Elsevier

Biochemical Pharmacology

Volume 99, 1 January 2016, Pages 11-17
Biochemical Pharmacology

Commentary
The UDP-glycosyltransferase (UGT) superfamily expressed in humans, insects and plants: Animal⿿plant arms-race and co-evolution

https://doi.org/10.1016/j.bcp.2015.10.001Get rights and content

Abstract

UDP-glycosyltransferases (UGTs) are major phase II enzymes of a detoxification system evolved in all kingdoms of life. Lipophilic endobiotics such as hormones and xenobiotics including phytoalexins and drugs are conjugated by vertebrates mainly with glucuronic acid, by invertebrates and plants mainly with glucose. Plant⿿herbivore arms-race has been the major driving force for evolution of large UGT and other enzyme superfamilies. 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. Plants developed toxic phytoalexins stored as glucosides. Upon herbivore attack these conjugates are converted to highly reactive compounds. In turn, animals developed large families of UGTs in their intestine and liver to detoxify these phytoalexins. Interestingly, phytoalexins, exemplified by quercetin glucuronides and glucosinolate-derived isocyanates, are known insect attractant pigments in plants, and antioxidants, anti-inflammatory and chemopreventive compounds of humans. It is to be anticipated that phytochemicals may provide a rich source in beneficial drugs.

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 1⿿8 have been reserved for mammals, 9⿿27 for nematodes, 31⿿50 for insects, 51⿿70 for fungi, 71⿿100 for plants, 101⿿200 for bacteria, 201 for non-insect arthropods. To provide an overview, UGT families in animals and plants, and their functions in animal⿿plant 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].

Animal⿿plant 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 ⿿animal⿿plant warfare⿿ [44], [45] or ⿿animal⿿plant 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 animal⿿plant 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.

References (68)

  • D. Warnecke et al.

    Cloning and functional expression of UGT genes encoding sterol glucosyltransferases from Saccharomyces cerevisiae, Candida albicans, Pichia pastoris, and Dictyostelium discoideum

    J. Biol. Chem.

    (1999)
  • Y. Li et al.

    Phylogenetic analysis of the UDP-glycosyltransferase multigene family of Arabidopsis thaliana

    J. Biol. Chem.

    (2001)
  • D. Bowles et al.

    Glycosyltransferases managers of small molecules

    Curr. Opin. Plant Biol.

    (2005)
  • S. Sawada et al.

    UDP-glucuronic acid: anthocyanin glucuronosyltransferase from red daisy (Bellis perennis) flowers

    J. Biol. Chem.

    (2005)
  • C.M. Ford et al.

    Cloning and characterization of Vitis vinifera UDP-glucose: flavonoid 3-O-glucosyltransferase, a homologue of the enzyme encoded by the maize Bronze-1 locus that may primarily serve to glucosylate anthocyanidins in vivo

    J. Biol. Chem.

    (1998)
  • L.M. Quiros et al.

    Glycosylation of macrolide antibiotics

    J. Biol. Chem.

    (2000)
  • F.J. Gonzalez et al.

    Evolution of the P450 gene superfamily: animal⿿plant ⿿warfare⿿, molecular drive and human genetic differences in drug oxidation

    Trends Genet.

    (1990)
  • K.W. Bock

    Vertebrate UDP-glucuronosyltransferases. Functional and evolutionary aspects

    Biochem. Pharmacol.

    (2003)
  • T. Kobayashi et al.

    Small intestinal UDP-glucuronosyltransferase sheUGT1A07: partial purification and cDNA cloning from sheep small intestine

    Arch. Biochem. Biophys.

    (1999)
  • K. Ishizawa et al.

    Metabolism of quercetin and its protective effect against arteriosclerosis

    J. Pharmacol. Sci.

    (2011)
  • K.W. Bock

    Homeostatic control of xeno- and endobiotics in the drug-metabolizing system

    Biochem. Pharmacol.

    (2014)
  • W. Miao et al.

    Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway

    J. Biol. Chem.

    (2005)
  • P.I. Mackenzie et al.

    The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence

    Pharmacogenetics

    (1997)
  • P.I. Mackenzie et al.

    Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily

    Pharm. Genom.

    (2005)
  • J.A. Campbell et al.

    A classification of nucleotide-diphospho-sugar glycosyltransferases based on amino acid sequence similarities

    Biochem. J.

    (1997)
  • L.L. Lairson et al.

    Glycosyltransferases structures, functions, and mechanisms

    Annu. Rev. Biochem.

    (2008)
  • D. Bowles et al.

    Glycosyltransferases of lipophilic small molecules

    Annu. Rev. Plant Biol.

    (2006)
  • R. Meech et al.

    A novel function for UDP glycosyltransferase 8: galactosidation of bile acids

    Mol. Pharmacol.

    (2015)
  • B. Achour et al.

    Protein expression of various hepatic uridine 5⿲-diphosphate glucuronosyltransferase (UGT) enzymes and their correlations. A meta-analysis

    Biopharm. Drug Dispens.

    (2014)
  • L. Laakkonen et al.

    A molecular model of the human UDP-glucuronosyltransferase 1A1, its membrane orientation, and the interactions between different parts of the enzyme

    Mol. Pharmacol.

    (2010)
  • Y. Wang et al.

    Characterization of the Zebrafish Ugt repertoire reveals a new class of drug-metabolizing UDP-glucuronosyltransferases

    Mol. Pharmacol.

    (2014)
  • K. Hasegawa et al.

    Allyl isothiocyanate that induces GST and UGT expression confers oxidative stress resistance on C. elegans, as demonstrated by Nematode biosensor

    PLoS One

    (2010)
  • S.T. Laing et al.

    Characterization of the xenobiotic response of Caenorhabditis elegans to the anthelmintic drug albendazole and the identification of novel drug glucoside metabolites

    Biochem. J.

    (2010)
  • A. Morello et al.

    UDP-glucosyltransferase activity of housefly microsomal fraction

    Biochem. J.

    (1979)
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