scholarly journals Concentration of phosphoribosyl pyrophosphate in the kidney during development and in experimental diabetic hypertrophy

1986 ◽  
Vol 234 (3) ◽  
pp. 579-585 ◽  
Author(s):  
S Kunjara ◽  
M Sochor ◽  
A Adeoya ◽  
P McLean ◽  
A L Greenbaum
Keyword(s):  
De Novo ◽  
Pentose Phosphate ◽  
Short Term ◽  
Phosphoribosyl Pyrophosphate ◽  
Nucleotide Synthesis ◽  
Immature Rat ◽  
Adult Rat ◽  
Developmental Growth ◽  
Kidney Hypertrophy ◽  
Salvage Pathways

The effect of developmental growth on the kidney content of phosphoribosyl pyrophosphate PPRibP was studied in rats at ages between the foetal animal and up to 100 days of age. In addition, the effect of short-term diabetes (up to 14 days) on the renal content of PPRibP was studied in immature rats and in adults aged approx. 60 days. The developmental pattern of PPRibP is such that the PPRibP content is lowest in the young rat and increases as the rate of kidney growth slows. In the adult rat, the early kidney hypertrophy of diabetes is accompanied by a fall in PPRibP content and, again, the PPRibP content returns to normal as the rate of kidney hypertrophy diminishes. Induction of diabetes in the immature rat causes a lesser degree of kidney hypertrophy and also a smaller depression of renal PPRibP content. The activity of PPRibP synthetase (EC 2.7.6.1) is not significantly affected by age or diabetes. The changes in PPRibP content are discussed in relation to the generation of ribose 5-phosphate by the pentose phosphate pathway and the utilization of PPRibP for nucleotide synthesis via the ‘de novo’ and salvage pathways.

scholarly journals Renal hypertrophy in experimental diabetes. The activity of the ‘de novo’ and salvage pathways of purine [corrected] synthesis

1988 ◽  
Vol 249 (3) ◽  
pp. 911-914 ◽  
Author(s):  
S Kunjara ◽  
S J Beardsley ◽  
A L Greenbaum
Keyword(s):  
Nucleic Acids ◽  
De Novo ◽  
Experimental Diabetes ◽  
Salvage Pathway ◽  
Phosphoribosyl Pyrophosphate ◽  
Renal Hypertrophy ◽  
Early Diabetes ◽  
Nucleotide Synthesis ◽  
Main Route ◽  
Salvage Pathways

Measurements were made of the activity of phosphoribosyl pyrophosphate amidotransferase (PPRibP-At, EC 2.4.2.14) and of adenine (APRT, EC 2.4.2.7) and hypoxanthine (HPRT, EC 2.4.2.8) phosphoribosyltransferases, representing the ‘de novo’ and salvage pathways respectively. PPRibP-At activity increased within 3 days of diabetes, whereas APRT and HPRT increased later. Incorporation of [14C]formate and of [8-14C]adenine into the nucleic acids of kidney slices showed that formate was incorporated earlier, and to a greater extent, than was adenine. These results indicate that, although the ‘de novo’ pathway for nucleotide synthesis is the main route in early diabetes, the salvage pathway assumes greater importance at later stages.

Effects of Chinese Herbal Medicines on DNA-Synthesizing Enzyme Activities in Mammary Tumors of Mice

1994 ◽  
Vol 22 (01) ◽  
pp. 43-50 ◽  
Author(s):  
Shinobu Sakamoto ◽  
Ryuta Furuichi ◽  
Manabu Matsuda ◽  
Hideki Kudo ◽  
Satoe Suzuki ◽  
...  
Keyword(s):  
Prolactin Level ◽  
De Novo ◽  
Herbal Medicines ◽  
Mammary Tumors ◽  
Serum Prolactin ◽  
Serum Prolactin Level ◽  
Nucleotide Synthesis ◽  
Chinese Herbal ◽  
Pyrimidine Nucleotide ◽  
Salvage Pathways

Sho-saiko-to (SST) and Juzen-taiho-to (JTT), Japanese modified Chinese herbal prescriptions, suppressed the activities of thymidylate synthetase and thymidine kinase involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively, in mammary tumors of SHN mice with the reduction of serum prolactin level. These results indicate that SST and JTT may have the anti-tumor effects on mammary tumors.

scholarly journals INFLUENCE OF X-RAY AND MICROWAVE RADIATION ON DEAMINATION OF PURINE NUCLEOTIDES IN YEAST CELLS CANDIDA GUILLIERMONDII NP-4

