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One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability
Queen Elizabeth Hospital, Peoples R China.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Queen Elizabeth Hospital, Peoples R China.
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 46428Article in journal (Refereed) Published
Abstract [en]

Thiopurine induced toxicity is associated with defects in the thiopurine methyltransferase (TPMT) gene. TPMT is a polymorphic enzyme, with most of the single nucleotide polymorphisms (SNPs) causing an amino acid change, altering the enzymatic activity of the TPMT protein. In this study, we characterize a novel patient allele c.719A amp;gt; C, named TPMT*41, together with the more common variant *3C c.719A amp;gt; G, resulting in an amino acid shift at tyrosine 240 to serine, p.Y240S and cysteine, p.Y240C respectively. We show that the patient heterozygote for c.719A amp;gt; C has intermediate enzymatic activity in red blood cells. Furthermore, in vitro studies, using recombinant protein, show that TPMT p.Y240S is less stable than both TPMTwt and TPMT p.Y240C. The addition of SAM increases the stability and, in agreement with Isothermal Titration Calorimetry (ITC) data, higher molar excess of SAM is needed in order to stabilize TPMT p.Y240C and TPMT p.Y240S compared to TPMTwt. Molecular dynamics simulations show that the loss of interactions is most severe for Y240S, which agrees with the thermal stability of the mutations. In conclusion, our study shows that SAM increases the stability of TPMT and that changing only one amino acid can have a dramatic effect on TPMT stability and activity.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 7, 46428
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-137842DOI: 10.1038/srep46428ISI: 000400451400001PubMedID: 28462921OAI: oai:DiVA.org:liu-137842DiVA: diva2:1105162
Note

Funding Agencies|LiU Cancer Network; Medical Research Council of Southeast Sweden; Lars Hiertas Memory Foundation; Samariten Foundation; Swedish Society of Medicine Linkoping; Ostgotaregionens Cancerfond; Swedish e-Science Research Center

Available from: 2017-06-02 Created: 2017-06-02 Last updated: 2017-06-02

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Helander, SaraZimdahl Kahlin, AnnaWallner, BjörnMårtensson, Lars-GöranLindqvist Appell, Malin
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