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Salvage Pathways De-novo synthesis of purines ..

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De novo and salvage pathway of purines - Science

Scheme of the purine metabolismpathways, showing the position of IMPDH2, APRT and PNP in purinenucleotide biosynthesis, adopted from a previous study (35). The de novo synthesis ofpurine nucleotides begins with the phosphorylation ofribose-5-phosphate to form PRPP. In a number of reactions, PRPPcreates the first fully formed nucleotide, IMP. IMP is converted byIMPDH2 to GMP. PNP catalyzes the reversible cleavage of purinenucleosides, releasing purine nucleobases (adenine, hypoxanthine,xanthine and guanine). In the salvage pathway the free nucleobasescan be reconverted back to nucleoside-5′-monophosphates in areaction with activated sugar (PRPP) catalyzed by APRT. IMPDH2,inosine-5′-monophosphate dehydrogenase 2; APRT, adeninephosphoribosyltransferase; PNP, purine nucleoside phosphorylase;PRPP, 5-phosphoribosyl-1-pyrophosphate; IMP,inosine-5′-monophosphate; GMP, guanosine-5′-monophosphate; dADP,deoxyadenosine diphosphate; ADP, adenosine diphosphate; GDP,guanosine diphosphate; dGDP, deoxyguanosine diphosphate; AMP,adenosine monophosphate; XMP, xanthosine monophosphate.

De novo synthesis and most of the salvage pathways involve the …

Christopherson RI and Lyons SD (1990) Potent inhibitors of de novo pyrimidine and purine biosynthesis as chemotherapeutic agents. Medicinal Research Reviews 10: 505–548.

De novo and salvage pathways of DNA synthesis in …

De novo and salvage pathways of DNA synthesis in primary cultured neurall stem cells

Disruption of the purine nucleotide metabolismgenerally results in an accumulation and/or a lack ofribonucleotides or deoxyribonucleotides or metabolic intermediateswith potentially cytotoxic consequences. The observed decreasedexpression of the 3 purine metabolism enzymes affects both synthesis and the salvage pathway of purine metabolism andmay also affect purine nucleotide homeostasis in TRAIL-resistantHBL-2/R cells. Such an imbalance may represent a selectivedisadvantage for the affected cells. Such a ‘weakness’ may not beapparent under normal circumstances but may become critical understress or unfavorable conditions. As the proliferation rates ofHBL-2/R and HBL-2 cells are comparable, the proposed imbalance inpurine nucleotide metabolism in TRAIL-resistant cells is possiblymild and/or well compensated . However, this‘weakness’ may become apparent due to lack of building blocks forDNA and RNA synthesis in the environment or upon further disruptionof purine metabolism. Since both pathways of purine metabolism arecompromised in TRAIL-resistant MCL cells, these cells should bevulnerable to further inactivation of purine nucleotide metabolismenzymes. Therefore, drugs that target (already disbalanced) purinemetabolism should be highly cytotoxic to TRAIL-resistant cells(compared to non-malignant cells) and may therefore be selectivelyeffective in the elimination of TRAIL-resistant MCL cells inexperimental therapy. There are several approved inhibitors ofpurine metabolism, such as methotrexate (inhibits purine synthesis via dihydrofolate reductase) (), ribavirin and mycophenolic acid(inhibitors of IMPDH2) (,) or forodesine (a novel inhibitor ofPNP) (,), available for clinical use.

The downregulation of the 3 key enzymes of purinemetabolism can have a profound effect on nucleotide homeostasis inTRAIL-resistant lymphoma cells. Purine nucleotides, the buildingblocks for synthesis of DNA, RNA and enzyme co-factors, arerecruited either from purine synthesis from lowmolecular weight precursors or by recycling of free nucleobases inthe so-called salvage pathway. Both pathways lead to the productionof nucleoside-5′-phosphates (). Both pathways can supply cellular demand independently;however, their importance in different tissues is variable. Inleukemic and lymphoma cells the salvage pathway is considered themajor source of purine nucleotides (,).

novo and salvage pathways of DNA synthesis in ..