2019 ◽  
Vol 62 (2) ◽  
pp. 48-52
Author(s):  
Seda V. Marutyan ◽  
Gayane H. Petrosyan ◽  
Syuzan A. Marutyan ◽  
Liparit A. Navasardyan ◽  
Armen H. Trchounian
Keyword(s):  
Electromagnetic Waves ◽  
De Novo ◽  
Candida Guilliermondii ◽  
Nucleotide Metabolism ◽  
Yeast Cells ◽  
X Rays ◽  
Purine Nucleotides ◽  
Nucleotide Synthesis ◽  
X Ray ◽  
Salvage Pathways

In metabolism of living cells a key role play purine nucleotides which cells can be supplied either by de novo synthesis from lower molecular weight precursors, or by alternate ways of nucleotide synthesis or so-called "nucleotide salvage pathways", which allow reusing of intermediate products of nucleotide metabolism in nucleotide synthesis. This way is important in the post-stress repair period, saving energy and substrates in the repairing cells. Purine nucleotides are allosteric inhibitors of enzymes of nucleotide salvage pathways, therefore the increase in their catabolism leads to a decrease of their amount in the cells, which contributes to the intensive work of the nucleotide salvage pathways and provides substrates for DNA synthesis. Investigation of deamination of purine nucleotides in yeasts Candida guilliermondii NP-4 irradiated with X-rays, millimeter and decimeter electromagnetic waves, as well as after post-radiation incubation of cells has been realized. It has been shown that under the influence of X-ray and microwave irradiation in yeasts, the intensity of deamination of purine nucleotide-polyphosphates - ADP, ATP, GDF and GTP, has changed, which in all probability is an adaptive mechanism in the repair of yeasts after irradiation, provides the work of nucleotide salvage pathways, and can be associated with the metabolism of these compounds.

Cell cycle regulation of purine synthesis by phosphoribosyl pyrophosphate and inorganic phosphate

2013 ◽  
Vol 454 (1) ◽  
pp. 91-99 ◽  
Author(s):  
Alla Fridman ◽  
Arindam Saha ◽  
Adriano Chan ◽  
Darren E. Casteel ◽  
Renate B. Pilz ◽  
...  
Keyword(s):  
De Novo ◽  
Fold Increase ◽  
Pentose Phosphate ◽  
S Phase ◽  
G1 Phase ◽  
Synthetase Activity ◽  
Phosphoribosyl Pyrophosphate ◽  
Purine Synthesis ◽  
Oxidative Pathway ◽  
Intracellular Phosphate

Cells must increase synthesis of purine nucleotides/deoxynucleotides before or during S-phase. We found that rates of purine synthesis via the de novo and salvage pathways increased 5.0- and 3.3-fold respectively, as cells progressed from mid-G1-phase to early S-phase. The increased purine synthesis could be attributed to a 3.2-fold increase in intracellular PRPP (5-phosphoribosyl-α-1-pyrophosphate), a rate-limiting substrate for de novo and salvage purine synthesis. PRPP can be produced by the oxidative and non-oxidative pentose phosphate pathways, and we found a 3.1-fold increase in flow through the non-oxidative pathway, with no change in oxidative pathway activity. Non-oxidative pentose phosphate pathway enzymes showed no change in activity, but PRPP synthetase is regulated by phosphate, and we found that phosphate uptake and total intracellular phosphate concentration increased significantly between mid-G1-phase and early S-phase. Over the same time period, PRPP synthetase activity increased 2.5-fold when assayed in the absence of added phosphate, making enzyme activity dependent on cellular phosphate at the time of extraction. We conclude that purine synthesis increases as cells progress from G1- to S-phase, and that the increase is from heightened PRPP synthetase activity due to increased intracellular phosphate.

scholarly journals Metabolic supervision by PPIP5K, an inositol pyrophosphate kinase/phosphatase, controls proliferation of the HCT116 tumor cell line

2021 ◽  
Vol 118 (10) ◽  
pp. e2020187118
Author(s):  
Chunfang Gu ◽  
Juan Liu ◽  
Xiaojing Liu ◽  
Haibo Zhang ◽  
Ji Luo ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Line ◽  
De Novo ◽  
Adenine Nucleotide ◽  
Hct116 Cell ◽  
Tumor Cell Line ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Phosphoribosyl Pyrophosphate ◽  
Inositol Pyrophosphate

