Characterization of novel human UDP glycosyltransferases

我们对小有机分子毒性作用的防御是由细胞内膜中发现的酶家族介导的，主要是在肝脏和胃肠道中。许多小的有机分子，如环境污染物、致癌物和治疗药物，都是脂溶性的，除非通过添加水溶性基团进行修饰，否则会在体内积累到有毒水平。在大多数情况下，经过修饰的化学物质毒性较小，而且很容易从体内排出。该项目的目的之一是鉴定和表征新发现的酶家族，利用糖残基修饰和消除脂溶性化学物质。它们在解毒过程中的作用以及它们在细胞中的控制方式将被确定。这是这个家族中最后一个待在人类身上鉴定的酶。除了外来化学物质和毒素外，该酶家族还调节细胞内信号分子的浓度，如类固醇激素和与基因调节蛋白结合的化学物质。这些酶的缺陷或变异可能改变这些信号分子的水平，导致不受控制的细胞生长（癌症）或细胞死亡。该项目的第二个目的是确定这些新酶是否参与控制信号浓度，并确定这些酶的遗传变异是否会改变信号传递过程。

Our defense against the toxic effects of small organic molecules is mediated by families of enzymes found in the internal membranes of cells, predominantly in the liver and gastrointestinal tract. Many small organic molecules, such as environmental pollutants, carcinogens and therapeutic drugs, are fat-soluble and will accumulate in the body to toxic levels unless they are modified by the addition of water-soluble groups. The modified chemical, in the majority of cases, is less toxic and readily removed from the body. One aim of this project is to identify and characterize newly discovered enzymes in the family that uses sugar residues to modify and eliminate fat-soluble chemicals. Their involvement in the detoxification process and how they are controlled in the cell will be determined. These are the final enzymes in this family remaining to be characterized in humans. In addition to foreign chemicals and toxins, this enzyme family also regulates the intracellular concentrations of signalling molecules such as steroid hormones and chemicals that bind to gene regulatory proteins. Defects and-or variations in these enzymes may alter the levels of these signalling molecules and lead to uncontrolled cell growth (cancer) or cell death. A second aim of this project is to determine whether these novel enzymes are involved in controlling signal concentrations and to determine whether inherited variations in these enzymes will alter the signalling process.