liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
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.
Show others and affiliations
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: 2017-06-28

Open Access in DiVA

fulltext(1410 kB)17 downloads
File information
File name FULLTEXT01.pdfFile size 1410 kBChecksum SHA-512
abb988bda52799fd6c867eca9d17fbb05af8390ca5c055543e594d801710d5bd151597aa979f38504fc9fc54e5d6a88c3d6e68d3feaf62d57fa5aae4ba478c57
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Helander, SaraZimdahl Kahlin, AnnaWallner, BjörnMårtensson, Lars-GöranLindqvist Appell, Malin
By organisation
Division of Drug ResearchFaculty of Medicine and Health SciencesBioinformaticsFaculty of Science & EngineeringChemistry
In the same journal
Scientific Reports
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 17 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 133 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf