TY - JOUR
T1 - Purine substrates for human thiopurine methyltransferase
AU - Deininger, Monika
AU - Szumlanski, Carol L.
AU - Otterness, Diane M.
AU - Loon, Jon Van
AU - Ferber, Wolfgang
AU - Weinshilboum, Richard M.
PY - 1994/11/29
Y1 - 1994/11/29
N2 - Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). A genetic polymorphism regulating TPMT activity in human tissue is an important factor responsible for individual differences in the toxicity and therapeutic efficacy of these drugs. Because of the clinical importance of this polymorphism, we studied 18 purine derivatives, including ribonucleosides and ribonucleotides, as potential substrates for purified human kidney TPMT. Sixteen of the compounds studied were substrates for the enzyme, with Km values that varied from 29.1 to 1270 μM and with Vmax values that varied from 75 to 2340 U/mg protein. The thiopurines tested had Km values that were uniformly lower than were those of the corresponding ribonucleosides or ribonucleotides. 6-Selenopurine derivatives had the lowest Km values of the compounds studied. Finally, oxidized purines with an OH in the 8-position were methylated by the enzyme, but 2-OH compounds were potent inhibitors of TPMT.
AB - Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). A genetic polymorphism regulating TPMT activity in human tissue is an important factor responsible for individual differences in the toxicity and therapeutic efficacy of these drugs. Because of the clinical importance of this polymorphism, we studied 18 purine derivatives, including ribonucleosides and ribonucleotides, as potential substrates for purified human kidney TPMT. Sixteen of the compounds studied were substrates for the enzyme, with Km values that varied from 29.1 to 1270 μM and with Vmax values that varied from 75 to 2340 U/mg protein. The thiopurines tested had Km values that were uniformly lower than were those of the corresponding ribonucleosides or ribonucleotides. 6-Selenopurine derivatives had the lowest Km values of the compounds studied. Finally, oxidized purines with an OH in the 8-position were methylated by the enzyme, but 2-OH compounds were potent inhibitors of TPMT.
KW - methylation
KW - pharmacogenetics
KW - thiopurine methyltransferase
KW - thiopurines
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U2 - 10.1016/0006-2952(94)90515-0
DO - 10.1016/0006-2952(94)90515-0
M3 - Article
C2 - 7802704
AN - SCOPUS:0028000052
SN - 0006-2952
VL - 48
SP - 2135
EP - 2138
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 11
ER -