De novo and salvage biosynthetic pathways of ..

Nucleotides released by enzymatic digestion of nucleic acids are rather efficiently reutilized for nucleic acid biosynthesis in most cells. However, pathways of nucleotide degradation are significant, as shown by sometimes unexpected and severe consequences of genetic deficiencies in humans of particular enzymes of purine degradation, as dealt with in the next section.

The early radiolabeling studies identified the precursors of the purine ring (Fig. 1) as glycine, glutamine amide nitrogen, CO2, aspartate amino nitrogen, along with the "one-carbon pool," which included formate or the b-carbon of serine but which is now known to come directly from the formyl group of N10-formyltetrahydrofolate (10-formyl-THF). The pathway is sensitive to inhibition by folate antagonists, such as methotrexate, and glutamine antagonists, such as azaserine, and this sensitivity largely explains the chemotherapeutic efficacy of these classes of antimetabolites. Aside from a number of parasitic protozoans, which lack the capacity for purine ring synthesis and depend on salvage pathways, the de novo purine synthetic pathway is virtually identical among all organisms examined to date.

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  • The purine salvage pathway Synthesis of bases denovo …

    Nucleotide Synthesis (De-novo and Salvage Pathways of Purine & Pyrimidine Biosynthesis PPT by easybiologyclass) 1

  • Both the salvage and de novo synthesis pathways of purine ..

    DE NOVO AND SALVAGE PATHWAYS OF PURINE SYNTHESIS. If you have a complicated or unusual topic and doubt that theres a …

  • Purine and Pyrimidine Metabolism - EHSL

    Nucleotide Synthesis (De-novo and Salvage Pathways of Purine & Pyrimidine Biosynthesis PPT by easybiologyclass)

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Activation of Ribose-5-Phosphate

An S, Kumar R, Sheets ED and Benkovic SJ (2008) Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science 320: 103–106.

Chapter 27 - Columbia University

Zhao H, French JB, Fang Y and Benkovic SJ (2013). The purinosome, a multi‐protein complex involved in the de novo biosynthesis of purines in humans. Chemical Communications 49: 4444–4452.

The Synthesis and Degradation of Nucleotides

The biosynthetic pathway for the purine ring was described in the 1950s, in a classic series of experiments carried out in the laboratories of John Buchanan and G. Robert Greenberg. Birds excrete most of their nitrogen in the form of uric acid, an oxidized purine. Therefore, by feeding radiolabeled precursors to pigeons and then chemically degrading the uric acid crystallized from their droppings, it was possible to identify precursors to each position in the ring, and this led to identification of the reactions and isolation of the enzymes involved. This pathway is called the de novo pathway because it involves synthesis of the purine ring from low-molecular-weight precursors. A separate set of pathways is referred to as salvage pathways because they involve reutilization of preformed purine ring-containing compounds, usually nucleosides or nucleobases released by nucleic acid degradation (see Salvage Pathways To Nucleotide Biosynthesis).

Nicotinamide adenine dinucleotide - Wikipedia

Overview of the pathways for the biosynthesis of purine and pyrimidine nucleotides (THF, tetrahydrofolate). Ribonucleoside triphosphates are blue; deoxyribonucleoside triphosphates are green. To emphasise that it is not a building block for deoxyribonucleic acid (DNA) synthesis dUTP is red. Both pathways start from a common set of precursor amino acids and other metabolites. Each arrow represents an enzymatic reaction.

Pathology Outlines - Gout and gouty arthritis

Normally, about two-thirds of the uric acid produced in purine catabolism is excreted through the kidneys; the remainder is further broken down by intestinal bacteria. Renal malfunction can lead to elevation of blood uric acid levels, which is a cause of gout. Gout also results from abnormally high purine nucleotide synthesis, which leads to degradation of the excess. Three specific biochemical changes are known to cause this condition. First, hyperactivity of PRPP synthetase elevates intracellular concentrations of PRPP, the substrate for PRPP amidotransferase, the first and rate-controlling step in the de novo pathway (reaction 1, Fig. 2), and this increases flux through the whole pathway.

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