TY - JOUR
T1 - Thiopurine S-methyltransferase pharmacogenetics
T2 - Functional characterization of a novel rapidly degraded variant allozyme
AU - Feng, Qiping
AU - Vannaprasaht, Suda
AU - Peng, Yi
AU - Angsuthum, Susothorn
AU - Avihingsanon, Yingyos
AU - Yee, Vivien C.
AU - Tassaneeyakul, Wichittra
AU - Weinshilboum, Richard M.
N1 - Funding Information:
Funded in part by National Institutes of Health (NIH) grants R01 GM28157, R01 CA132780, U01 GM61388 (The Pharmacogenetics Research Network) and a PhRMA Foundation “Center of Excellence in Clinical Pharmacology” Award. The TPMT study in renal transplant recipients in Thailand was funded by the National Center for Genetic Engineering and Biotechnology, Thailand.
PY - 2010/4/1
Y1 - 2010/4/1
N2 - 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.
AB - 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.
KW - Autophagy
KW - Pharmacogenetics
KW - Protein degradation
KW - TPMT27
KW - Thiopurine S-methyltransferase
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U2 - 10.1016/j.bcp.2009.11.016
DO - 10.1016/j.bcp.2009.11.016
M3 - Article
C2 - 19945438
AN - SCOPUS:77449149797
SN - 0006-2952
VL - 79
SP - 1053
EP - 1061
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 7
ER -