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1pjz

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{{STRUCTURE_1pjz| PDB=1pjz | SCENE= }}
{{STRUCTURE_1pjz| PDB=1pjz | SCENE= }}
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'''Solution structure of thiopurine methyltransferase from Pseudomonas syringae'''
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===Solution structure of thiopurine methyltransferase from Pseudomonas syringae===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_14556746}}
==About this Structure==
==About this Structure==
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1PJZ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Pseudomonas_syringae_pv._pisi Pseudomonas syringae pv. pisi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PJZ OCA].
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1PJZ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Pseudomonas_syringae_pv._pisi Pseudomonas syringae pv. pisi]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PJZ OCA].
==Reference==
==Reference==
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[[Category: Polymorphism]]
[[Category: Polymorphism]]
[[Category: S-adenosylmethionine]]
[[Category: S-adenosylmethionine]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 05:10:20 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 15:10:17 2008''

Revision as of 12:10, 29 July 2008

Image:1pjz.png

Template:STRUCTURE 1pjz

Solution structure of thiopurine methyltransferase from Pseudomonas syringae

Template:ABSTRACT PUBMED 14556746

About this Structure

1PJZ is a Single protein structure of sequence from Pseudomonas syringae pv. pisi. Full experimental 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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