The Biogenesis of Orotic Acid in Liver Slices.

Reichard, Peter; Lagerkvist, Ulf; Pesola, Rainer; Virtanen, Artturi I.; Sørensen, Nils Andreas

doi:10.3891/acta.chem.scand.07-1207

Cited by 42 publications

(7 citation statements)

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“…We also determined tissue contents of some intermediates (Table 2). Previous studies showed the occurrence and synthesis of certain intermediates of pyrimidine synthesis in sliced rat liver [33,34] and other tissues [34], Ehrlich ascites cells in vitro [35], sliced mouse spleen [36], and perfused rat liver [7], but did not reveal their exact amounts and turnover.…”

Section: Discussionmentioning

confidence: 99%

Control of de novo Pyrimidine Biosynthesis in Mammalian Tissues. Levels and Turnover of Early Intermediates in Mouse Spleen in vivo

Hisata

Tatibana

1980

Eur J Biochem

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A single subcutaneous administration of sodium [14C] bicarbonate was given to anemic mice previously treated with acetylphenylhydrazine. 14C rapidly appeared in the arterial blood, reached a peak value in less than 3 min, and disappeared with a half‐life of about 7 min. The tracer thus administered offered a quasi pulse‐labeling technique. The radioactive intermediates and end products in the hyperplastic and hematopoietic spleen were separated by repeated chromatography on anion‐exchange resin. A relatively large amount of radioactivity appeared in carbamoylaspartate (peak value at 5 min), while definite but low radioactivity was found in dihydroorotate and orotate plus its derivatives (∑ orotate). The 14C in the uracil 5′‐nucleotide pool (∑UMP) reached a maximum at 30 min and then declined with a half‐life of about 60 min. l‐[ureido‐14C] Citrulline or l‐[guanidino‐14C] arginine induced no significant labeling of uracil nucleotides. Steady‐state levels of carbamoyl phosphate, carbamoylaspartate, ∑ orotate, and ∑UMP were 0.12, 69.0, 5.0, and 513 nmol/g spleen. The above observations were consistent with the notion that production of carbamoyl phosphate limits the pathway, under the conditions used. When mice Were pretreated with 6‐azauridine, a potent inhibitor of orotate conversion to UMP, there was a marked enhancement in the tissue contents of the intermediates, as well as a considerable accumulation of the 14C label, thus demonstrating that intermediates do not readily permeate through cell membranes. Kinetic analysis of the 14C label in carbamoylaspartate, together with reasonable assumptions, gave a value of 0.43 μmol × h−1× g−1 for the flow rate of the pathway. This value was close to the apparent turnover rate of ∑UMP (0.36 μmol × h−1× g−1), calculated from the half‐life of the decline of the radioactivity and the pool size of ∑UMP (0.52 μmol/g).

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Section: Discussionmentioning

confidence: 99%

Control of de novo Pyrimidine Biosynthesis in Mammalian Tissues. Levels and Turnover of Early Intermediates in Mouse Spleen in vivo

Hisata

Tatibana

1980

Eur J Biochem

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“…In Experiment 29, all animals were fasted 24 hours prior to exposure, to eliminate dietary pyrimidines. Experiments with dihydro-orotic acid (Experiment 30), the precursor to orotic acid, (32,18), also revealed an inhibition of the carcinogenic activity of urethane. Ureidosuccinic acid, a metabolic precursor of dihydro-orotic acid (32) on the other hand, had no significant activity at the dose level used (Experiments 31 and 32, Table I).…”

Section: ~~ Any Its ~[ E ~S Mmentioning

confidence: 95%

“…That its action is suggestive of competitive inhibition may prove especially pertinent (Experiments 28 and 29, Charts 6 and 7). Nevertheless, the inhibitory activity of dihydro-orotic acid (Experiment 30) suggests that the point of interference of the carcinogen lies among the precursors of orotic acid since dihydro-orotic acid is its precursor (32,18). The inhibition of the in dtro activity of the carcinogen by ureidosucdnic acid, the precursor to dihydro-orotic acid (32), adds further weight to this view (Experiments 33 and 34).…”

