Human Thiopurine Methyltransferase

The methylation of a variety of biologically active molecules is a common theme in biology.
The functional roles of methylation are wide ranging and include biosynthesis, metabolism, detoxification,
signal transduction, protein sorting and repairing, nucleic acid processing, gene silencing and imprinting.
The majority of methylation reactions are carried out by the S-adenosylmethionine (SAM)-dependent methyltransferases.

We have solved the crystal structure of human thiopurine S-methyltransferase (TPMT)
in complex with S-adenosyl-L-homocysteine (SAH) at 1.55 Ã… resolution.
TPMT is a cytosolic drug-metabolizing enzyme that catalyzes the S-methylation of thiopurine drugs
such as 6-mercaptopurine, azathioprine, 6-thioguanine, even though the endogenous function of TPMT is not clear yet.
Thiopurine drugs can be converted into 6-thioguanine nucleotides (6-TGNs) by certain metabolic machinery.
The anti-tumor and immunosuppressive activities of thiopurine drugs
are via the incorporation of 6-TGNs into DNA to trigger programmed cell death.
S-methylation of these drugs by TPMT diverts these compounds from their route of efficacy
by formation of inactive metabolites.

TPMT activity exhibits genetic polymorphism: approximately 90% of individuals inherit high activity,
10% inherit intermediate activity because of heterozygosity, and 0.3% has low or no detectable activity
because they inherit 2 nonfunctional TPMT alleles.
TPMT-deficient patients are at risk for severe hematologic toxicities when treated with thiopurine drugs.
TPMT belongs to the subfamily of small molecule SAM-dependent methyltransferase.
However, this enzyme does not share any recognizable sequence similarity
to other SAM-dependent methyltransferases.
It also lacks any of the known SAM-binding consensus motifs.
Our crystal structure of TPMT provides detailed information of SAM-binding site in this enzyme.
It will also help to understand catalytic mechanism of S-methylation.