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3bgd

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{{STRUCTURE_3bgd| PDB=3bgd | SCENE= }}
{{STRUCTURE_3bgd| PDB=3bgd | SCENE= }}
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'''Thiopurine S-Methyltransferase'''
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===Thiopurine S-Methyltransferase===
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==Overview==
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Thiopurine S-methyltransferase (TPMT) modulates the cytotoxic effects of thiopurine prodrugs such as 6-mercaptopurine by methylating them in a reaction using S-adenosyl- l-methionine as the donor. Patients with TPMT variant allozymes exhibit diminished levels of protein and/or enzyme activity and are at risk for thiopurine drug-induced toxicity. We have determined two crystal structures of murine TPMT, as a binary complex with the product S-adenosyl- l-homocysteine and as a ternary complex with S-adenosyl- l-homocysteine and the substrate 6-mercaptopurine, to 1.8 and 2.0 A resolution, respectively. Comparison of the structures reveals that an active site loop becomes ordered upon 6-mercaptopurine binding. The positions of the two ligands are consistent with the expected S N2 reaction mechanism. Arg147 and Arg221, the only polar amino acids near 6-mercaptopurine, are highlighted as possible participants in substrate deprotonation. To probe whether these residues are important for catalysis, point mutants were prepared in the human enzyme. Substitution of Arg152 (Arg147 in murine TPMT) with glutamic acid decreases V max and increases K m for 6-mercaptopurine but not K m for S-adenosyl- l-methionine. Substitution at this position with alanine or histidine and similar substitutions of Arg226 (Arg221 in murine TPMT) result in no effect on enzyme activity. The double mutant Arg152Ala/Arg226Ala exhibits a decreased V max and increased K m for 6-mercaptopurine. These observations suggest that either Arg152 or Arg226 may participate in some fashion in the TPMT reaction, with one residue compensating when the other is altered, and that Arg152 may interact with substrate more directly than Arg226, consistent with observations in the murine TPMT crystal structure.
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{{ABSTRACT_PUBMED_18484748}}
==About this Structure==
==About this Structure==
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[[Category: Methyltransferase]]
[[Category: Methyltransferase]]
[[Category: S-adenosyl-l-methionine]]
[[Category: S-adenosyl-l-methionine]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 10:47:05 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 16:42:24 2008''

Revision as of 13:42, 28 July 2008

Image:3bgd.png

Template:STRUCTURE 3bgd

Thiopurine S-Methyltransferase

Template:ABSTRACT PUBMED 18484748

About this Structure

3BGD is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.

Reference

Structural basis of substrate recognition in thiopurine s-methyltransferase., Peng Y, Feng Q, Wilk D, Adjei AA, Salavaggione OE, Weinshilboum RM, Yee VC, Biochemistry. 2008 Jun 10;47(23):6216-25. Epub 2008 May 17. PMID:18484748

Page seeded by OCA on Mon Jul 28 16:42:24 2008

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