UDPGlucuronyltransferases

The UDP-Glucuronyltransferases (UGT, EC 2.4.1.17) superfamily is comprised of the UGT1, UGT2, UGT3, and UGT8 gene families which code for enzymes that attach glycosyl groups to lipophilic substrates.136 Xenobiotic glucuronidation

Figure 2 Structural features of human CES 1. The enzyme exists in a trimer-hexamer equilibrium, and each protein monomer contains three ligand-binding sites.The active site (red) incorporates the catalytic triad of the enzyme and facilitates the docking of structurally distinct substrates; in some cases, substrates dock in more than one orientation simultaneously, as illustrated for the heroin analog naloxone (green and gold).The Z-site (blue) is a surface ligand-binding groove that might be allosteric and controls the trimer-hexamer equilibrium of the enzyme. It is relatively nonspecific, and is shown here with the anticancer drug tamoxifen (yellow) bound. The side-door site (magenta) is a secondary pore to the active site that could facilitate the release of product (as indicated here for a fatty acid (cyan)) or the entrance of substrate. (Reproduced from Redinbo, M.; Potter, P. Drug Disc. Today 2004, 10, 313-325, copyright (2004), with permission from Elsevier.132)

0 Active site: catalytic processing Z-site: control of trimer-hexamer \ Side door: subslrate via serine hydrolase mechanism * equilibrium; allostery? —" and product trafficking

Figure 2 Structural features of human CES 1. The enzyme exists in a trimer-hexamer equilibrium, and each protein monomer contains three ligand-binding sites.The active site (red) incorporates the catalytic triad of the enzyme and facilitates the docking of structurally distinct substrates; in some cases, substrates dock in more than one orientation simultaneously, as illustrated for the heroin analog naloxone (green and gold).The Z-site (blue) is a surface ligand-binding groove that might be allosteric and controls the trimer-hexamer equilibrium of the enzyme. It is relatively nonspecific, and is shown here with the anticancer drug tamoxifen (yellow) bound. The side-door site (magenta) is a secondary pore to the active site that could facilitate the release of product (as indicated here for a fatty acid (cyan)) or the entrance of substrate. (Reproduced from Redinbo, M.; Potter, P. Drug Disc. Today 2004, 10, 313-325, copyright (2004), with permission from Elsevier.132)

is catalyzed by glucuronyltransferase enzymes that specifically utilize the cofactor UDPGA).98 UGTs are ~60kDa, microsomal (and nuclear) enzymes which, in contrast to the P450s, are localized to the luminal side of the endoplasmic reticulum. In addition to drugs and xenobiotics, there also many 'endogenous' glucuronide acceptors, e.g., bile acids and steroids. Regardless, a common endpoint is enhanced polarity of the original aglycone and facilitated renal excretion. In some cases, glucuronide conjugates may themselves be pharmacologically active. For example, morphine forms both 3-OH and 6-OH glucuronides, with the latter exhibiting more activity than parent drug, at least with some classes of opiate receptors. In addition, acyl glucuronides can have intrinsic chemical reactivity and have been associated with immune toxicities that can occur with some nonsteroidal antiinflammatory drugs.99

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