycosyltransferases is poorly understood. We used iterative searches of sequence databases, motif extraction, structural comparison, and analysis of completely sequenced genomes to track the origins of modern-type glycosyltransferases. We show that >75% of recognized glycosyltransferase families belong to one of only three monophyletic superfamilies of proteins, namely, (1) a recently described GPGTF/GT-B superfamily; (2) a nucleoside-diphosphosugar transferase (GT-A) superfamily, which is characterized by a DxD sequence signature and also includes nucleotidyltransferases; and (3) a GT-C superfamily of integral membrane glycosyltransferases with a modified DxD signature in the first extracellular loop. Several developmental regulators in Metazoans, including Fringe and Egghead homologs, belong to the second superfamily. Interestingly, Tout-velu/Exostosin family of developmental proteins found in all multicellular eukaryotes, contains separate domains belonging to the first and the second superfamilies, explaining multiple glycosyltransferase activities in one protein.
authors.affiliation: Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO 64110, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Arcady
authors.initials: A
authors.lastname: Mushegian
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence / Q000235:genetics; D030562:Databases, Protein; D019143:Evolution, Molecular; D016695:Glycosyltransferases / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009713:Nucleotidyltransferases / Q000235:genetics; D010802:Phylogeny; D017510:Protein Folding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013223:Statistics as Topic
chemical_list: D016695:Glycosyltransferases; D009713:Nucleotidyltransferases