Understanding Glucuronidation: A Systems Biology Approach
Consortium leader: Professor ADRIAN GOLDMAN,
Institute of Biotechnology, University of Helsinki
Other leaders of the consortium:
Moshe Finel, Department of Pharmacy, University of Helsinki
Mauno Vihinen , professor, Institute of Medical Technology, University of Tampere
Doctoral students of the consortium:
Anne-Sisko Patana
Mika Kurkela
Other researchers of the consortium: -
Key words: drug discovery, x-ray crystallography, bioinformatics, data mining, UGT, UDP
Project desciption and main results:
We propose to study the family of UDP-glucuronosyltransferases (UGTs), which comprise one part of the triad of the body's "non-self" defense mechanisms (the other two being acquired and natural immunity). Our environment contains an ever-increasing variety of exogenous harmful organic molecules (xenobiotics) that enter the body in the air we breathe, the food and drinks we consume, and, indeed as medicines. The defence systems in our bodies against such xenobiotics must be able to bind and neutralize such molecules without prior exposure, and therefore without the ability to evolve high affinity towards them. Our body also has to excrete endobiotics such as bilirubin, bile salts and steroid hormones, all of which are difficult to dispose of due to their high hydrophobicity. Glucuronidation of small lipophilic molecules, either directly or after transformation by one of the cytochrome P450 enzymes, is the main mechanism by which both these important tasks are executed.
The human genome contains 16 expressed UGTs that are divided into two main subfamilies, UGT1A and UGT2B. The UGTs are somewhat promiscuous with respect to their small organic substrates and vice versa. Each UGT isoform can glucuronidate several different compounds, and the same compound can be glucuronidated by several UGTs. This is therefore a complex and important system to study: defects in UGTs lead to disease and differences in UGTs between individuals explain differences in drug metabolism - differences that can sometimes be fatal.
Our proposed research has three components. First, we will use data mining and bioinformatics to link up all the known sequence, species and small-organic molecule (pharmacophore) information on all UGTs. We expect this to generate hypotheses about what differences in sequence are responsible for differences in UGT activity. Second, we will use systematic molecular biology and expression of all human and rat UGTs to be able to perform direct studies of UGT binding and activity. We will also interchange residues and regions between different UGTs to test the bioinformatics ideas. Third, we will solve as many UGTs as we can in a "structural genomics" approach so as to fully understand the structures. These data will feed back into the bioinformatics and molecular biology approaches. All of the data will be available on the web and will, in time, make it possible to tailor drugs to individuals.
Publications: