1pjz
From Proteopedia
OCA (Talk | contribs)
(New page: 200px<br /><applet load="1pjz" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pjz" /> '''Solution structure of thiopurine methyltrans...)
Next diff →
Revision as of 21:45, 20 November 2007
|
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
Page seeded by OCA on Tue Nov 20 23:52:39 2007
