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PubMed2006

Comprehensive detection of disorders of purine and pyrimidine metabolism by HPLC with electrospray ionization tandem mass spectrometry.

BACKGROUND: Clinical presentation and disease severity in disorders of purine and pyrimidine metabolism vary considerably. We present a method that allows comprehensive, sensitive, and specific diagnosis of the entire spectrum of abnormalities in purine and pyrimidine metabolism in 1 analytical run. METHODS: We used reversed-phase HPLC electrospray ionization tandem mass spectrometry to investigate 24 metabolites of purine and pyrimidine metabolism in urine samples from healthy persons and from patients with confirmed diagnoses of inherited metabolic disorders. Urine samples were filtered and diluted to a creatinine concentration of 0.5 mmol/L. Stable-isotope-labeled internal standards were used for quantification. The metabolites were analyzed by multiple-reaction monitoring in positive and negative ionization modes. RESULTS: Total time of analysis was 20 min. Recovery (n = 8) of a compound after addition of a known concentration was 85%-133%. The mean intraday variation (n = 10) was 12%. The interday variation (n = 7) was < or =17%. Age-related reference intervals were established for each compound. Analysis of patient urine samples revealed major differences in tandem mass spectrometry profiles compared with those of control samples. Twelve deficiencies were reliably detected: hypoxanthine guanine phosphoribosyl transferase, xanthine dehydrogenase, purine nucleoside phosphorylase, adenylosuccinate lyase, uridine monophosphate synthase, adenosine deaminase, adenine phosphoribosyl transferase, molybdenum cofactor, thymidine phosphorylase, dihydropyrimidine dehydrogenase, dihydropyrimidinase, and beta-ureidopropionase. CONCLUSION: This method enables reliable detection of 13 defects in purine and pyrimidine metabolism in a single analytical run.

Adolescent↗

PubMed2002

Chlorella virus pyrimidine dimer glycosylase excises ultraviolet radiation- and hydroxyl radical-induced products 4,6-diamino-5-formamidopyrimidine and 2,6-diamino-4-hydroxy-5-formamidopyrimidine from DNA.

A DNA glycosylase specific for UV radiation-induced pyrimidine dimers has been identified from the Chlorella virus Paramecium Bursaria Chlorella virus-1. This enzyme (Chlorella virus pyrimidine dimer glycosylase [cv-pdg]) exhibits a 41% amino acid identity with endonuclease V from bacteriophage T4 (T4 pyrimidine dimer glycosylase [T4-pdg]), which is also specific for pyrimidine dimers. However, cv-pdg possesses a higher catalytic efficiency and broader substrate specificity than T4-pdg. The latter excises 4,6-diamino-5-formamidopyrimidine (FapyAde), a UV radiation- and hydroxyl radical-induced monomeric product of adenine in DNA. Using gas chromatography-isotope-dilution mass spectrometry and y-irradiated DNA, we show in this work that cv-pdg also displays a catalytic activity for excision of FapyAde and, in addition, it excises 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua). Kinetic data show that FapyAde is a better substrate for cv-pdg than FapyGua. On the other hand, cv-pdg possesses a greater efficiency for the extension of FapyAde than T4-pdg. These two enzymes exhibit different substrate specificities despite substantial structural similarities.

Chlorella↗

PubMed1988

Metabolism of pyrimidine bases and nucleosides by Pseudomonas fluorescens biotype F.

Pyrimidine metabolism in Pseudomonas fluorescens biotype F, and its ability to grow in liquid culture on pyrimidines and related compounds was investigated. It was found that uracil, uridine, cytosine, cytidine, deoxycytidine, dihydrouracil, dihydrothymine, beta-alanine or beta-aminoisobutyric acid could be utilized by this pseudomonad as a sole nitrogen source. Only uridine, cytidine, beta-alanine, beta-aminoisobutyric acid or ribose were capable of supporting its growth as a sole source of carbon. In solid medium, the pyrimidine analogue 5-fluorouracil or 5-fluorouridine could prevent P. fluorescens biotype F growth at a low concentration while a 20-fold higher concentration of 5-fluorocytosine, 5-fluorodeoxyuridine or 6-azauracil was necessary to block its growth. The pyrimidine salvage enzymes cytosine deaminase, nucleoside hydrolase, uridine phosphorylase, thymidine phosphorylase and cytidine deaminase were assayed. Only cytosine deaminase and nucleoside hydrolase activities could be detected under the assay conditions used. The effect of growth conditions on cytosine deaminase and nucleoside hydrolase levels in the micro-organism was explored. Cytosine deaminase activity was shown to increase if glycerol was substituted for glucose as the sole carbon source or if asparagine replaced (NH4)2SO4 as the sole nitrogen source in each respective medium. In contrast, nucleoside hydrolase activity remained virtually unchanged whether the carbon source in the medium was glucose or glycerol. A decrease in nucleoside hydrolase activity was witnessed when asparagine was present in the medium instead of (NH4)2SO4 as the sole source of nitrogen.

