Glycosyltransferase GT1 family: Phylogenetic distribution, substrates coverage, and representative structural features

Glycosyltransferases (GTs) are responsible for transferring glycosyl moieties from activated sugar donors to certain acceptors, among which the GT1 family enzymes have been known for their outstanding glycosylation capacities toward diverse natural products, such as glycolipids, flavonoids and macrolides etc. However, there still lacks a systematic collation of this important family members. In this minireview, all the GT1 family sequences were phylogenetically analyzed, and the grouping of GT1 proteins exhibited a taxonomic life domain-dependent pattern, revealing many untapped clades of GTs. The further phylogenetic analysis of the characterized GTs facilitated the classification of substrates coverage of GT1 family enzymes from different life domains, whereby the GTs from bacteria can tolerate a wider spectrum of chemical skeletons as substrates, showing higher promiscuity than those from other domains. Furthermore, the sequence sizes of GTs from different domains were compared to understand their different substrates selectivity. Based on the multiple sequence alignments of 28 representative GT1 enzymes with crystal structures, two critical regions located in the N-terminal of GTs were identified, which were most variable among sequences from different taxonomic domains and essential for substrates binding and/or catalysis. The key roles of these two regions were validated by enumerating the influential residues that interacted with substrates in the representative structures from bacteria and plants. The atlas for GT1 family in terms of phylogeny, substrates selectivity, sequence length, and critical motifs provides the clues for the exploration of unknown GT1s and rational engineering of known enzymes, synthesizing novel promising glycoconjugates for pharmaceutical application.