CommentaryThe UDP-glycosyltransferase (UGT) superfamily expressed in humans, insects and plants: Animalplant arms-race and co-evolution
Graphical abstract
Introduction
UGT-catalyzed conjugation of small lipophilic compounds with sugars is an important detoxification and homeostatic function in all living organisms. The UGT superfamily is defined by a common protein structure and signature sequence of 44 amino acids responsible for binding the UDP moiety of the sugar donor [1], [2]. The UGT family belongs to group 1 of a larger family of glycosyltransferases that have a similar protein structure (GT-B Rossmann-fold) [3], [4]. Notably, UGT is used here as the abbreviation of UDP-glycosyltransferase to include all sugar conjugating enzymes of this superfamily. UGT is commonly defined as UDP-glucuronosyltransferase as most articles deal with mammalian UGTs which use mainly UDP-glucuronic acid as sugar donor. The reason for selecting glucuronic acid as the conjugating sugar by vertebrates is unknown. It may be speculated that mammals developed efficient anionic transporters to eliminate glucuronides. Plants store conjugates in vacuoles and can use the more readily available glucose as conjugating sugar.
In addition to human and rodent UGTs, large UGT families have been identified in insects [5], non-insect arthropods such as the spider mite Tetranychus urticae [6] and plants [7]. Mammalian and insect UGTs contain a transmembrane domain since they are bound to endoplasmic reticulum membranes. In contrast, bacterial and plant UGTs lack a transmembrane domain and are present in the cytosol.
The present UGT homepage [http: www.flinders.edu.au/medicine/sites/clinical-pharmacology/ugt-homepage.cfm] consists of a large list of UGT families, subfamilies and hundreds of approved UGTs. Families (UGT1) and subfamilies (UGT1A) are defined at >40% and >60% amino acid sequence identity, respectively. Families 18 have been reserved for mammals, 927 for nematodes, 3150 for insects, 5170 for fungi, 71100 for plants, 101200 for bacteria, 201 for non-insect arthropods. To provide an overview, UGT families in animals and plants, and their functions in animalplant arms race and co-evolution are discussed. Discussion of UGT functions is focused on two well studied phytoalexins, the flavonoid quercetin and glucosinolates. In addition to defense against herbivores, quercetin has also been identified as UV-shielding compound in insects, and both quercetin and glucosinolates are important antioxidative, anti-inflammatory, and anti-atherosclerotic agents in the human diet.
Section snippets
Humans and rodents
Mammals express 4 families of UGTs: nine members of the UGT1 and 10 members of the UGT2 family have been identified in humans that conjugate endo- and xenobiotics with glucuronic acid; UGT3A1 and UGT3A2 are involved in conjugation with N-acetylglucosamine and glucose, respectively [8]; UGT8A1 is involved in conjugation of ceramides and bile acids with galactose [9]. In rodents similar UGT families have been identified. In fact, the structural arrangement of UGT1 genes in the UGT1 locus suggests
Invertebrates
In comparison with humans, selected UGTs and functions of some invertebrate and plant UGTs are listed in Table 1. The list remains incomplete since most UGTs in different species have not been indentified, particularly in nematodes, sea urchin and fungi, or are poorly characterized.
Fungi (UGT51-70)
In Saccharomyces cerevisiae, the model organism of yeasts, UGT51 has been characterized to conjugate sterols such as ergosterol and sitosterol [28]. More work on fungal UGTs is necessary and may be promising.
Plants (UGT71-100)
Plants adapted to life on land. Hundreds of UGT genes have been sequenced in Arabidopsis thaliana and several other plant species. Phylogenetic analysis of all known plant UGTs revealed that UGT families are highly conserved among different plant species. In addition, UGT sequences were found to be clustered on various chromosomes [29]. To understand evolutionary relationships, genome sequences from six plants were compared (the moss Physcomitrella patents, Selaginella moellendorffii, Populus
Bacteria (UGT101-200)
Bacterial UGTs are involved in synthesis of macrolide antibiotics such as oleandomycin and vancomycin, the latter providing selectivity against vancomycin-resistant enterococci [40], [41]. Interestingly, the UGT family-defining signature sequence was identified in studies of zeaxanthin glucosyltransferase from Erwinia herbicola [42]. This enzyme provides zeaxanthin glucosides that make up the vast majority of carotenoids [43].
Animalplant arms-race and co-evolution
Intestinal UGTs became important when herbivores began to live on plants that protected themselves by accumulating toxic phytoalexins. This phenomenon has been termed animalplant warfare [44], [45] or animalplant co-evolution, the latter due to many symbiotic phenomena [8]. Daniel Nebert and Frank Gonzalez stated in their abstract in 1990: drug-metabolizing enzymes, such as those encoded by the cytochrome P450 genes, are noted for their high degree of interspecies and intraspecies
Conclusions
The role of animalplant arms-race and co-evolution, first described in the evolution of CYPs by Daniel Nebert and Frank Gonzalez 25 years ago [44], [66], also plays a major role in evolution of the UGT superfamily. UGTs are major phase II enzymes of a detoxification system evolved in all kingdoms of life. Vertebrates mainly conjugate with glucuronic acid, invertebrates with glucose. The UGT superfamily is defined by a common protein structure and signature sequence of 44 amino acids
Acknowledgement
Valuable help of Dr. Christoph Köhle in preparing the figures is greatly appreciated.
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