Section: Oo Urethane and Its Mechanism Ol~ Actionmentioning

confidence: 99%

Studies of the Mechanism of Action of Urethane in Initiating Pulmonary Adenomas in Mice

Rogers

1957

The Journal of Experimental Medicine

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Urethane (ethyl carbamate) is a broad spectrum carcinogen which has been demonstrated to produce neoplasms of the lungs (1), liver (2), mesenchyreal tissue (3), and skin (4) in at least two species, the mouse and the rat. Because of the simplicity of its chemical structure it has proved a particularly interesting carcinogen for those studying the mechanism of carcinogenesis by classic chemical means. Studies of the carcinogenicity (5) or mitotic poisoning effects (6) of various esters of carbamic acid chemically related to urethane, the carcinogenicity of alkylated urethanes (7), of potential urethane degradation products (8), and a wide variety of general hypnotics (9) have, however, yielded no information upon the mechanism of action of urethane other than its relation to the specificity of the molecular structure of urethane. Observations on the influence of urethane on enzymatic and other less discrete in vitro systems have not yet been correlated with its carcinogenic or antileukemic action though they have given rise to many interesting speculations (10). Because the general biological importance of nucleic acid to the maintenance of heritable characteristics is generally recognized and, because of the nuclear poisoning effects of urethane (11), much attention has been directed toward the carcinogen's possible influence upon nucleic acid synthesis. Recent experiments have discounted the assumption that urethane has a direct nucleotoxic action in initiating tumors (5,6,12). Evidence perhaps in favor of an influence upon nucleic acids, however, has been reported by Cowen (13). Since the effect of pentosenucleotides on leucocytes is the opposite of that of urethane, he tested the protective effect of these substances upon its carcinogenic action. Fewer pulmonary tumors developed in mice receiving multiple injections of these nucleotides. However, the nucleotides were largely given after urethane injections had been discontinued. In addition, the tested animals suffered severe ill effects, thereby casting considerable doubt upon the validity of the results; for it is well known that the state of the animal influences greatly the overt occurrence and growth of tumors (14).

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“…However the optically active compound L-CA does not crystallize under the conditions described by these authors. Several atDihydroorotase (DHOase, 2 L-5,6-dihydroorotate amitempts at L-CA isolation have been subsequently undohydrolase; EC 3.5.2.3) catalyzes the cyclization of Ndertaken using ion-exchange chromatography (3)(4)(5), carbamyl-L-aspartate (L-CA) into L-5,6-dihydroorotate but gradual cyclization of L-CA into 5-carboxymethyl-(L-DHO), the third reaction in the de novo biosynthesis hydantoin ( Fig. 1) always occurred during isolation as of pyrimidines (Fig.…”

Section: Anion-exchange Column This Hplc Method Which Ismentioning

confidence: 99%

Assay ofEscherichia coliDihydroorotase with Enantiomeric Substrate: Practical Preparation of Carbamyll-Aspartate and High-Performance Liquid Chromatography Analysis of Catalysis Product

Daniel

Kokel

Caminade

et al. 1996

Analytical Biochemistry

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The Biogenesis of Orotic Acid in Liver Slices.

Cited by 42 publications

References 0 publications

Control of de novo Pyrimidine Biosynthesis in Mammalian Tissues. Levels and Turnover of Early Intermediates in Mouse Spleen in vivo

Control of de novo Pyrimidine Biosynthesis in Mammalian Tissues. Levels and Turnover of Early Intermediates in Mouse Spleen in vivo

Studies of the Mechanism of Action of Urethane in Initiating Pulmonary Adenomas in Mice

Assay ofEscherichia coliDihydroorotase with Enantiomeric Substrate: Practical Preparation of Carbamyll-Aspartate and High-Performance Liquid Chromatography Analysis of Catalysis Product

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