Cytosine Deaminase↗

PubMed1979

Interaction of metal ions with nucleic acids. Interaction of copper(II) with pyrimidine nucleosides and their derivatives.

1. In aqueous and non-aqueous solutions, copper(II) interacts with the N-3 of cytidine but not with the carbonyl group oxygens of pyrimidine nucleosides. 2. In aqueous solution, copper(II) interacts with the phosphate group and ribose of pyrimidine nucleotides, and additionally with N-3 of 5'-CMP. 3. Broadening of resonance signals of the H-5 proton of 5'-UMP and C-5 of 5'-UMP and 5'-TMP results probably from the interaction between metal ion and the phosphate group situated in direct vicinity of the above atoms. 4. In the copper(II)-pyrimidine nucleotide complexes in solid state, copper is coordinated with the phosphate group, and in 5'-CMP additionally with the pyrimidine moiety of the nucleotide.

Binding Sites↗

PubMed1984

Effect of uridine on response of 5-azacytidine-resistant human leukemic cells to inhibitors of de novo pyrimidine synthesis.

A uridine-cytidine kinase-deficient human promyelocytic leukemic subline (HL-60-5-aza-Cyd) has been isolated which is highly resistant to the antileukemic agent 5-azacytidine. Resistant cells exposed to 10(-5) M 5-azacytidine for 2 hr exhibit a marked reduction in both the total intracellular accumulation of 5-azacytidine (11.9 versus 156.0 pmol/10(6) cells) as well as its incorporation into RNA (3.1 versus 43.4 pmol/micrograms D-ribose) compared to the parent line. These biochemical changes are associated with nearly a 100-fold decrease in sensitivity to the growth inhibitory effects of 5-azacytidine (concentration of drug associated with a 50% reduction in cell growth, 3.5 X 10(-5) versus 5.0 X 10(-7) M). 5-Azacytidine-resistant cells exhibit cross-resistance to 3-deazauridine, 6-azauridine, and 5-fluorouridine, but not to 1-beta-D-arabinofuranosylcytosine, 2'-deoxyazacytidine, or 5-aza-1-beta-D-arabinofuranosylcytosine. Coadministration of 50 microM uridine prevented depletion of pyrimidine nucleoside triphosphates and inhibition of colony formation of HL-60 cells exposed to 3 mM N-(phosphonacetyl)-L-aspartate) or 5 X 10(-6) M pyrazofurin but was not capable of protecting HL-60-5-azacytidine under the same conditions. This uridine concentration was also able to restore control colony formation to normal human bone marrow progenitor cells (granulocyte-macrophage colony-forming units) exposed to de novo pyrimidine biosynthetic blockade. These in vitro studies suggest that 5-azacytidine resistant cells lacking the pyrimidine salvage pathway enzyme uridine-cytidine kinase may be selectively vulnerable to a regimen using pyrimidine antagonists administered in conjunction with the naturally occurring nucleoside uridine.

Azacitidine↗

PubMed1982

Hemolytic anemia in hereditary pyrimidine 5'-nucleotidase deficiency: nucleotide inhibition of G6PD and the pentose phosphate shunt.

