Glucuronidation is a major metabolic pathway for the inactivation and detoxification of endogenous and exogenous compounds in the human body. Glucuronides are formed by a super family of uridine diphosphoglucuronosyl transverses (UGTs) that convert a number of lipophilic xenobiotics (drugs, steroids, pollutants and pesticides) into more hydrophilic species by linking them to a polar sugar, which are then more readily eliminated from the body. UGTs have been shown to be active toward compounds with a wide variety of chemical structures, such as amines, hydroxylated compounds, and carboxylic acids. Therefore, phase II metabolism (conjugation) is often independent of phase I (functionalization) metabolic pathways, as the vast majority of foreign chemicals (drugs, steroids, pesticides and pollutants) already contain functional groups. This has led to an increasing interest in these metabolites for analytical, pharmacological, and toxicological investigations. Glucuronosyl derivatives of xenobiotic compounds are useful as standards in the analysis of urine or blood samples for illegal drugs, or exposure to biocides. They are also important in studies of the metabolism of new drugs, as metabolites might be more toxic or cause undesirable side effects. More recently, glucuronyl derivatives of pharmacologically active compounds have been investigated as potential prodrugs. As a result, efficient and economical methods for glucuronide production have been sought. While chemical methods are available, they are often unsuitable for a variety of reasons. Consequently, the use of enzymic methods remains to be the desired technique. However, a major limitation for the use of enzymes in the preparative synthesis of glucuronides is the high cost of the co-factor, UDP-glucuronic acid, UDPGA. In phase 1 research, a novel UDGPA regeneration system employing a coupled enzyme system will be developed. This process will enable the UDPGA co-factor to be used in catalytic, rather than stoichiometric amounts, as is the current practice - thus significantly reducing the cost of production.
Thesaurus Terms: chemical reaction, cofactor, enzyme mechanism, method development, uridine diphosphate glucuronate catalyst, chemical conjugate, detoxification, glucose dehydrogenase, glucuronide, hexosyltransferase, recombinant protein, sucrose, uridine diphosphate Escherichia coli
