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

Traut, Thomas W.

doi:10.1016/0003-9861(80)90391-4

Cited by 21 publications

(27 citation statements)

References 22 publications

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“…However, for all cases of metabolic resistance, there must be an upper limit beyond which the substrate cannot accumulate. High concentrations of Cbm-P and OMP may be enzymatically degraded in some types of mammalian cells [4,20], limiting the effectiveness of metabolic resistance. Accumulation of H,folate from an initial concentration of 0.03 pM ( in response to methotrexate may be limited, at least in the short term, because the total concentration of the folate pool is only 5.5 pM [23].…”

Section: Theorymentioning

confidence: 99%

Metabolic Resistance: The Protection of Enzymes against Drugs which are Tight‐Binding Inhibitors by the Accumulation of Substrate

Christopherson

Duggleby

1983

European Journal of Biochemistry

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Blockade of a metabolic pathway by interaction of a drug with a particular 'target enzyme' results in depletion of essential end-products of the pathway and accumulation of intermediates prior to the blockade. Metubolic resistance to a particular drug can arise if the substrate of the inhibited enzyme accumulates to levels sufficiently high to compete effectively with the inhibitor, leading to restoration of full activity of the metabolic pathway after a transitory delay.Such resistance has recently been demonstrated in vitro for the interaction of the tight-binding inhibitor N-phosphonacetyl-L-aspartate (PAcAsp) with the aspartate transcarbamoylase activity of the trifunctional protein which initiates pyrimidine biosynthesis in mammals [Christopherson, R. I. and Jones, M. E. (1980) J . Biol. Chem. 255, 11 381 -11 3951. Carbamoyl phosphate, the product of the carbamoyl phosphate synthetase activity of this trifunctional protein, accumulates to a sufficiently high concentration that the inhibitory effect of PAcAsp is effectively abolished. We have developed a theoretical model for metabolic resistance which quantitatively accounts for these experimental data. This model has been used to simulate the interaction between the following potential or proven anti-cancer drugs and their target enzyme, under conditions similar to those which would occur in vivo: PAcAsp with aspartate transcarbamoylase; various OMP analogues [the 5'-monophosphates of 6-azauridine, pyrazofurin and I-(P-D-ribofuranosy1)-barbituric acid] with OMP decarboxylase; 5-fluorodeoxyUMP with thymidylate synthase; methotrexate with dihydrofolate reductase; and deoxycoformycin with adenosine deaminase.

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Section: Theorymentioning

confidence: 99%

Metabolic Resistance: The Protection of Enzymes against Drugs which are Tight‐Binding Inhibitors by the Accumulation of Substrate

Christopherson

Duggleby

1983

European Journal of Biochemistry

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“…A similar situation may exist in Schistosoma mansoni and can explain the lack of “channeling” effect along with inability to separate orotate phosphoribosyltransferase and OMP decarboxylase from one another observed by Iltzsch et al (1984). Regardless of whether or not these enzymes comprise a multienzyme complex in S. mansoni , there does not appear to be a “channeling effect” as seen for mouse liver and other mammalian cells (Traut and Jones, 1977; Reyes, 1977; Traut, 1980). …”

Section: Enzymes Of De Novo Pyrimidine Biosynthesismentioning

confidence: 82%

“…This is due to the fact that in mammalian cells, orotate phosphoribosyltransferase and OMP decarboxylase exist as a multienzyme complex (Jones, 1980). Therefore, OMP is “channeled” directly to OMP decarboxylase to form UMP (Traut and Jones, 1977; Traut, 1980; Reyes, 1977). As a result, no OMP or orotidine are detected in the cell (Janeway and Cha, 1977).…”