We evaluated the erythrocytes of two patients with hereditary pyrimidine 5'-nucleotidase deficiency. Significant findings included an increased reduced glutathione content, increased incubated Heinz body formation, a positive ascorbate cyanide test, and decreased intraerythrocytic pH. The pentose phosphate shunt activity of the patients' red cells as measured by the release of 14CO2 from 14C-1-glucose was decreased compared to high reticulocyte controls. Glucose-6-phosphate dehydrogenase (G6PD) activity in hemolysates from control erythrocytes was inhibited 43% by 5.5 mM cytidine 5'-triphosphate (CTP) and 50% by 5.5 mM in uridine 5'-triphosphate (UTP) at pH 7.1. CTP was a competitive inhibitor for G6P (Ki = 1.7 mM) and a noncompetitive inhibitor for NADP+ (Ki = 7.8 mM). Glutathione peroxidase, glutathione reductase, and 6-phosphogluconate dehydrogenase were not affected by these compounds. Pentose phosphate shunt activity in control red cell hemolysate at pH 7.1 was inhibited to a similar degree by 5.5 mM CTP or UTP. Since the intracellular concentrations of G6P and NADP+ are below their KmS for G6PD, these data suggest that high concentrations of pyrimidine 5'-nucleotides depress pentose phosphate shunt activity in pyrimidin 5'-nucleotidase deficiency. Thus, this impairment of the pentose phosphate pathway appears to contribute to the pathogenesis of hemolysis in pyrimidine 5'-nucleotidase deficiency hemolytic anemia.

5'-Nucleotidase↗

PubMed1977

Dietary feedback regulation of purine and pyrimidine biosynthesis in man.

Ten days after a healthy person has consumed a purine-free isoenergetic diet, the excretion of (endogenous) uric acid reaches a minimum and remains constant thereafter. Purines are absorbed in different degrees from various biochemical sources added to such a diet--little from DNA, nearly all from ribomononucleotides--presumably owing to different rates of hydrolysis. There is always a linear relationship between dietary purine content and uric acid excretion, independent of the source of purine. The findings suggest that dietary purines play a minor role (if any) in the regulation of purine synthesis, contrary to the conclusions of other workers. The demonstration that oral administration of uridine diminishes the oroticaciduria in patients with hereditary oroticaciduria suggested dietary feedback regulation of pyrimidine biosynthesis by pyrimidine nucleosides in the diet. The reduction of allopurinol-induced oroticaciduria by dietary RNA pointed in the same direction. Closer analysis with RNA hydrolysate and isolated purine as well as pyrimidine nucleotides, however, revealed that not only pyrimidine derivatives but also purine mononucleotides diminish oroticaciduria. The nucleotides had no influence on the change in the activity of orotidine-5'-phosphate decarboxylase (EC 4.1.1.23), induced by allopurinol; this makes an effect on the decarboxylase unlikely. The feedback regulation is assumed to act by inhibition of an earlier step.

Allopurinol↗

PubMed1977

Purine and pyrimidine nucleotides in some mutant human lymphoblasts.

To study the role of purine ribonucleotides as possible regulators of the rate of de novo purine biosynthesis in living human cells, we measured intracellular ribonucleotide concentrations by high-pressure liquid chromatography in a series of cloned human lymphoblast mutants selected by resistance to 8-azaguanine, in which the severity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency could be correlated with increases in the rate of de novo purine biosynthesis and increases in intracellular concentrations of phosphoribosyl pyrophosphate (PP-ribose-P). Compared with appropriate normal controls, intracellular purine ribonucleotide concentrations were not reduced in HGPRT-deficient lymphoblasts but there were striking increases in intracellular concentrations of some pyrimidine nucleotides and nucleotide sugars which appeared to be related to the degree of the deficiency. Similar changes were found in lymphoblasts from a Lesch-Nyhan boy. These data support the hypothesis that the accelerated rate of purine biosynthesis in HGPRT-deficient cells result from increases in intracellular PP-ribose-P concentration and not from changes in intracellular purine ribonucleotide concentrations. The possibility that the abnormality of pyrimidine nucleotide metabolism results from coordinate regulation of purine and pyrimidine biosynthesis by PP-ribose-P was not substantiated by measurement of rates of pyrimidine synthesis and experimental elevation of intracellular concentrations of PP-ribose-P after incubation of cells with inorganic phosphate.

Adenine Nucleotides↗

PubMed2005

Pyrimidine as constituent of natural biologically active compounds.

This review describes the various manifestations of the pyrimidine system (alkylated, glycosylated, benzo-annelated.). These comprise pyrimidine nucleosides as well as alkaloids and antibiotics--some of them have been discovered and isolated from natural sources already long time ago, others have been reported very recently. A short overview on pyrimidine syntheses (prebiotic synthesis, biosynthesis, and metabolism) is given. The biological activities of most of the pyrimidine analogs are briefly described, and, in some cases, syntheses are formulated.

