Pyrimidine Metabolism in Erythrocytes of the Newborn

Tax, W.J.M.; Veerkamp, J.H.; Schretlen, E. D. A. M.

doi:10.1159/000241162

Cited by 8 publications

(2 citation statements)

References 12 publications

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“…This will lead not only to an accumulation of orotic acid, but also of that of orotidine, since OMP is a good substrate for pyrimidine 5' nucleotidase [16]. Both orotic acid and orotidine accumulation have been reported after incubation of cells with pyrazofurin [17] or after treatment of mice with pyrazofurin [12,18].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390)

et al. 1987

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The mechanism of action of NSC 368390 (DUP-785, 6-fluoro-2-(2'-fluoro-1, 1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt) was studied using three different approaches. First, we studied growth inhibition by DUP-785 in L1210 leukemia cells and M5 melanoma cells. The concentrations causing 50% growth inhibition after 48 hr of culture were 5.8 and 0.6 microM, respectively. DUP-785 had to be present continuously throughout culture. Growth inhibition by 25 microM DUP-785 could be prevented by addition of 1 mM uridine or orotic acid to cultures of these cell lines; in M5 cells cytidine was also able to prevent growth inhibition. Dihydro-orotic acid (DHO) and carbamyl-aspartate were not able to prevent growth inhibition by DUP-785. Second, we studied accumulation of orotic acid and of orotidine induced by incubation with 1 microM pyrazofurin, an inhibitor of the orotate phosphoribosyl-transferase-orotidine-monophosphate decarboxylase complex. Addition of DUP-785 to the culture medium prevented the orotic acid accumulation. Furthermore, DUP-785 prevented accumulation of H14CO3- into orotic acid of pyrazofurin-treated L1210 cells. Third, we measured the effect of DUP-785 on DHO-dehydrogenase (DHO-DH), since the results indicated that this enzyme was affected by DUP-785. DHO-DH was assayed in isolated rat liver mitochondria. The Km for L-DHO was about 12 microM. DUP-785 appeared to be a potent inhibitor of DHO-DH with an apparent Ki of about 0.1 microM and an apparent Ki' of about 0.8 microM. The mode of inhibition appeared to be linear mixed type. After exposure of L1210 cells to 25 microM DUP-785 for 2 hr DHO-DH was almost completely inhibited. After suspension in fresh medium without drug, DHO-DH activity was recovered to about 60% after 24 hr. In conclusion, DUP-785 is a potent inhibitor of pyrimidine de novo biosynthesis, by inhibition of the mitochondrial enzyme DHO-DH.

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Section: Discussionmentioning

confidence: 99%

Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390)

et al. 1987

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“…It was previously believed that in mammalian cells a single nonspecific 5'-Nase reacts with all nucleoside 5'-monophosphates until a separate 5'-Nase specific for pyrimidines (1,2) was found. It has been suggested that the pyrimidine 5'-Nase acts on both orotidine 5'-monophosphate (OMP) and UMP (3,4).…”

mentioning

confidence: 99%

Isolation and partial characterization of a 5'-nucleotidase specific for orotidine-5'-monophosphate.

Kouni¹,

Cha²

1982

Proc. Natl. Acad. Sci. U.S.A.

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A previously unknown 5'nucleotidase (5'-ribonucleotide phosphohydrolase, EC 3.1.3.5) (5'-Nase) specific for orotidine 5'-monophosphate (OMP) hs been discovered. This enzyme orotidine 5'-monophosphate phosphohydrolase (OMPase), was isolated from mouse liver microsomes as a separate entity from the nonspecific 5'-Nase. OMPase was partially purified and is shown to cleave OMP to orotidine and inorganic phosphate. The enzyme has negligible activity towards UMP, CMP, dTMP, AMP, IMP, GMP, XMP, 6-azauridine 5'-monophosphate, 1-beta-D-ribofuranosylbarbituric acid 5'-monophosphate (BMF), 2'-UMP, 3'-UMP, 2'-AMP, 3'-AMP, ribose 5-phosphate and beta-glycerophosphate, all of which--with the exception of the 2' or 3' monophosphates, ribose 5'-phosphate, and beta-glycerophosphate--are substrates for 5'-Nase. Both enzymes are inhibited by NaF, but only OMPase is inhibited by SF reagents. OMPase is not inhibited by orotidine, orotate, BMP, concanavalin A, or tetramisole (an alkaline phosphatase inhibitor). OMPase had a Mr 53,000, Km value of 1 mM for OMP, and Vmax value of 49 nmol/min . mg of protein at the present stage of purification. OMPase activity has also been detected in various mammalian tissues including normal human tissues, human tumor xenografts, lymphocytes, and rat liver. OMPase may be responsible, in part, for the low levels of intracellular "free" OMP and for orotidine accumulation in cells treated with 6-azauridine and patients suffering from aortic aciduria.

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Significance of the enzyme complex that synthesizes UMP in ehrlich ascites cells

Traut

1980

Archives of Biochemistry and Biophysics

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Pyrimidine Metabolism in Erythrocytes of the Newborn

Cited by 8 publications

References 12 publications

Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390)

Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390)

Isolation and partial characterization of a 5'-nucleotidase specific for orotidine-5'-monophosphate.

Significance of the enzyme complex that synthesizes UMP in ehrlich ascites cells

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