Glycosyltransferases: mechanisms and applications in natural product development

Liang, Dongmei; Liu, Jiaheng; Wu, Hao; Wang, Binbin; Zhu, Hongtao; Qiao, Jianjun

doi:10.1039/c5cs00600g

Cited by 206 publications

(237 citation statements)

References 293 publications

(326 reference statements)

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“…7). Similar mutations in plant and human UGTs have shown equivalent results (29). These results suggest that UGT58A1 utilizes a classic catalytic mechanism in which His47 acts as a general base and catalytic residue for enzymatic activity to abstract a proton from the acceptor substrate.…”

Section: Figsupporting

confidence: 50%

“…UGT58A1 showed the highest identity (20%) to the template UGT85H2 in the Protein Data Bank, a (iso)flavonoid UGT from Medicago truncatula. Structure-based research on UGT85H2 revealed that an acceptor-His21-Asp125 triad was formed to accomplish the glycosylation reaction, which is similar to the serine hydrolases (28,29). In the serine hydrolase, the histidine group of the catalytic triad of Ser-His-Asp deprotonates serine for nucleophilic attack at the substrate; protonation of the histidine is subsequently stabilized through an interaction with the aspartate (28).…”

Section: Resultsmentioning

confidence: 99%

“…These findings indicate that the mechanism of sugar donor recognition of UGT58A1 is also similar to that of known UGTs. The conversed key residues would form hydrogen bonds with the UDP part and interact with the sugar moiety of the sugar donor (28)(29)(30)(31). Although a single residue plays a decisive role in recognizing the sugar, donor recognition was thought to be complex and to require multiple amino acids (30,31).…”

Section: Ugt58a1 (mentioning

confidence: 99%

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Two Novel Fungal Phenolic UDP Glycosyltransferases from Absidia coerulea and Rhizopus japonicus

Xie

Dou

Chen

et al. 2017

Appl Environ Microbiol

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In the present study, two novel phenolic UDP glycosyltransferases (PUGTs), UGT58A1 and UGT59A1, which can transfer sugar moieties from active donors to phenolic acceptors to generate corresponding glycosides, were identified in the fungal kingdom. UGT58A1 (from Absidia coerulea) and UGT59A1 (from Rhizopus japonicas) share a low degree of homology with known UGTs from animals, plants, bacteria, and viruses. These two P-UGTs are membrane-bound proteins with an N-terminal signal peptide and a transmembrane domain at the C terminus. Recombinant UGT58A1 and UGT59A1 are able to regioselectively and stereoselectively glycosylate a variety of phenolic aglycones to generate the corresponding glycosides. Phylogenetic analysis revealed the novelty of UGT58A1 and UGT59A1 in primary sequences in that they are distantly related to other UGTs and form a totally new evolutionary branch. Moreover, UGT58A1 and UGT59A1 represent the first members of the UGT58 and UGT59 families, respectively. Homology modeling and mutational analysis implied the sugar donor binding sites and key catalytic sites, which provided insights into the catalytic mechanism of UGT58A1. These results not only provide an efficient enzymatic tool for the synthesis of bioactive glycosides but also create a starting point for the identification of P-UGTs from fungi at the molecular level.IMPORTANCE Thus far, there have been many reports on the glycosylation of phenolics by fungal cells. However, no P-UGTs have ever been identified in fungi. Our study identified fungal P-UGTs at the molecular level and confirmed the existence of the UGT58 and UGT59 families. The novel sequence information on UGT58A1 and UGT59A1 shed light on the exciting and new P-UGTs hiding in the fungal kingdom, which would lead to the characterization of novel P-UGTs from fungi. Molecular identification of fungal P-UGTs not only is theoretically significant for a better understanding of the evolution of UGT families but also can be applied as a powerful tool in the glycodiversification of bioactive natural products for drug discovery.

