Thiopurine S-methyltransferase pharmacogenetics: Functional characterization of a novel rapidly degraded variant allozyme

Qiping Feng, Suda Vannaprasaht, Yi Peng, Susothorn Angsuthum, Yingyos Avihingsanon, Vivien C. Yee, Wichittra Tassaneeyakul, Richard M. Weinshilboum

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

A novel human thiopurine S-methyltransferase (TPMT) variant allele, (319 T > G, 107Tyr > Asp, *27), was identified in a Thai renal transplantation recipient with reduced erythrocyte TPMT activity. The TPMT*27 variant allozyme showed a striking decrease in both immunoreactive protein level and enzyme activity after transient expression in amammalian cell line.Weset out to explore themechanism(s) responsible for decreased expression of this novel variant of an important drug-metabolizing enzyme. We observed accelerated degradation of TPMT*27 protein in a rabbit reticulocyte lysate. TPMT*27 degradation was slowed by proteasome inhibition and involved chaperone proteins-similar to observations with regard to the degradation of the common TPMT*3A variant allozyme. TPMT*27 aggresome formation was also observed in transfected mammalian cells after proteasome inhibition. Inhibition of autophagy also decreased TPMT*27 degradation. Finally, structural analysis and molecular dynamics simulation indicated that TPMT*27 was less stable than was the wild type TPMT allozyme. In summary, TPMT*27 serves to illustrate the potential importance of protein degradation - both proteasome and autophagy-mediated degradation - for the pharmacogenetic effects of nonsynonymous SNPs.

Original languageEnglish (US)
Pages (from-to)1053-1061
Number of pages9
JournalBiochemical Pharmacology
Volume79
Issue number7
DOIs
StatePublished - Apr 1 2010

Keywords

  • Autophagy
  • Pharmacogenetics
  • Protein degradation
  • TPMT*27
  • Thiopurine S-methyltransferase

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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