Identification of common patterns of cancer metabolic reprogramming could assist the development of new therapeutic strategies. Recent attention in this field has focused on identifying and targeting signal transduction pathways that interface directly with major metabolic control processes. In the current study we demonstrate the importance of signaling by the diphosphoinositol pentakisphosphate kinases (PPIP5Ks) to the metabolism and proliferation of the HCT116 colonic tumor cell line. We observed reciprocal cross talk between PPIP5K catalytic activity and glucose metabolism, and we show that CRISPR-mediated PPIP5K deletion suppresses HCT116 cell proliferation in glucose-limited culture conditions that mimic the tumor cell microenvironment. We conducted detailed, global metabolomic analyses of wild-type and PPIP5K knockout (KO) cells by measuring both steady-state metabolite levels and by performing isotope tracing experiments. We attribute the growth-impaired phenotype to a specific reduction in the supply of precursor material for de novo nucleotide biosynthesis from the one carbon serine/glycine pathway and the pentose phosphate pathway. We identify two enzymatic control points that are inhibited in the PPIP5K KO cells: serine hydroxymethyltransferase and phosphoribosyl pyrophosphate synthetase, a known downstream target of AMP-regulated protein kinase, which we show is noncanonically activated independently of adenine nucleotide status. Finally, we show the proliferative defect in PPIP5K KO cells can be significantly rescued either by addition of inosine monophosphate or a nucleoside mixture or by stable expression of PPIP5K activity. Overall, our data describe multiple, far-reaching metabolic consequences for metabolic supervision by PPIP5Ks in a tumor cell line.

scholarly journals Down-Regulation of Phosphoribosyl Pyrophosphate Synthetase 1 Inhibits Neuroblastoma Cell Proliferation

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 955
Author(s):  
Jifu Li ◽  
Junhong Ye ◽  
Shunqin Zhu ◽  
Hongjuan Cui
Keyword(s):  
Cell Proliferation ◽  
De Novo ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Phosphoribosyl Pyrophosphate ◽  
Down Regulation ◽  
Nucleotide Synthesis ◽  
Phosphoribosyl Pyrophosphate Synthetase

Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is a key enzyme in de novo nucleotide synthesis and nucleotide salvage synthesis pathways that are critical for purine and pyrimidine biosynthesis. Abnormally high expression of PRPS1 can cause many diseases, including hearing loss, hypotonia, and ataxia, in addition to being associated with neuroblastoma. However, the role of PRPS1 in neuroblastoma is still unclear. In this study, we found that PRPS1 was commonly expressed in neuroblastoma cells and was closely related to poor prognosis for cancer. Furthermore, down-regulation of PRPS1 inhibited neuroblastoma cell proliferation and tumor growth in vitro and in vivo via disturbing DNA synthesis. This study provides new insights into the treatment of neuroblastoma patients and new targets for drug development.

scholarly journals Enzymes of the pathway of purine synthesis in the rat mammary gland. Changes in the lactation cycle and the effects of diabetes

1988 ◽  
Vol 250 (2) ◽  
pp. 395-399 ◽  
Author(s):  
S Beardsley ◽  
S Kunjara ◽  
A L Greenbaum
Keyword(s):  
Mammary Gland ◽  
De Novo ◽  
Salvage Pathway ◽  
Adenine Phosphoribosyltransferase ◽  
Phosphoribosyl Pyrophosphate ◽  
Purine Synthesis ◽  
Enzyme Change ◽  
Rat Mammary Gland ◽  
Salvage Pathways ◽  
Lactation Cycle

Measurements were made of the activities of the enzymes of the ‘de novo’ and salvage pathways of purine synthesis [phosphoribosyl pyrophosphate amidotransferase (EC 2.4.2.14), adenine phosphoribosyltransferase (EC 2.4.2.7) and hypoxanthine phosphoribosyltranferase (EC 2.4.2.8)] at different stages of the lactation cycle, and the effects of diabetes on the activity of these enzymes in lactation were studied. A distinctive pattern of enzyme change was observed, in which the ‘de novo’ pathway enzyme phosphoribosyl pyrophosphate amidotransferase increased sharply between days 10 and 14 of pregnancy, and then remained sensibly constant until the height of lactation, whereas the enzymes of the salvage pathway increased later in pregnancy and continued to rise during lactation. Diabetes severely depressed the activity of the enzymes of the salvage pathway, but appeared to be without effect on the ‘de novo’ pathway enzyme. These results are discussed in relation to the provision of purine precursors from tissues outside the mammary gland.

scholarly journals Purine-Metabolising Enzymes and Apoptosis in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1354 ◽  
Author(s):  
Camici ◽  
Garcia-Gil ◽  
Pesi ◽  
Allegrini ◽  
Tozzi
Keyword(s):  
Molecular Mechanisms ◽  
Purine Nucleoside Phosphorylase ◽  
De Novo ◽  
Tumour Cells ◽  
Purine Nucleotide ◽  
Salvage Pathway ◽  
Nucleotide Synthesis ◽  
Deoxynucleoside Triphosphate ◽  
Hypoxanthine Guanine Phosphoribosyltransferase ◽  
Salvage Pathways

