Structure, function and regulation of human cytosolic sulfotransferases

磺基转移酶家族在药物和外来化学物质的代谢中起着重要的作用。它们还代谢一系列通常存在于体内的化学物质，如荷尔蒙和与大脑功能有关的物质(神经递质)。临床研究的观察表明，磺基转移酶活性的差异可能是某些类型的癌症和神经退行性疾病发病率的原因之一。最近在了解这些酶的分子生物学方面的进展向我们表明，体内存在多种形式的磺基转移酶。在这一领域，我的实验室一直处于克隆和鉴定这些酶的前沿。事实上，我们是第一个克隆主要的人类磺基转移酶(SULT1A3)的实验室，该酶负责脑神经递质的代谢。我们还使用了新技术来确定这种重要酶的形状。在撰写本文时，我的实验室已经确定了总共七种人类磺基转移酶的特征，但与SULT1A3不同的是，我们对其他六种磺基转移酶的功能意义知之甚少。此外，我们对不同组织中是什么调节磺基转移酶的量的知识实际上是不存在的。这个项目的主旨是扩大我们对这些酶的生理功能的研究，并通过使用分子生物学技术来了解是什么控制了它们在不同人体组织中的表达水平。这一认识将为理解磺基转移酶在药物和化学代谢中所起的作用提供基础。这也将有助于我们了解它们在激素和神经递质代谢中的作用，并有助于确定它们是否与癌症和神经退行性疾病等疾病有关。

The sulfotransferase family of enzymes serve an important role in the metabolism of drugs and foreign chemicals. They also metabolise a range of chemicals that are normally present in the body such as hormones and substances that are involved in brain function (neurotransmitters). Observations from clinical studies suggest that differences in sulfotransferases activities may be a causal factor in the incidence of certain types of cancer and neurodegenerative diseases. Recent advances in understanding the molecular biology of these enzymes have shown us that multiple forms of sulfotransferase existed within the body. In this area my laboratory has been at the forefront of the cloning and characterisation of these enzymes. Indeed, we were the first laboratory to clone the major human sulfotransferase (SULT1A3) responsible for the metabolism of brain neurotransmitters. We have also used new technology to determine the shape of this important enzyme. At the time of writing my laboratory has characterised a total seven human sulfotransferases but unlike SULT1A3, our knowledge of the functional significance of the other six sulfotransferase is poorly understood. Further, our knowledge of what regulates the amount of sulfotransferase in different tissues is practically nonexistent. The thrust of this project is to extend our studies on the physiological function of these enzymes and also through the use of molecular biology techniques understand what controls the level of their expression in different human tissues. This knowledge will provide a basis for understanding the role of sulfotransferases play in drug and chemical metabolism. It will also aid our understanding of their role in hormone and neurotransmitter metabolism and help determine whether they are involved in such diseases as cancer and neurodegenerative diseases.