Disease relevance of Uridine diphosphoglucuronic acid

• E. coli K5, which synthesizes UDP-glucuronic acid for production of its endogenous capsular polysaccharide, can make HA if it contains a plasmid encoding the intact 42-kDa protein [1].
• The biosynthesis of glucuronosyl diacylglycerol from UDP-glucuronate and diacylglycerol is catalyzed by an enzyme found in both the 34,800 X g supernatant and particulate preparations from disrupted Pseudomonas diminuta (ATCC 11586) [2].
• The type 3 polysaccharide synthase from Streptococcus pneumoniae catalyzes sugar transfer from UDP-Glc and UDP-glucuronic acid (GlcUA) to a polymer with the repeating disaccharide unit of [3)-beta-d-GlcUA-(1-->4)-beta-d-Glc-(1-->] [3].
• Sequence analysis reveals that the Bacillus subtilis 168 tuaABCDEFGH operon encodes enzymes required for the polymerization of teichuronic acid as well as for the synthesis of one of its precursors, the UDP-glucuronate [4].
• The regulation of glucuronidation during hypoxia was studied in isolated hepatocytes by analysing the dependence of acetaminophen glucuronidation rate on the intracellular concentrations of UTP, glucose 1-phosphate, UDP-glucose and UDP-glucuronic acid [5].

High impact information on Uridine diphosphoglucuronic acid

• The data obtained with increasing UDP-glucuronic acid concentration did not obey conventional single-site kinetics, suggesting the presence of more than one binding site on the enzyme or a membrane transporter for this nucleotide sugar [6].
• A region at the C terminus of the encoded protein is closely related to the UDP-glucuronic acid binding site consensus sequence, and the protein encoded by PsUGT1 catalyzes conjugation of UDP-glucuronic acid to an unknown compound [7].
• We found that sqv-4 encodes a protein similar to UDP-glucose dehydrogenases and showed that the SQV-4 protein specifically catalyzes the conversion of UDP-glucose to UDP-glucuronic acid, which is essential for the biosynthesis of chondroitin and heparan sulfate proteoglycans [8].
• We propose that the regulation of UDP-glucuronic acid production in a specific subset of vulval cells helps determine the shape of the vulva [8].
• Functional cloning and characterization of a UDP- glucuronic acid decarboxylase: the pathogenic fungus Cryptococcus neoformans elucidates UDP-xylose synthesis [9].

Chemical compound and disease context of Uridine diphosphoglucuronic acid

• UDP-GlcNAc (UDP-N-acetylglucosamine) and UDP-GlcA (UDP-glucuronic acid) were oxidized by periodate in the ribose ring and utilized as inhibitors for hyaluronate synthase in membrane fractions from the B6 cell line and in cell cultures of B6 cells and human fibrosarcoma HT 1080 [10].
• The enzyme preparation consisted of EDTA-treated Acetobacter xylinum cells and UDP-glucose, GDP-mannose, UDP-glucuronic acid and TDP-rhamnose were employed as sugar donors [11].
• In the Salmonella/microsome plate or liquid assay, the addition of glutathione (GSH) and uridine 5'-diphosphoglucuronic acid (UDPGA), both cofactors for GSH-S-transferases or UDPGA-transferases, altered the rat-liver microsome-mediated mutagenesis of benzo[a]pyrene (BP) and aflatoxin B1 (AFB) [12].
• The recombinant protein expressed in Escherichia coli catalyzed conversion of UDP-D-glucuronate to UDP-D-xylose, confirming that the isolated clone encoded UDP-D-glucuronate carboxy-lyase [13].
• BHA-feeding (1% for 10 days) increased hepatic UDP-glucuronic acid content by 240% and enhanced hepatic UDP-glucuronosyltransferase activities (expressed per kg body weight) toward valproic acid, phenolphthalein, iopanoic acid and bilirubin 220, 180, 120 and 60%, respectively [14].

Biological context of Uridine diphosphoglucuronic acid

• UDPglucuronosyltransferase [UDPglucuronate beta-D-glucuronosyltransferase (acceptor-unspecific), EC 2.4.1.17] is a group of enzymes with distinct but partially overlapping substrate specificity [15].
• By rescuing the kiwi phenotype with both UDP-glucuronate and the glycosaminoglycan heparan sulfate, we show that kiwi function in the embryo is crucial for the production of heparan sulfate in the extracellular matrix [16].
• These data indicate that the GT2P form of UDP-glucuronyltransferase catalyzes the hydrolysis of UDP-glucuronic acid at a significant rate and that lysophosphatidylcholines can influence this rate [17].
• The oxidative decarboxylation of UDP-glucuronic acid is catalyzed by the 345-residue C-terminal domain of ArnA [18].
• This result was unexpected because epinephrine activated glycogenolysis and elevated hepatic UDP-glucuronic acid contents [19].

