Probing UDP-glucuronosyltransferase protein-protein interactions: The power of two.

药物和其他化学品(如饮食成分、环境污染物和人体内自然产生的化学物质(如类固醇激素)被称为酶的特殊蛋白质分解。这一过程被称为生物转化，或“新陈代谢”。药物和化学代谢是一种解毒机制(因为代谢产物通常没有生物活性)，也是将这些物质从体内消除的一种手段。UDP-葡萄糖醛酸基转移酶(UGT)是参与药物代谢和化学代谢的重要酶之一。与其代谢如此大量化合物的能力一致，UGT被认为是作为结构相关蛋白质的‘超家族’而存在的。尽管UGT很重要，但人们对这些负责识别和结合不同类别化学品的酶的结构特征知之甚少。来自该实验室和其他实验室的越来越多的证据表明，单个UGT蛋白可能会与自身结合(形成同源二聚体)，并与其他UGT蛋白结合(形成异二聚体)。该项目主要寻求定义UGT同源和异源二聚化的范围，识别负责结合的蛋白质的结构元素，并表征二聚化的功能意义。该项目将进一步探索UGT和其他蛋白质之间的联系，即白蛋白。UGT二聚体的特征以及与其他蛋白质的联系是我们理解这种酶如何发挥作用和选择特定化学物质进行新陈代谢的基础。这项工作对体外(或“试管”)预测药物如何在人体内代谢的方法的开发和解释也有重要的意义。这类测试被广泛应用于研究和制药公司的实验室，用来预测人体在给药前如何“处理”新药。

Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransferase (UGT) is one of the most important enzymes involved in drug and chemical metabolism. Consistent with its ability to metabolise such a large number of compounds, UGT is known to exist as a 'superfamily' of structurally related proteins. Despite the importance of UGT, little is known about the structural characteristics of these enzymes that are responsible for recognising and binding different classes of chemicals. Accumulating evidence from this and other laboratories indicates that the individual UGT proteins may combine with themselves (to form a homodimer) and with other UGT proteins (to form heterodimers). This project largely seeks to define the scope of UGT homo- and hetero- dimerisation, identify the structural elements of the proteins responsible for association and characterise the functional significance of dimerisation. The project will further explore associations between UGTs and other proteins, namely albumin. Characterisation of UGT dimerisation and associations with other proteins is fundamental to our understanding of how this enzyme functions and selects particular chemicals for metabolism. The work also has important implications for the devlopment and interpretation of in vitro (or 'test-tube') approaches for predicting how drugs are metabolised in humans. Such tests are widely employed in research and pharmaceutical company laboratories to predict how the body 'handles' new drugs prior to their administration to humans.