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Facts About: UDP-Glucuronic Acid and Glucuronosyltransferases in the ER

January 13, 2025

By: Richard D. Cummings

The endoplasmic reticulum (ER) of many types of cells contain members of a family of UDP-glucuronosyltransferases (UGTs).  These enzymes utilize uridine diphosphate glucuronic acid (UDP-GlcA) as a donor and add GlcA to a tremendous variety of aglycone hydrophobic compounds.  These include drugs (xenobiotics) such as acetaminophen and morphine and other opioids, as well as endogenous compounds, such as bilirubin, β-estradiol and testosterone (1-3).  These modifications are part of a process termed detoxification by glucuronidation (4).  This makes the compounds relatively biological inactive and more water soluble, which supports their excretion from cells and eventual excretion from the body.  This glucuronidation is part of phase 2 conjugation, which can also involve enzymes that add sulfate and other moieties to hydrophobic compounds.  This phase 2 conjugation is often preceded by phase 1 conjugation, which typically involves the oxidative metabolism of drugs by a family of cytochrome P450s (CYPs).  Such enzymes add an –OH, –COOH or –NH2  group to hydrophobic compounds, making them substrates for the UGTs (5).  The glucuronylated products move from the ER and the secretory pathway and are released from cells and found in urine, bile, and feces (4).  

At least 22 genes encoding UGTs have been identified, which can be divided into 4 subfamilies (UGT1, UGT2, UGT3 and UGT8) (2,6-8).  Multiple splice forms of these enzymes occur and may also have varying effects on activities of these enzymes.  Many of these UGTs are also functionally regulated post-transcriptionally by miRNAs (8).  The UGTs are single pass membrane proteins in the ER with their catalytic N-terminal domain facing the ER lumen, and their relatively small C-terminal domain residing in the cytoplasm.  [Note:  The topology of the CYPs in the ER membrane is same orientation but their active sites are oppositely located compared to the UGTs.  CYPs are single pass membrane proteins with their C-terminal catalytic domain facing the cytosol and their N-terminal domain residing in the ER lumen.]  There is a unique transporter (SLC35D1) that transports UDP-GlcA from the cytoplasm into the ER for use by the UGTs; SLC35D1 can transport both UDP-GlcA and UDP-GalNAc (9).  All UGTs are β-glucuronosyltransferases and the products have the sequence GlcAβ1-R (where R is a compound with a functional group modifiable by addition of GlcA).  It has been predicted that CYPs and UGTs may associate in the ER membrane to create a ‘metabolosome’, which facilitates rapid phase 1 and 2 conjugations (10).  It is unclear how the products of the CYP, which would be produced in the cytosol, gain access to the catalytic domains of the UGTs, which are in the ER lumen, but protein-associations between CYPs and UGTs and membrane alterations as a result may create a process that enhances movement of CYP products into the ER lumen (11).  

The activities of UGTs are essential to normal homeostasis as alterations in activities of UGTs are associated with several disease processes.  These include hyperbilirubinemia, which in Crigler-Najjar syndrome is caused by mutations in both copies of UGT1A1 (12), and Gilbert’s syndrome, which is also termed a benign hyperbilirubinemia, is less severe and is caused by mutations in one copy of UGT1A1 (13). UGT1A1, which adds glucuronic acid to bilirubin, is primarily expressed in hepatocytes of the liver; these syndromes are both inherited in an autosomal recessive process.  Interestingly, in the field of Congenital Disorders of Glycosylation (CDGs), these syndromes do not typically appear to be included.  There is some speculation that this milder form of Gilbert’s syndrome resulting in hyperbilirubinemia may have some benefits from an evolutionary perspective, as bilirubin is a potent antioxidant (14).  In addition, of importance in cancer biology and susceptibility is the relationship of polymorphisms in the UGT genes and their ability to metabolize drugs (15,16).  Also of great interest is that members of the gut microbiome express multiple β-glucuronidase enzymes that can remove GlcA from the excreted glucuronides, as microbes may utilize GlcA as a carbon source.  Unfortunately, this process results in regeneration of the hydrophobic compounds/drugs, which can lead to their reabsorption and potential detrimental effects (17).

