ArticleJournal of molecular biology2008
Four human thiopurine s-methyltransferase alleles severely affect protein structure and dynamics.
Article in Journal of molecular biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 34 citations in OpenAlex.
- Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia.British journal of clinical pharmacology · 2013Trial
- Structural and Functional Disruption of Thiopurine S‑Methyltransferase by the A80P Variant: A Simulation and Genotyping Study.ACS omega · 2026Article
- Severe myelosuppression and alopecia after thiopurine initiation in a patient with NUDT15 deficiency.British journal of clinical pharmacology · 2025Article
- A bioinformatics approach to the identification of novel deleterious mutations of human TPMT through validated screening and molecular dynamics.Scientific reports · 2022Article
- In Vitro Protein Stability of Two Naturally Occurring ThiopurineACS omega · 2017Article
- One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability.Scientific reports · 2017Article
- Assessment of Thiopurine-based drugs according to Thiopurine S-methyltransferase genotype in patients with Acute Lymphoblastic Leukemia.Iranian journal of pediatric hematology and oncology · 2014Review
- Genetic analysis of thiopurine methyltransferase polymorphism in the Jordanian population.European journal of clinical pharmacology · 2010Article
- Polymorphisms and disease: hotspots of inactivation in methyltransferases.Trends in biochemical sciences · 2010Article
- Dynameomics: a comprehensive database of protein dynamics.Structure (London, England : 1993) · 2010Article
- The R46Q, R131Q and R154H polymorphs of human DNA glycosylase/beta-lyase hOgg1 severely distort the active site and DNA recognition site but do not cause unfolding.Journal of the American Chemical Society · 2009Article
- Distribution of TPMT risk alleles for thiopurine [correction of thioupurine] toxicity in the Israeli population.European journal of clinical pharmacology · 2009Article
- Clinical implication of thiopurine methyltransferase polymorphism in children with acute lymphoblastic leukemia: A preliminary Egyptian study.Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric OncologyArticle
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Thiopurine S-methyltransferase (TPMT) metabolizes cytotoxic thiopurine drugs used in the treatment of leukemia and inflammatory bowel disease. TPMT is a major pharmacogenomic target with 23 alleles identified to date. Several of these alleles cause rapid protein degradation and/or aggregation, making it extremely difficult to study the structural impact of the TPMT polymorphisms experimentally. We, therefore, have performed multiple molecular dynamics simulations of the four most common alleles [TPMT*2 (A80P), *3A (A154T/Y240C), *3B (A154T) and *3C (Y240C)] to investigate the molecular mechanism of TPMT inactivation at an atomic level. The A80P polymorphism in TPMT*2 disrupts helix alpha3 bordering the active site, which breaks several salt-bridge interactions and opens up a large cleft in the protein. The A154T polymorphism is located within the co-substrate binding site. The larger threonine alters the packing of substrate-binding residues (P68, L69, Y166), increasing the solvent exposure of the polymorphic site. This packing rearrangement may account for the complete lack of activity in the A154T mutant. The Y240C polymorphism is located in beta-strand 9, distant from the active site. Side-chain contacts between residue 240 and helix alpha8 are lost in TPMT*3C. Residues 154 and 240 in TPMT*3A are connected through a hydrogen-bonding network. The dual polymorphisms result in a flattened, slightly distorted protein structure and an increase in the thiopurine-binding site solvent accessibility. The two variants that undergo the most rapid degradation in vivo, TPMT*2 and *3A, are also the most deformed in the simulations.
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