Unusual Glucuronides

Abstract

ABSTRACT:Glucuronidation reaction is catalyzed by mammalian uridine diphosphoglucuronosyl transferases by using uridine diphosphoglucuronic acid as a cosubstrate. Conjugation of glucuronic acid to nucleophilic functional groups in chemical entities results in formation of glucuronides. As anticipated, a number of nucleophilic functional groups such as hydroxyl, phenolic, acyl, primary secondary and tertiary amino, etc. in a diverse set of chemical compounds are known to form the corresponding glucuronides. Glucuronides have been reported to be formed at carbon atoms, selenium atoms, and upon N-carbamoylation of primary and secondary amino groups. Glucuronides are also believed to be the end products of metabolism. However, there are examples where glucuronidation results in further oxidative or conjugative biotransformation reactions. The objective of this review is to highlight unusual glucuronide conjugates. Diglucuronide conjugates reported in the literature fall under two distinct categories. Use of prefixes such as "bis" versus "di" has been previously proposed for separating the two types of diglucuronides. In spite of this, literature reports for diconjugative glucuronide metabolites reflect interchangeable use of "bisglucuronides" and "diglucuronides." Furthermore, the application of such prefixes does not adhere to recommendations of International Union of Pure and Applied Chemistry nomenclature for substituent groups. Therefore, an effort is made in this review to document the historic reports for diglucuronides into two distinct types for sake of clarity and to allow differentiation between the two types of diconjugative metabolites. Overall, this commentary centers on unusual glucuronide metabolites that result from conjugation at uncommon functional groups, glucuronides undergoing ensuing oxidative or conjugative metabolic transformations. Structural and mechanistic aspects are also discussed.

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

“…M7, a dihydroxylated metabolite of LB, was further metabolized to form two glucuronide conjugates, M3 and M6. It is possible that M3 and M6 may have resulted from oxidation of glucuronide metabolites M2 and M5, a pathway documented for certain glucuronides (Argikar, 2012), but whether this pathway exists cannot be ascertained in the present investigation.…”

Dog UDP-Glucuronosyltransferase Enzymes of Subfamily 1A: Cloning, Expression, and Activity

“…8). This suggests that to generate such linked diglucuronides, the 29-hydroxyl of the first bound glucuronic acid should bind close to the "catalytic His" of the enzyme because this is the hydroxyl group previously found to be conjugated in such diglucuronides by the second glucuronic acid moiety (Murai et al, 2005;Argikar, 2012). The new finding-that the dUGT1A8 (or dUGT1A10) could bind either E 2 -3-glucuronide or E 2 -17-glucuronide in a "productive" way-gives rise to linked diglucuronides and may help future modeling of its binding site with bound E 2 -glucuronide in either orientation.…”

“…For further examination of this glucuronide, which turned out to be estrogen diglucuronides (or linked glucuronides; Argikar, 2012), dUGT1A8 and dUGT1A10 were also incubated with either of the two E 2 -monoglucuronides, namely, E 2 -3-glucuronide or …”

“…It was previously shown by Murai et al (2005) that, under suitable assay conditions, dog liver microsomes could produce diglucuronides of several steroids. The detailed description presented in their study used MS for determining whether the product is a diglucuronide (linked diglucuronide, according to the terminology of Argikar, 2012) or a bis-glucuronide. Our LC-MS/MS analysis yielded the value previously assigned for two glucuronic acid moieties linked to each other, indicating that the first eluting peak was a linked diglucuronide.…”

Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance

“…Unusual glucuronides, i.e. glucuronides which are S-linked, C-linked, Se-linked, carbamoyl linked, and di-glucuronides, classified as ‘linked’ and ‘discrete’ are seldom observed (83). Application of softer ionization techniques coupled with high resolution accurate mass spectrometry that yields robust fragmentation has made it easier to elucidate putative structures of glucuronide conjugates (84).…”