References

  1. Jarrar, Y., and Lee, S. J. (2021) The Functionality of UDP-Glucuronosyltransferase Genetic Variants and their Association with Drug Responses and Human Diseases. J Pers Med 11
  2. Hu, D. G., Hulin, J. U., Nair, P. C., Haines, A. Z., McKinnon, R. A., Mackenzie, P. I., and Meech, R. (2019) The UGTome: The expanding diversity of UDP glycosyltransferases and its impact on small molecule metabolism. Pharmacol Ther 204, 107414
  3. Dutton, G. J. (1978) Developmental aspects of drug conjugation, with special reference to glucuronidation. Annu Rev Pharmacol Toxicol 18, 17-35
  4. Yang, G., Ge, S., Singh, R., Basu, S., Shatzer, K., Zen, M., Liu, J., Tu, Y., Zhang, C., Wei, J., Shi, J., Zhu, L., Liu, Z., Wang, Y., Gao, S., and Hu, M. (2017) Glucuronidation: driving factors and their impact on glucuronide disposition. Drug Metab Rev 49, 105-138
  5. McDonnell, A. M., and Dang, C. H. (2013) Basic review of the cytochrome p450 system. J Adv Pract Oncol 4, 263-268
  6. Rowland, A., Miners, J. O., and Mackenzie, P. I. (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol 45, 1121-1132
  7. Yang, N., Sun, R., Liao, X., Aa, J., and Wang, G. (2017) UDP-glucuronosyltransferases (UGTs) and their related metabolic cross-talk with internal homeostasis: A systematic review of UGT isoforms for precision medicine. Pharmacol Res 121, 169-183
  8. Hu, D. G., Mackenzie, P. I., Hulin, J. A., McKinnon, R. A., and Meech, R. (2022) Regulation of human UDP-glycosyltransferase (UGT) genes by miRNAs. Drug Metab Rev 54, 120-140
  9. Muraoka, M., Kawakita, M., and Ishida, N. (2001) Molecular characterization of human UDP-glucuronic acid/UDP-N-acetylgalactosamine transporter, a novel nucleotide sugar transporter with dual substrate specificity. FEBS Lett 495, 87-93
  10. Fujiwara, R., and Itoh, T. (2014) Extensive protein interactions involving cytochrome P450 3A4: a possible contributor to the formation of a metabolosome. Pharmacol Res Perspect 2, e00053
  11. Ishii, Y., Iwanaga, M., Nishimura, Y., Takeda, S., Ikushiro, S., Nagata, K., Yamazoe, Y., Mackenzie, P. I., and Yamada, H. (2007) Protein-protein interactions between rat hepatic cytochromes P450 (P450s) and UDP-glucuronosyltransferases (UGTs): evidence for the functionally active UGT in P450-UGT complex. Drug Metab Pharmacokinet 22, 367-376
  12. Sambati, V., Laudisio, S., Motta, M., and Esposito, S. (2024) Therapeutic Options for Crigler-Najjar Syndrome: A Scoping Review. Int J Mol Sci 25
  13. Tukey, R. H., and Strassburg, C. P. (2000) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40, 581-616
  14. Vitek, L., and Tiribelli, C. (2023) Gilbert's syndrome revisited. J Hepatol 79, 1049-1055
  15. Shen, M. L., Xiao, A., Yin, S. J., Wang, P., Lin, X. Q., Yu, C. B., and He, G. H. (2019) Associations between UGT2B7 polymorphisms and cancer susceptibility: A meta-analysis. Gene 706, 115-123
  16. Liu, W., Li, J., Zhao, R., Lu, Y., and Huang, P. (2022) The Uridine diphosphate (UDP)-glycosyltransferases (UGTs) superfamily: the role in tumor cell metabolism. Front Oncol 12, 1088458
  17. Pollet, R. M., D'Agostino, E. H., Walton, W. G., Xu, Y., Little, M. S., Biernat, K. A., Pellock, S. J., Patterson, L. M., Creekmore, B. C., Isenberg, H. N., Bahethi, R. R., Bhatt, A. P., Liu, J., Gharaibeh, R. Z., and Redinbo, M. R. (2017) An Atlas of beta-Glucuronidases in the Human Intestinal Microbiome. Structure 25, 967-977 e965
See also: Interesting Facts About Glycans