Hide menu

Folding and stability of TPMT

Folding and stability of the pharmacogenetically important enzyme Thiopurine Methyltransferase

Thiopurine methyltransferase (TPMT) is a polymorphic enzyme catalyzing S-methylation of thiopurine drugs. Today at least 23 non-functional TPMT variant alleles are known and approximately 1 out of 300 in a population has an almost undetectable enzyme level of TPMT.

In treatment of diseases such as Acute lymphoblastic Leukemia as well as Inflammatory Bowel disease with drugs such as 6-methylguanine, azathioprine or 6-thioguanine the polymorphism causing severe side effects such as thiopurine toxicity and genotype screening are often the method used before treatment using these drugs.

Even though the medical importance of this enzyme has been known for a long time very little in vitro studies has been made, the structure of the human variant was solved and the structure was published recently (Wu et al, (2007) Proteins 67:198-208).

In a newly initiated project in collaboration with Department of Clinical Pharmacology at University Hospital in Linköping we have now started to make mutants of all these different variants and characterize them biophysically, using a repertoire of various spectroscopic techniques such as enzyme activity measurements, circular dichroism, fluorescence and differential scanning calorimetry.

In parallel we are also screening conditions to crystallize the various variants.

Figure: 3D structures of Thiopurine methyltransferase (TPMT) with cofactor SAH (red) (PDB code: 2bzg)

Responsible for this page: Maria Sunnerhagen
Last updated: 05/27/08