The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.

scholarly journals Metabolic interaction between amino acid deprivation and cisplatin synergistically reduces phosphoribosyl-pyrophosphate and augments cisplatin cytotoxicity

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nisreen Wahwah ◽  
Debanjan Dhar ◽  
Hui Chen ◽  
Shunhui Zhuang ◽  
Adriano Chan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Essential Amino Acid ◽  
De Novo ◽  
Synthetase Activity ◽  
Amino Acid Deprivation ◽  
Phosphoribosyl Pyrophosphate ◽  
Nucleotide Synthesis ◽  
Intracellular Phosphate ◽  
Dna Strand

AbstractCisplatin is a mainstay of cancer chemotherapy. It forms DNA adducts, thereby activating poly(ADP-ribose) polymerases (PARPs) to initiate DNA repair. The PARP substrate NAD+ is synthesized from 5-phosphoribose-1-pyrophosphate (PRPP), and we found that treating cells for 6 h with cisplatin reduced intracellular PRPP availability. The decrease in PRPP was likely from (1) increased PRPP consumption, because cisplatin increased protein PARylation and PARP1 shRNA knock-down returned PRPP towards normal, and (2) decreased intracellular phosphate, which down-regulated PRPP synthetase activity. Depriving cells of a single essential amino acid decreased PRPP synthetase activity with a half-life of ~ 8 h, and combining cisplatin and amino acid deprivation synergistically reduced intracellular PRPP. PRPP is a rate-limiting substrate for purine nucleotide synthesis, and cisplatin inhibited de novo purine synthesis and DNA synthesis, with amino acid deprivation augmenting cisplatin’s effects. Amino acid deprivation enhanced cisplatin’s cytotoxicity, increasing cellular apoptosis and DNA strand breaks in vitro, and intermittent deprivation of lysine combined with a sub-therapeutic dose of cisplatin inhibited growth of ectopic hepatomas in mice. Augmentation of cisplatin’s biochemical and cytotoxic effects by amino acid deprivation suggest that intermittent deprivation of an essential amino acid could allow dose reduction of cisplatin; this could reduce the drug’s side effects, and allow its use in cisplatin-resistant tumors.

scholarly journals The influence of ammonia on purine and pyrimidine nucleotide biosynthesis in rat liver and brain in vitro

1978 ◽  
Vol 172 (3) ◽  
pp. 457-464 ◽  
Author(s):  
Stephen D. Skaper ◽  
William E. O'Brien ◽  
Irwin A. Schafer
Keyword(s):  
De Novo ◽  
Liver Homogenate ◽  
Purine Biosynthesis ◽  
Purine Nucleotide ◽  
Carbamoyl Phosphate ◽  
Phosphoribosyl Pyrophosphate ◽  
Nucleotide Synthesis ◽  
Nucleotide Biosynthesis ◽  
Pyrimidine Nucleotide

1. The effect of ammonia on purine and pyrimidine nucleotide biosynthesis was studied in rat liver and brain in vitro. The incorporation of NaH14CO3 into acid-soluble uridine nucleotide (UMP) in liver homogenates and minces was increased 2.5–4-fold on incubation with 10mm-NH4Cl plus N-acetyl-l-glutamate, but not with either compound alone. 2. The incorporation of NaH14CO3 into orotic acid was increased 3–4-fold in liver homogenate with NH4Cl plus acetylglutamate. 3. The 5-phosphoribosyl 1-pyrophosphate content of liver homogenate was decreased by 50% after incubation for 10min with 10mm-NH4Cl plus acetylglutamate. 4. Concomitant with this decrease in free phosphoribosyl pyrophosphate was a 40–50% decrease in the rates of purine nucleotide synthesis, both de novo and from the preformed base. 5. Subcellular fractionation of liver indicated that the effects of NH4Cl plus acetylglutamate on pyrimidine and purine biosynthesis required a mitochondrial fraction. This effect of NH4Cl plus acetylglutamate could be duplicated in a mitochondria-free liver fraction with carbamoyl phosphate. 6. A similar series of experiments carried out with rat brain demonstrated a significant, though considerably smaller, effect on UMP synthesis de novo and purine base reutilization. 7. These data indicate that excessive amounts of ammonia may interfere with purine nucleotide biosynthesis by stimulating production of carbamoyl phosphate through the mitochondrial synthetase, with the excess carbamoyl phosphate in turn increasing pyrimidine nucleotide synthesis de novo and diminishing the phosphoribosyl pyrophosphate available for purine biosynthesis.

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