Biological Products↗

PubMed1989

Alternating purine-pyrimidine tracts may promote chromosomal translocations seen in a variety of human lymphoid tumours.

Chromosomal abnormalities which are prevalent in human lymphoid tumours are believed to be involved in tumour pathogenesis and their formation may be the result of erroneous activity by the V-D-J recombinase. Frequently, recombinase accessibility is provided by prior transcription of the chromosomal regions involved. However, this may not always be so and in those cases DNA structural features must be involved. Here we examine the breakpoints of three different tumour-specific translocations in the proximity of which we can detect no transcription; two of the translocations involve regions of chromosome 11, (t[11;14] [p13;q11] and t[11;14] [q13;q32]), and the third is a newly described translocation, t[7;10] [q35;q24], involving the T cell receptor beta-gene on chromosome 7. In each case, a purine--pyrimidine tract (potential Z-DNA) occurs near the translocation breakpoints. Four independent tumours with translocation t[11;14] [p13;q11] reveal a 2 kb breakpoint cluster region at 11p13 with an adjacent potential Z-DNA region of 62 bp in length; the analogous purine--pyrimidine tract at 10q24 is 32 bp long. The purine--pyrimidine tract at the 11q13 chromosome breakpoint, however, is very large as it covers approximately 800 bp. The position, surrounding sequence and potential Z-DNA tract of the human 11p13 TALLber is conserved in rodents. These results suggest that the purine--pyrimidine tracts, presumably in the Z-DNA form, can influence chromatin structure giving access for recombinase-mediated translocations. Such putative alterations of chromatin organization are supported by the observation of DNase I hypersensitive sites near to translocation breakpoints on 10q24 and 11p13.

Animals↗

PubMed1996

A Xenopus laevis homologue of the La autoantigen binds the pyrimidine tract of the 5' UTR of ribosomal protein mRNAs in vitro: implication of a protein factor in complex formation.

In Xenopus and other vertebrates, ribosomal protein mRNAs share a common sequence in the 5' untranslated region (5' UTR), in particular a pyrimidine tract at the 5' end, which has been demonstrated to be involved in the translational regulation of this class of mRNAs. In previous studies, carried out in the Xenopus system, we demonstrated the specific binding of two proteins (57 kDa and 47 kDa) to the pyrimidine tract of the mRNAs for three different ribosomal proteins. Here, we show that the two binding proteins are in fact one; one being the cleavage product of the other. By immunoprecipitation and protein purification, this binding protein has been identified as the Xenopus homologue of the human La autoantigen, an RNA-binding protein previously reported to be implicated in RNA polymerase III transcription termination and in translation initiation of poliovirus and immunodeficiency virus type 1 RNAs. We show that the specific interaction of La with the 5' pyrimidine tract of ribosomal protein mRNA is mediated by a protease-sensitive factor, which, after assisting La-RNA binding, dissociates from the complex and becomes again available to promote further binding. We show that mutations in the 5' UTR pyrimidine tract, known to disrupt the translational control of ribosomal protein mRNA, severely impair La binding. Although a direct relationship between ribosomal protein mRNA translation and La binding is not yet available, the properties of the interaction suggest that La protein, possibly together with other components, might be involved in translational regulation.

Animals↗

PubMed1999

The role of essential pyrimidines in the hairpin ribozyme-catalysed reaction.

The hairpin ribozyme is an example of a small catalytic RNA that catalyses the endonucleolytic transesterification of RNA in a highly sequence-specific manner. We have utilised chemical synthesis of RNA to create mutants of the hairpin ribozyme in which a nucleoside analogue replaces one of the essential pyrimidines in the ribozyme. Individual pyrimidine nucleosides were substituted by 4-thiouridine, O4-methyluridine, O2-methyluridine or 2-pyrimidinone-1-beta-d-riboside. To facilitate the synthesis of oligoribonucleotides containing 4-thiouridine, we have devised a new synthetic route to the key intermediate 5'-O-(4, 4'-dimethoxytrityl)-2'-O-tert-butyldimethylsilyl-S-cyanoethyl-4-thiou ridine. The ability of the modified ribozymes to support catalysis was studied and the steady-state kinetic parameters were determined for each mutant. The range of analogues used in this study allows the important functional groups of the essential pyrimidines to be identified. The results demonstrate that each pyrimidine (U41, U42 and C25) plays an important role in hairpin ribozyme catalysis. The findings are discussed in terms of the various models that have been proposed for loop B of the hairpin ribozyme.