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Section: Figsupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Ugt58a1 (mentioning

confidence: 99%

See 1 more Smart Citation

Two Novel Fungal Phenolic UDP Glycosyltransferases from Absidia coerulea and Rhizopus japonicus

Xie

Dou

Chen

et al. 2017

Appl Environ Microbiol

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“…All of the identified GT-C enzymes are integral membrane proteins with non-Leloir, inverting GT activity and many are involved in N-glycosylation of proteins (Liang et al 2015). They typically require a divalent cation for activity and use a lipid-phosphate as the sugar donor.…”

Section: Glycosyltransferase Tertiary Structurementioning

confidence: 99%

Advances in flavonoid glycosyltransferase research: integrating recent findings with long-term citrus studies

McIntosh

Owens

2016

Phytochem Rev

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Flavonoid glycosides are required for a number of crucial roles in planta and have the potential for development in a variety of agricultural, medicinal, and biotechnological applications. A number of recent advancements have been made in characterizing glycosyltransferases, the enzymes that are responsible for the synthesis of these important molecules. In this review, glycosyltransferases are considered with regard to biochemical properties, expression patterns, levels of enzyme activity during development, and structure/function relationships. This is presented with historical context to highlight critical findings, particularly with regard to the innovative work that has come from research on citrus species. The plant glycosyltransferase crystal structures that have been solved over the past decade, either alone or in complex with sugar donor and/or acceptor molecules, are discussed. The application of results from these structures to inform current structure/function work as well as implications and goals for future crystallography and tertiary modeling studies are considered. A thorough understanding of the properties of glycosyltransferases will be a critical step in any future biotechnological application of these enzymes in areas such as crop improvement and custom design of enzymes to produce desired compounds for nutritional and/or medicinal usage.

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“…Glycosyltransferases represent a very large family of enzymes that determine the biosynthesis of glycans by group-transfer reaction. In this reaction, the monosaccharide moiety of a simple nucleotide sugar donor substrate, such as UDP-Gal (Uridine diphosphate galactose), GDP-Fuc (Guanosine 5’-diphospho-fucose), or CMP-Sia (Cytidine 5’-monophospho-N-acetylneuraminic acid), is transferred to the acceptor substrate that includes oligosaccharides, monosaccharides, polypeptides, lipids, small organic molecules, and even DNA [59]. These enzymes, not only act in intracellular medium, but they also contribute to the glycosylation of cell surface receptors and extracellular matrix components, modulating signaling pathways and tumor behavior [60, 61].…”

Section: Hypoxia Regulates Glycosyltransferases Glycosidases and Nucmentioning

confidence: 99%

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

Silva-filho¹,

Sena²,

Lima

et al. 2017

Cell Physiol Biochem

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Post-translational and co-translational enzymatic addition of glycans (glycosylation) to proteins, lipids, and other carbohydrates, is a powerful regulator of the molecular machinery involved in cell cycle, adhesion, invasion, and signal transduction, and is usually seen in both in vivo and in vitro cancer models. Glycosyltransferases can alter the glycosylation pattern of normal cells, subsequently leading to the establishment and progression of several diseases, including cancer. Furthermore, a growing amount of research has shown that different oxygen tensions, mainly hypoxia, leads to a markedly altered glycosylation, resulting in altered glycan-receptor interactions. Alteration of intracellular glucose metabolism, from aerobic cellular respiration to anaerobic glycolysis, inhibition of integrin 3α1β translocation to the plasma membrane, decreased 1,2-fucosylation of cell-surface glycans, and galectin overexpression are some consequences of the hypoxic tumor microenvironment. Additionally, increased expression of gangliosides carrying N-glycolyl sialic acid can also be significantly affected by hypoxia. For all these reasons, it is possible to realize that hypoxia strongly alters glycobiologic events within tumors, leading to changes in their behavior. This review aims to analyze the complexity and importance of glycoconjugates and their molecular interaction network in the hypoxic context of many solid tumors.

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Glycosyltransferases: mechanisms and applications in natural product development

Cited by 206 publications

References 293 publications

Two Novel Fungal Phenolic UDP Glycosyltransferases from Absidia coerulea and Rhizopus japonicus

Two Novel Fungal Phenolic UDP Glycosyltransferases from Absidia coerulea and Rhizopus japonicus

Advances in flavonoid glycosyltransferase research: integrating recent findings with long-term citrus studies

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

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