Mammalian UDP-glucuronosyltransferases (UGTs) catalyze the transfer of glucuronic acid from UDP-glucuronic acid to various xenobiotics and endobiotics. Since UGTs comprise rate-limiting enzymes for metabolism of various compounds, co-administration of UGT-inhibiting drugs and genetic deficiency of genes can cause an increased blood concentration of these compounds. During the last few decades, extensive efforts have been made to advance the understanding of gene structure, function, substrate specificity, and inhibition/induction properties of UGTs. However, molecular mechanisms and physiological importance of the oligomerization and protein-protein interactions of UGTs are still largely unknown. While three-dimensional structures of human UGTs can be useful to reveal the details of oligomerization and protein-protein interactions of UGTs, little is known about the protein structures of human UGTs due to the difficulty in solving crystal structures of membrane-bound proteins. Meanwhile, soluble forms of plant and bacterial UGTs as well as a partial domain of human UGT2B7 have been crystallized and enabled us to predict three-dimensional structures of human UGTs using a homology-modeling technique. The homology-modeled structures of human UGTs do not only provide the detailed information about substrate binding or substrate specificity in human UGTs, but also contribute with unique knowledge on oligomerization and protein-protein interactions of UGTs. Furthermore, various approaches indicate that UGT-mediated glucuronidation is involved in cell death, apoptosis, and oxidative stress as well. In the present review article, recent understandings of UGT protein structures as well as physiological importance of the oligomerization and protein-protein interactions of human UGTs are discussed.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075577 | PMC |
http://dx.doi.org/10.3389/fphar.2016.00388 | DOI Listing |
Int J Mol Sci
December 2024
State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China.
Mycophenolic acid (MPA) is a commonly used immunosuppressant. In the human body, MPA is metabolized into mycophenolic acid 7-O-glucuronide (MPAG) and mycophenolic acid acyl-glucuronide (AcMPAG) mainly through liver glucuronidation, which involves UDP-glucuronosyltransferase (UGTs) and transfer proteins. Research has indicated that the pharmaceutical excipient PEG400 can impact drug processes in the body, potentially affecting the pharmacokinetics of MPA.
View Article and Find Full Text PDFPharmaceutics
December 2024
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
SPT-07A, a D-borneol, is currently being developed in China for the treatment of ischemic stroke. We aimed to create a whole-body physiologically-based pharmacokinetic (PBPK) model to predict the pharmacokinetics of SPT-07A in rats, dogs, and humans. The in vitro metabolism of SPT-07A was studied using hepatic, renal, and intestinal microsomes.
View Article and Find Full Text PDFBiomedicines
November 2024
Rowan-Virtua School of Translational Biomedical Engineering and Sciences and School of Osteopathic Medicine, 2 Medical Center Drive, Stratford, NJ 08084, USA.
Background: Autism spectrum disorders (ASDs), attention-deficit disorder (ADHD), Parkinson's disease (PD), polycystic ovary disease (PCOS), and Alzheimer's disease (AD) have all been linked to exposure to bisphenol A (BPA).
Methods: This paper is a review and discussion of the published literature.
Results: Animal studies have shown BPA to be a broad-spectrum endocrine disruptor.
Clin Transl Sci
January 2025
Department of Chemistry, York College, City University of New York, New York, USA.
The two most extensively studied cannabinoids, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), are used for myriad conditions. THC is predominantly eliminated via the cytochromes P450 (CYPs), whereas CBD is eliminated through both CYPs and UDP-glucuronosyltransferases (UGTs). The fractional contributions of these enzymes to cannabinoid metabolism have shown conflicting results among studies.
View Article and Find Full Text PDFBasic Clin Pharmacol Toxicol
January 2025
Collaborative Innovation Center of Targeted Development of Medicinal Resources (iCTM) & Research Center of Aquatic Organism Conservation and Water Ecosystem Restoration, Anqing Normal University, Anqing, China.
UDP-glucuronosyltransferases (UGTs) are responsible for inactivation of a variety of drugs, endogenous hormones and environmental toxicants. Chemical inhibitors are a common factor decreasing UGT activities and furtherly inducing health problems. Although simultaneously encountering different inhibitors is readily to occur, no information is available for combined inhibition of UGT.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!