Enzymes of uracil catabolism in normal and neoplastic human tissues.
Enzymes of the pyrimidine base catabolism, dihydrouracil dehydrogenase (EC 1.3.1.2), dihydropyrimidinase (EC 3.5.2.2), and beta-ureidopropionase (EC 3.5.1.6) were compared in the cytosolic extract of several normal and neoplastic human tissues. The activity was measured by following the catabolism of [6-14C]-uracil to dihydrouracil, carbamyl-beta-alanine, and beta-alanine. Substrate inhibition, hysteresis, allosterism, and the lack of dihydropyrimidinase are pointed out as special problems in assaying enzymes of pyrimidine degradation. The activity of dihydrouracil dehydrogenase has been demonstrated in several human extrahepatic tissues and tumors. The enzyme is rate limiting in extrahepatic solid tumors but not in their normal counterparts. Some of these solid tumors contain greater amounts of activity than do their normal equivalents, which encourages the use of inhibitors of this enzyme in conjunction with treatment of these tumors by 5-fluorouracil. Because of the lack of a pattern in dihydrouracil dehydrogenase activity between tumors and normal tissues, the enzyme is not a good marker for tumorigenicity. Dihydropyrimidinase, on the other hand, is highly active in all solid tumors studied but not in their normal counterparts; therefore, we suggest that dihydropyrimidinase can serve as a good marker of tumorigenicity as well as a target for cancer chemotherapy of human solid tumors.
D000581:Amidohydrolases / Q000032:analysis*; D050744:Dihydrouracil Dehydrogenase (NAD+); D005472:Fluorouracil / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009369:Neoplasms / Q000201:enzymology*; D010088:Oxidoreductases / Q000032:analysis* / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D014498:Uracil / Q000031:analogs & derivatives / Q000378:metabolism; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000378:metabolism
C007419:dihydrouracil; D015091:beta-Alanine; C035122:N-carbamoyl-beta-alanine; D014498:Uracil; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050744:Dihydrouracil Dehydrogenase (NAD+); D000581:Amidohydrolases; C021590:beta-ureidopropionase; C020047:dihydropyrimidinase; D005472:Fluorouracil