1pjz
From Proteopedia
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'''Solution structure of thiopurine methyltransferase from Pseudomonas syringae''' | '''Solution structure of thiopurine methyltransferase from Pseudomonas syringae''' | ||
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[[Category: Lolis, E.]] | [[Category: Lolis, E.]] | ||
[[Category: Scheuermann, T H.]] | [[Category: Scheuermann, T H.]] | ||
| - | [[Category: | + | [[Category: Drug metabolism]] |
| - | [[Category: | + | [[Category: Methyltransferase]] |
| - | [[Category: | + | [[Category: Polymorphism]] |
| - | [[Category: | + | [[Category: S-adenosylmethionine]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 05:10:20 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 02:10, 3 May 2008
Solution structure of thiopurine methyltransferase from Pseudomonas syringae
Overview
In humans, the enzyme thiopurine methyltransferase (TPMT) metabolizes 6-thiopurine (6-TP) medications, including 6-thioguanine, 6-mercaptopurine and azathioprine, commonly used for immune suppression and for the treatment of hematopoietic malignancies. S-Methylation by TPMT prevents the intracellular conversion of these drugs into active 6-thioguanine nucleotides (6-TGNs). Genetic polymorphisms in the TPMT protein sequence have been associated with decreased tissue enzymatic activities and an increased risk of life-threatening myelo-suppression from standard doses of 6-TP medications. Biochemical studies have demonstrated that TPMT deficiency is primarily associated with increased degradation of the polymorphic proteins through an ubiquitylation and proteasomal-dependent pathway. We have now determined the tertiary structure of the bacterial orthologue of TPMT from Pseudomonas syringae using NMR spectroscopy. Bacterial TPMT similarly catalyzes the S-adenosylmethionine (SAM)-dependent transmethylation of 6-TPs and shares 45% similarity (33% identity) with the human enzyme. Initial studies revealed an unstructured N terminus, which was removed for structural studies and subsequently determined to be required for enzymatic activity. Despite lacking sequence similarity to any protein of known three-dimensional structure, the tertiary structure of bacterial TPMT reveals a classical SAM-dependent methyltransferase topology, consisting of a seven-stranded beta-sheet flanked by alpha-helices on both sides. However, some deviations from the consensus topology, along with multiple insertions of structural elements, are evident. A review of the many experimentally determined tertiary structures of SAM-dependent methyltransferases demonstrates that such structural deviations from the consensus topology are common and often functionally important.
About this Structure
1PJZ is a Single protein structure of sequence from Pseudomonas syringae pv. pisi. Full crystallographic information is available from OCA.
Reference
Tertiary structure of thiopurine methyltransferase from Pseudomonas syringae, a bacterial orthologue of a polymorphic, drug-metabolizing enzyme., Scheuermann TH, Lolis E, Hodsdon ME, J Mol Biol. 2003 Oct 24;333(3):573-85. PMID:14556746 Page seeded by OCA on Sat May 3 05:10:20 2008