Kinetics↗

PubMed2001

Selective recognition of pyrimidine motif triplexes by a protein encoded by the bacterial transposon Tn7.

The bacterial transposon Tn7 is distinguished among mobile genetic elements by its targeting abilities. Recently, we reported that Tn7 is able to selectively insert adjacent to triple-helical DNA. The binding of TnsC, a Tn7-encoded protein, to the triplex DNA target leads to the specific transposition of Tn7 adjacent to both inter- and intramolecular pyrimidine motif triplexes. Here, we further probe how Tn7 targets triplex DNA. We report that TnsC discriminates between different types of triplexes, showing binding preference for pyrimidine but not for purine motif intermolecular triplex DNA. The binding preferences of TnsC and the Tn7 insertion profiles were obtained using psoralenated, triplex- forming oligonucleotides annealed to plasmid DNAs. Although the presence of psoralen is not required for targeting nor is it alone able to attract TnsC, we show that the location of psoralen within the pyrimidine motif triplex does alter the position of Tn7 insertion relative to the triplex. Comparison between the triplex-targeting pathway and the highly site-specific targeting pathway mediated by the binding of the Tn7-encoded protein, TnsD, to the unique site attTn7, suggests that similar structural features within each target DNA are recognized by TnsC, leading to site-specific transposition. This work demonstrates that a prokaryotic protein involved in the targeting and regulation of Tn7 translocation, TnsC, can selectively recognize pyrimidine motif triplexes.

Animals↗

PubMed1999

Pyrimidine-rich region mutations compensate for a stem-loop V lesion in the 5' noncoding region of poliovirus genomic RNA.

Five revertants of a linker-scanning mutation adjacent to the stem-loop V attenuation determinant (X472) in the 5' noncoding region of poliovirus RNA were independently isolated from neuroblastoma cells and contained RNAs with seven nucleotide changes in the pyrimidine-rich region. Generation of the identical rare second-site mutations suggests the existence of a replicase-dependent mutagenesis mechanism during poliovirus replication. Enzymatic structure probing of the mutated pyrimidine-rich domain identified secondary structure changes between stem-loops V and VI. A consensus secondary structure model is presented for wild-type stem-loops V and VI and the pyrimidine-rich region located in the 5' noncoding region of poliovirus RNA. A pyrimidine-rich region mutant (X472-R4N) produced large plaques in neuroblastoma cells and small plaques in HeLa cells, but the plaque size differences were not due to cell-type differences in viral translation or RNA replication. Release of X472-R4N from HeLa cells was 10-fold lower than release from neuroblastoma cells, which may explain the small plaque phenotype of X472-R4N in HeLa cells. Wild-type poliovirus was also released more efficiently from neuroblastoma cells (approximately 4-fold increase compared with release from HeLa cells), indicating that poliovirus neurotropism may be influenced by the cell-type efficiency of virus release. Thermal treatment increased the levels of infectious X472-R4N virions but not wild-type virus particles; thus RNA sequence and structural changes in the mutated 5' noncoding region of X472-R4N may have altered RNA-protein interactions necessary for virus infectivity.

5' Untranslated Regions↗

PubMed1977

Purine and pyrimidine nucleotide concentrations in cells with decreased hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) activity.

1. In order to investigate the role of purine ribonucleotides in the regulation of de novo purine synthesis in living human cells deficient in HGPRT, intracellular ribonucleotide concentrations have been measured in HGPRT lymphoblasts, fibroblasts and erythrocytes and in appropriate HGPRT controls by high pressure liquid chromatography. 2. Purine Purine ribonucleotide concentrations were not reduced in HGPRT cells, supporting the hypothesis that accelerated purine biosynthesis de novo results from increased availability of PP-ribose-P and not from altered feedback regulation by purine ribonucleotides in HGPRT deficient cells. 3. Striking increases in intracellular concentrations of some pyrimidine nucleotides and nucleotide sugars were detected in HGPRT lymphoblasts and erythrocytes, but not in fibroblasts. 4. The possibiiity that this abnormality of pyrimidine metabolism might result from coordinate regulation of purine and pyrimidine synthesis de novo by PP-ribose-P was not substantiated by measurements of rates of pyrimidine synthesis and experimental elevation of intracellular concentrations of PP-ribose-P following incubation of cells with inorganic phosphate.

