SAR studies toward discovery of emvododstat (PTC299), a potent dihydroorotate dehydrogenase (DHODH) inhibitor
Ramil BaiazitovHongyan QiTamil ArasuWilliam LennoxLiangxian CaoMarla WeetallBansri FuriaJin ZhuoSoongyu ChoiMin Jung KimJosephine SheedyThomas W. DavisYoung‐Choon Moon
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Dihydroorotate Dehydrogenase
Pyrimidine metabolism
The pyrimidine metabolism of Tritrichomonas foetus (KV 1) was studied using whole cells and cell homogenates. Pyrimidines and pyrimidine nucleosides were readily incorporated into nucleic acids. Orotate and aspartate were not incorporated into pyrimidine bases. Enzymes of the pyrimidine salvage pathway (i.e., thymidine and uridine phosphorylases and uridine kinase) were detected in trophozoite homogenates, but the activities of de novo pyrimidine synthesis enzymes (i.e., carbamoylphosphate synthase, aspartate transcarbamoylase, dihydroorotase and dihydroorotate dehydrogenase) were below the level of detection in these same homogenates. The evidence presented supports the proposal that T. foetus is incapable of synthesizing pyrimidines de novo but is capable of salvaging preformed pyrimidines and pyrimidine nucleosides from the growth medium and that enzymes of this parasite's pyrimidine salvage pathway are not organelle-associated.
Pyrimidine metabolism
Dihydroorotate Dehydrogenase
Tritrichomonas foetus
Aspartate carbamoyltransferase
Nucleotide salvage
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Pyrimidine metabolism
Aspartate carbamoyltransferase
Nucleotide salvage
Orotic acid
Dihydroorotate Dehydrogenase
Giardia lamblia
De novo synthesis
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Dihydroorotate Dehydrogenase
Pyrimidine metabolism
Enterococcus faecalis
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The effect of carbon source on the regulation of pyrimidine biosynthesis in the opportunistic human pathogen Pseudomonas oryzihabitans was studied at the level of enzyme synthesis. Although pyrimidine supplementation of glucose-grown Ps. oryzihabitans cells produced a slight but statistically significant effect on the de novo pyrimidine biosynthetic pathway enzyme activities, catabolite repression of the enzyme activities by glucose appeared to be occurring. Pyrimidine limitation experiments undertaken using an orotidine 5'-monophosphate decarboxylase mutant strain grown on glucose indicated that repression of enzyme synthesis by pyrimidines was occurring. Following pyrimidine limitation of the mutant strain cells, dihydroorotase and dihydroorotate dehydrogenase activities were found to about double while aspartate transcarbamoylase and orotate phosphoribosyltransferase activities were slightly elevated compared to their activities in the mutant strain cells grown on excess uracil.
Pyrimidine metabolism
Aspartate carbamoyltransferase
Dihydroorotate Dehydrogenase
Uracil
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Dihydroorotate Dehydrogenase
Pyrimidine metabolism
Cellular respiration
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Aspartate carbamoyltransferase
Uracil
Dihydroorotate Dehydrogenase
Pyrimidine metabolism
Phosphoribosyltransferase
Cytidine
Cytosine
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The repressive effects of exogenous cytidine on growing cells was examined in a specially constructed strain in which the pool sizes of endogenous uridine 5'-diphosphate and uridine 5'-triphosphate cannot be varied by the addition of uracil and/or uridine to the medium. Five enzymes of the pyrimidine biosynthetic pathway and one enzyme of the arginine biosynthetic pathway were assayed from cells grown under a variety of conditions. Cytidine repressed the synthesis of dihydroorotase (encoded by pyrC), dihydroorotate dehydrogenase (encoded by pyrD), and ornithine transcarbamylase (encoded by argI). Moreover, aspartate transcarbamylase (encoded by pyrB) became further derepressed upon cytidine addition, whereas no change occurred in the levels of the last two enzymes (encoded by pyrE and pyrF) of the pyrimidine pathway. Quantitative nucleotide pool determinations have provided evidence that any individual ribo- or deoxyribonucleoside mono-, di-, or triphosphate of cytosine or uracil is not a repressing metabolite for the pyrimidine biosynthetic enzymes. Other nucleotide derivatives or ratios must be considered.
Cytidine
Uracil
Dihydroorotate Dehydrogenase
Pyrimidine metabolism
Nucleotide salvage
Cytosine
Aspartate carbamoyltransferase
Carbamyl Phosphate
Ornithine transcarbamylase
Ornithine Carbamoyltransferase
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Dihydroorotate Dehydrogenase
Pyrimidine metabolism
Phosphoribosyltransferase
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Abstract Dichloroallyl lawsone [2-hydroxy-3-(3,3-dichloroallyl)-1,4-naphthoquinone, NSC 126771] is of interest as an antitumor agent. Like certain other naphthoquinones, it is known to be a respiratory poison as a result of interference with electron transport, but it has not been shown that this action is responsible for its toxicity or antitiumor activity. Studies in cultured L1210 cells showed that dichloroallyl lawsone (a) stimulated the incorporation of [14C]uridine into macromolecules, (b) specifically decreased the pool sizes of uridine triphosphate, (c) prevented the pyrazofurin-induced accumulation of orotidine and orotic acid, and (d) exerted cytotoxicity that could be prevented or reversed almost completely by uridine. This evidence that dichloroallyl lawsone specifically inhibited biosynthesis of pyrimidine nucleotides in intact cells was confirmed by studies in homogenates; these showed that this agent inhibited the conversion of [14C]carbamylphosphate to orotate and uridine monophosphate but not its conversion to dihydroorotate and that it was without effect on the conversion of [6-14C]orotate to uridine monophosphate. That the site of inhibition was dihydroorotate dehydrogenase was confirmed in studies with isolated mitochondria from mouse liver. An enzyme from this source catalyzed the oxidation of [6-14C]dihydroorotate (apparent Km, 6.7 × 10−6m), and dichloroallyl lawsone functioned as an inhibitor uncompetitive with dihydroorotate (Ki, 2.7 × 10−8m). Addition of ubiquinone was without effect on the reaction. Dichloroallyl lawsone, however, did not inhibit dihydroorotate dehydrogenase from Zymobacterium oroticum. These results indicate that the blockade of pyrimidine biosynthesis resulting from inhibition of dihydroorotate dehydrogenase is primarily responsible for the cytotoxicity of dichloroallyl lawsone to L1210 cells. More limited studies with the structurally related quinone, lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone], indicated that it exerts similar effects on biosynthesis of pyrimidines.
Dihydroorotate Dehydrogenase
Lawsone
Pyrimidine metabolism
Cytidine
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Citations (41)
Pyrimidine metabolism
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