Anatomical context of Uridine diphosphoglucuronic acid

• Bilirubin diglucuronide synthesis by a UDP-glucuronic acid-dependent enzyme system in rat liver microsomes [20].
• Diethylnitrosamine, added to microsomes in vitro, enhances the affinity of UDP-glucuronyltransferase for the UDP portion of UDP-glucuronic acid [21].
• (5) Mechanisms were presented for translocation of UDP-glucuronic acid (UDPGA) into the lumenal location of UDPGA transferase in the endoplasmic reticulum, as well as the enhancement of this process by N-acetyl-glucosamine [22].
• In fibroblast homogenates, addition of the UGT cosubstrate UDP-glucuronic acid reduced B(a)P covalent binding, corroborating the cytoprotective importance of UGTs [23].
• UDP-glucuronate carboxy-lyase in cultured chondrocytes [24].

Associations of Uridine diphosphoglucuronic acid with other chemical compounds

• Despite the defective conformation of the UDP-glucuronic acid binding site of UDP-glucuronyltransferase from Gunn rats this enzyme is activated in the normal way by UDP-N-acetylglucosamine, which is a K-type effector with regard to UDP-glucuronic acid [21].
• PmrI (renamed ArnA) was overexpressed using a T7 construct, and shown by itself to catalyze the unprecedented oxidative decarboxylation of UDP-glucuronic acid to form uridine 5'-(beta-l-threo-pentapyranosyl-4"-ulose diphosphate) [25].
• Additional mutations affected the relative specificities for the sugar donors UDP-galactose and UDP-glucuronic acid, although UDP-glucose was always preferred [26].
• Analysis of the UDP-glucuronic acid-binding site by computational modeling in conjunction with site-directed mutagenesis indicated that both residues interact with glucuronic acid [27].
• The absence of immunoinhibition of hyodeoxycholic acid conjugation with UDP sugars other than UDP-glucuronic acid suggests the involvement of different enzymatic systems in the glucosidation and xylosylation of hyodeoxycholic acid [28].

Gene context of Uridine diphosphoglucuronic acid

• Pathological overproduction of extracellular matrix components may be linked to the availability of UDP-glucuronic acid; therefore UGDH is an intriguing therapeutic target [29].
• In contrast, the Michaelis-Menten kinetics for UDPGA observed with UGT2B7 (K(m)(app) 493.2 microM) suggested that kinetic interactions with UGTs were specific to the xenobiotic substrate and the co-substrate (UDPGA) [30].
• SLC35D2 was localized in the Golgi membrane and exhibited around 50% similarity with three nucleotide sugar transporters: human SLC35D1 (UDP-glucuronic acid/UDP-N-acetylgalactosamine transporter), fruitfly fringe connection (frc) transporter, and nematode SQV-7 transporter, the latter two being involved in developmental and organogenetic processes [31].
• Despite the identical primary structure of the C-terminal halves of the UGT1A isoforms, there were marked differences in the respective K(m) values for UDPGA, ranging from 52 microM for UGT1A6 to 1256 microM for UGT1A8 [32].
• The glucuronidation of entacapone by UGT1A9 was inhibited by 1-naphthol in a competitive fashion, with respect to entacapone, and an uncompetitive fashion, with respect to UDP-glucuronic acid (UDPGA) [32].

Analytical, diagnostic and therapeutic context of Uridine diphosphoglucuronic acid

• In vitro enzymatic activity of GlcAT-I was measured by thin-layer chromatography, with radiolabeled UDP-glucuronic acid and a digalactoside derivative as substrates [33].
• DEAE-cellulose chromatography of partially purified preparations of UDP-glucuronate carboxy-lyase from wheat germ results in the separation of two forms of the enzyme [34].
• Gunn rats lack UDP-glucuronate glucuronyltransferase activity (EC 2.4.1.17), have normal bilirubin glucuronoside glucuronosyltransferase activity, cannot form bilirubin monoglucuronide in vitro or in vivo, and do not excrete bilirubin glucuronides after intravenous injection of unconjugated bilirubin [35].
• OleI and OleD intracellular proteins were partially purified by affinity chromatography in an UDP-glucuronic acid agarose column and OleR was detected as a major band from the culture supernatant [36].
• Peptide fingerprinting of the latter polypeptide identified it as a form of UDP-glucuronate decarboxylase and functionality was established by expressing the cognate cDNA in E. coli [37].

References