Cell Line↗

PubMed1982

Mutability of bacteriophage M13 by ultraviolet light: role of pyrimidine dimers.

The role of pyrimidine dimers in mutagenesis by ultraviolet light was examined by measuring the UV-induced reversion of six different bacteriophage M13 amber mutants for which the neighboring DNA sequences are known. The mutational response at amber (TAG) codons preceded by a guanine or adenine (where no pyrimidine dimer can be formed) were compared with those preceded by thymine or cytosine (where dimer formation is possible). Equivalent levels of UV-induced mutagenesis were observed at both kinds of sites. This observation demonstrates that there is no requirement for a pyrimidine dimer directly at the site of UV-induced mutation in this single-stranded DNA phage. UV irradiation of the phage was also performed in the presence of Ag+ ions, which specifically sensitize the DNA to dimer formation. The two methods of irradiation, when compared at equal survival levels (and presumably equal dimer frequencies), produced equivalent frequencies of reversion of the amber phage. We believe these results indicate that while the presence of pyrimidine dimers may be a prerequisite for UV mutagenesis, the actual mutagenic event can occur at a site some distance removed from a dimer.

Base Sequence↗

PubMed1977

The structure of animal mitochondrial DNA (base composition, pyrimidine clusters, character of methylation).

Base composition, content of pyrimidine isopliths and the degree of methylation of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) from various vertebrates and protozoon Crithidia oncopelti have been studied. MtDNAs from mammals (ox, rat) do not differ in fact in the GC content from the respective nDNA. The GC content in mtDNA from fishes (sheat fish) and birds (duck, chicken) is 1.5-2.5 mole % higher than in the respective nDNA. Kinetoplast DNA (kDNA) from Crithidia oncopelti (GC = 42.9 mole %) differs significantly in base composition from nDNA (GC = 51.3 mole %). All the mtDNA and kDNA studied differ from the respective nDNA by a lower degree of pyrimidine clustering. The amount of mono and dipyrimidine fragments in mtDNA is more than 30 mole %, whereas in nDNA it does not exceed 23 mole %. The quantity of long pyrimidine clusters (hexa and others) is 2-4 times lower in mtDNA than in nDNA. The lower degree of clustering of pyrimidine nucleotides seems to be a specific feature of all the mtDNA studied. This may be indicative of common traits in the organization and origin of mtDNA. All mtDNA of vertebrates contain 5-methylcytosine as a 'minor' base (1.5- 3.15 mole %) and surpass by 1.5-2 times the respective nDNA in the methylation degree. It has been found that in animals mtDNA is species specific as far as the 5-methyl-cytosine content is concerned. In mitochondria and nuclei of rat liver certain DNA methylase activity has been detected, which provides in vitro the methylation of cytosine residues both in homologous DNA and various heterologous DNAs. The specificity of methylation in vitro of cytosine residues in the same heterologous DNA from E. coli B varies with the source of enzymes. The mitochondrial enzyme methylates cytosine as the lone monopyrimidine residue, whereas the nuclear enzyme methylase cytosine in the di- and tripyrimidine fragments.

Animals↗

PubMed2003

De novo synthesis of pyrimidine nucleotides; emerging interfaces with signal transduction pathways.

The de novo biosynthesis of pyrimidine nucleotides provides essential precursors for multiple growth-related events in higher eukaryotes. Assembled from ATP, bicarbonate and glutamine, the uracil and cytosine nucleotides are fuel for the synthesis of RNA, DNA, phospholipids, UDP sugars and glycogen. Over the past 2 decades considerable progress has been made in elucidating the mechanisms by which cellular pyrimidines are modulated to meet the needs of the cell. Recent studies demonstrate that CAD, a rate-limiting enzyme in the de novo synthesis of pyrimidines, is regulated through reversible phosphorylation, Myc-dependent transcriptional changes and caspase-mediated degradation. These studies point to increasing evidence for cooperation between key cell signaling pathways and basic elements of cellular metabolism, and suggest that these events have the potential to determine distinct cellular fates, including growth, differentiation and death. This review highlights some of the recent advances in the regulation of pyrimidine synthesis by growth-factor-stimulated signaling pathways.

Allosteric Regulation↗