1pjz
From Proteopedia
(New page: 200px<br /><applet load="1pjz" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pjz" /> '''Solution structure of thiopurine methyltrans...) |
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'''Solution structure of thiopurine methyltransferase from Pseudomonas syringae'''<br /> | '''Solution structure of thiopurine methyltransferase from Pseudomonas syringae'''<br /> | ||
==Overview== | ==Overview== | ||
| - | In humans, the enzyme thiopurine methyltransferase (TPMT) metabolizes | + | 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== | ==About this Structure== | ||
| - | 1PJZ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Pseudomonas_syringae_pv._pisi Pseudomonas syringae pv. pisi]. Active as [http://en.wikipedia.org/wiki/Thiopurine_S-methyltransferase Thiopurine S-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.67 2.1.1.67] Full crystallographic information is available from [http:// | + | 1PJZ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Pseudomonas_syringae_pv._pisi Pseudomonas syringae pv. pisi]. Active as [http://en.wikipedia.org/wiki/Thiopurine_S-methyltransferase Thiopurine S-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.67 2.1.1.67] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PJZ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Thiopurine S-methyltransferase]] | [[Category: Thiopurine S-methyltransferase]] | ||
| - | [[Category: Hodsdon, M | + | [[Category: Hodsdon, M E.]] |
[[Category: Lolis, E.]] | [[Category: Lolis, E.]] | ||
| - | [[Category: Scheuermann, T | + | [[Category: Scheuermann, T H.]] |
[[Category: drug metabolism]] | [[Category: drug metabolism]] | ||
[[Category: methyltransferase]] | [[Category: methyltransferase]] | ||
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[[Category: s-adenosylmethionine]] | [[Category: s-adenosylmethionine]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:29:42 2008'' |
Revision as of 12:29, 21 February 2008
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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. Active as Thiopurine S-methyltransferase, with EC number 2.1.1.67 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
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