Section: Enzymes Of De Novo Pyrimidine Biosynthesismentioning

confidence: 99%

Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets

Kouni

2017

Comparative Biochemistry and Physiology Part B: Biochemistry an

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Schistosomes are responsible for the parasitic disease schistosomiasis, an acute and chronic parasitic ailment that affects more than 240 million people in 70 countries worldwide. It is the second most devastating parasitic disease after malaria. At least 200,000 deaths per year are associated with the disease. In the absence of the availability of vaccines, chemotherapy is the main stay for combating schistosomiasis. The antischistosomal arsenal is currently limited to a single drug, Praziquantel, which is quite effective with a single-day treatment and virtually no host-toxicity. Recently, however, the question of reduced activity of Praziquantel has been raised. Therefore, the search for alternative antischistosomal drugs merits the study of new approaches of chemotherapy. The rational design of a drug is usually based on biochemical and physiological differences between pathogens and host. Pyrimidine metabolism is an excellent target for such studies. Schistosomes, unlike most of the host tissues, require a very active pyrimidine metabolism for the synthesis of DNA and RNA. This is essential for the production of the enormous numbers of eggs deposited daily by the parasite to which the granulomas response precipitate the pathogenesis of schistosomiasis. Furthermore, there are sufficient differences between corresponding enzymes of pyrimidine metabolism from the host and the parasite that can be exploited to design specific inhibitors or “subversive substrates” for the parasitic enzymes. Specificities of pyrimidine transport also diverge significantly between parasites and their mammalian host. This review deals with studies on pyrimidine metabolism in schistosomes and highlights the unique characteristic of this metabolism that could constitute excellent potential targets for the design of safe and effective antischistosomal drugs. In addition, pyrimidine metabolism in schistosomes is compared with that in other parasites where studies on pyrimidine metabolism have been more elaborate, in the hope of providing leads on how to identify likely chemotherapeutic targets which have not been looked at in schistosomes.

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“…Traut (1980) has pointed out recently that an extract from Ehrlich ascites carcinoma, which contains uridylate synthase, also contains a nucleotidase activity that has a measurable activity with OMP as substrate whereas yeast, which has no such activity, has separate decarboxylase and transferase activities. These observations led to the proposal that the mammalian enzyme thus evolved into a complex that could protect OMP from needless degradation by channeling the intermediate efficiently to UMP (Traut, 1980(Traut, , 1982 Christopherson et al, 1981).…”

mentioning

confidence: 99%

Does the bifunctional uridylate synthase channel orotidine 5'-phosphate? Kinetics of orotate phosphoribosyltransferase and orotidylate decarboxylase activities fit a noninteracting sites model

McClard¹,

Shokat²

1987

Biochemistry

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Uridylate synthase is a bifunctional protein that first forms orotidine 5'-phosphate (OMP) from orotate via its orotate phosphoribosyltransferase activity (EC 2.4.2.10) and then converts OMP to uridine 5'-phosphate (UMP) via the OMP decarboxylase activity (EC 4.1.1.23). A computer modeling analysis of the experiments that led to the proposal [Traut, T.W., & Jones, M.E. (1977) J. Biol. Chem. 252, 8374-8381] that uridylate synthase channels intermediate OMP suggests that the experimental results do not demonstrate preferential use of OMP generated in the bifunctional complex as against exogenous OMP. This analysis shows that the experimentally observed amounts of [6-14C]UMP from [6-14C]orotate in the presence of various amounts of exogenous [7-14C]OMP agree well with the amounts predicted by the computer simulations. Thus we conclude that uridylate synthase does not channel OMP. Additionally, the subsequent suggestion that channeling of OMP occurs to protect the intermediate from degradation by a nucleotidase [Traut, T.W. (1980) Arch. Biochem. Biophys. 200, 590-594] seems unlikely. The appropriate computer simulation demonstrates that low transient levels of OMP and protection of the intermediate are provided for strictly by the kinetic parameters of orotate phosphoribosyltransferase, OMP decarboxylase, and the nucleotidase. Additionally, calculations show that, in both sets of published experiments, the concentration of transient OMP greatly exceeded the concentration of OMP decarboxylase active sites. Thus, channeling of OMP by the bifunctional complex cannot be invoked to explain the evolution of uridylate synthase, and that event must be the result of some other selective pressure.

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

Cited by 21 publications

References 22 publications

Metabolic Resistance: The Protection of Enzymes against Drugs which are Tight‐Binding Inhibitors by the Accumulation of Substrate

Metabolic Resistance: The Protection of Enzymes against Drugs which are Tight‐Binding Inhibitors by the Accumulation of Substrate

Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets

Does the bifunctional uridylate synthase channel orotidine 5'-phosphate? Kinetics of orotate phosphoribosyltransferase and orotidylate decarboxylase activities fit a noninteracting sites model

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