Dataset Information

Role of UDP-Glycosyltransferase (ugt) Genes in Detoxification and Glycosylation of 1-Hydroxyphenazine (1-HP) in Caenorhabditis elegans.

ABSTRACT: Caenorhabditis elegans is a useful model organism to study the xenobiotic detoxification pathways of various natural and synthetic toxins, but the mechanisms of phase II detoxification are understudied. 1-Hydroxyphenazine (1-HP), a toxin produced by the bacterium Pseudomonas aeruginosa, kills C. elegans. We previously showed that C. elegans detoxifies 1-HP by adding one, two, or three glucose molecules in N2 worms. Our current study evaluates the roles that some UDP-glycosyltransferase (ugt) genes play in 1-HP detoxification. We show that ugt-23 and ugt-49 knockout mutants are more sensitive to 1-HP than reference strains N2 or PD1074. Our data also show that ugt-23 knockout mutants produce reduced amounts of the trisaccharide sugars, while the ugt-49 knockout mutants produce reduced amounts of all 1-HP derivatives except for the glucopyranosyl product compared to the reference strains. We characterized the structure of the trisaccharide sugar phenazines made by C. elegans and showed that one of the sugar modifications contains an N-acetylglucosamine (GlcNAc) in place of glucose. This implies broad specificity regarding UGT function and the role of genes other than ogt-1 in adding GlcNAc, at least in small-molecule detoxification.

SUBMITTER: Asif MZ

PROVIDER: S-EPMC11022241 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Role of UDP-Glycosyltransferase (ugt) Genes in Detoxification and Glycosylation of 1-Hydroxyphenazine (1-HP) in Caenorhabditis elegans.

Asif Muhammad Zaka MZ Nocilla Kelsey A KA Ngo Li L Shah Man M Smadi Yosef Y Hafeez Zaki Z Parnes Michael M Manson Allie A Glushka John N JN Leach Franklin E FE Edison Arthur S AS

Chemical research in toxicology 20240315 4

Caenorhabditis elegans is a useful model organism to study the xenobiotic detoxification pathways of various natural and synthetic toxins, but the mechanisms of phase II detoxification are understudied. 1-Hydroxyphenazine (1-HP), a toxin produced by the bacterium Pseudomonas aeruginosa, kills C. elegans. We previously showed that C. elegans detoxifies 1-HP by adding one, two, or three glucose molecules in N2 worms. Our current study evaluates the roles that some UDP-g ...[more]

PMID: 38488606

Similar Datasets

Project description:Simple Summary The human UDP-glycosyltransferase (UGT) superfamily is involved in the metabolism of numerous anticancer drugs and endobiotic signaling molecules with pro/anti-cancer activities. Previous studies have shown abundant expression of UGT genes in many human cancers, indicative of the active intratumoral metabolism of drugs and endobiotics through the UGT conjugation pathway. Mutations of UGT genes in tumors that can affect this pathway have not yet been reported. In the present study, our analysis of somatic mutations in 10,069 tumors from 33 different cancer types identified 3427 somatic mutations in UGT genes, over half of which have been predicted to code for variant UGT proteins with no or reduced activity. As a result, somatic mutations of UGT genes may reduce the capacity of cancer cells to metabolize anticancer drugs and pro/anti-cancer endobiotics, and hence, they are likely to alter therapeutic efficacy and cancer growth, highlighting their potential utility as biomarkers predicting therapeutic efficacy and clinical outcomes. Abstract The human UDP-glycosyltransferase (UGTs) superfamily has a critical role in the metabolism of anticancer drugs and numerous pro/anti-cancer molecules (e.g., steroids, lipids, fatty acids, bile acids and carcinogens). Recent studies have shown wide and abundant expression of UGT genes in human cancers. However, the extent to which UGT genes acquire somatic mutations within tumors remains to be systematically investigated. In the present study, our comprehensive analysis of the somatic mutation profiles of 10,069 tumors from 33 different TCGA cancer types identified 3427 somatic mutations in UGT genes. Overall, nearly 18% (1802/10,069) of the assessed tumors had mutations in UGT genes with huge variations in mutation frequency across different cancer types, ranging from over 25% in five cancers (COAD, LUAD, LUSC, SKCM and UCSC) to less than 5% in eight cancers (LAML, MESO, PCPG, PAAD, PRAD, TGCT, THYM and UVM). All 22 UGT genes showed somatic mutations in tumors, with UGT2B4, UGT3A1 and UGT3A2 showing the largest number of mutations (289, 307 and 255 mutations, respectively). Nearly 65% (2260/3427) of the mutations were missense, frame-shift and nonsense mutations that have been predicted to code for variant UGT proteins. Furthermore, about 10% (362/3427) of the mutations occurred in non-coding regions (5′ UTR, 3′ UTR and splice sites) that may be able to alter the efficiency of translation initiation, miRNA regulation or the splicing of UGT transcripts. In conclusion, our data show widespread somatic mutations of UGT genes in human cancers that may affect the capacity of cancer cells to metabolize anticancer drugs and endobiotics that control pro/anti-cancer signaling pathways. This highlights their potential utility as biomarkers for predicting therapeutic efficacy and clinical outcomes.

Dataset Information

Role of UDP-Glycosyltransferase (ugt) Genes in Detoxification and Glycosylation of 1-Hydroxyphenazine (1-HP) in Caenorhabditis elegans.

Publications

Role of UDP-Glycosyltransferase (<i>ugt</i>) Genes in Detoxification and Glycosylation of 1-Hydroxyphenazine (1-HP) in <i>Caenorhabditis elegans</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets