REACTIONS OF RIBONUCLEOTIDE DERIVATIVES OF PURINE ANALOGS AT THE CATALYTIC SITE OF INOSINE 5'PHOSPHATE DEHYDROGENASE
Mechanisms involved in the action of the antileukemic drugs 6- chloropurine, 6-mercaptopurine, and 6-thioguanine are discussed. 6-Chloro-9- BETA -D-ribofuranosylpurine 5'phosphate irreversibly inactivates an inosine 5'- phosphate dehydrogenase. The process is slowed by non-inhibitory concentrations of inosine 5'-phosphate and accelerated by glutathione. The nucleoside was 200 times less effective for inactivation. Biochemical effects of 6-chloropurine in vivocan be ascribed to biosynthesis of its ribonucleoside 5'-phosphate and subsequent inhibitlon of xanthosine 5'-phosphate formation. 6-Thioinosine 5'- phosphate and inosine 5'-phosphate compete as substrates for the dehydrogenase when glutathione is present. When glutathione is absent, 6-thioinosine 5'- phosphate becomes markedly more inhibitory. This inhibition was reversible by glutathione but not by inosine 5'-phosphate. 6-Thioguamosine 5"-phosphate also inhibits much more strongly when glutathione is omitted, but the 5'-phosphates of guanosine and of 9- BETA -D-ribofuranosylpurine do not. 6-Thioinosine and its mixed 2'- and 3'-phosphates were not substrates and were much less potent inhibitors than 6-thioinosine 5'-phosphate. The 6-chloro- and the two 6-thio- nucleotides evidently bind to the reaction site in place of inosine 5'-phosphate and there react with a sulfhydryl group to form stable thioether and disulfide bonds, respectively. They also undergo similar non-enzymatic reactions with mercaptans under analogous conditions. A mechanism is postulated for xanthosine 5'-phosphate formation in whlch activation of inosine 5'-phosphate involves addition of a sulfhydryl group of the enzyme across the 1,6 double bond. (auth)
- Research Organization:
- Sloan-Kettering Inst. for Cancer Research, New York
- DOE Contract Number:
- AT(30-1)-910
- NSA Number:
- NSA-17-015542
- OSTI ID:
- 4755969
- Report Number(s):
- TID-18138
- Resource Relation:
- Other Information: Orig. Receipt Date: 31-DEC-63
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
AMINO ACIDS
BIOCHEMISTRY
DEHYDROGENASES
DRUGS
ENZYMES
ETHERS
GLUTATHION
GUANOSINE
HETEROCYCLICS
HYDROGEN SULFIDES
INOSINE
LEUKEMIA
MEDICINE
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
PHOSPHATES
PURINES
QUANTITY RATIO
RADIOTHERAPY
REACTION KINETICS
SULFIDES
THERAPY
VARIATIONS
XANTHOSINE