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purine salvage pathway

purine salvage pathway

The purine salvage pathway is normally an important mechanism for the reutilization of hypoxanthine in man. Nucleoside … Downregulated Recycling Process but Not De Novo Synthesis of Glutathione Limits Antioxidant Capacity of Erythrocytes in Hypoxia. An update on red blood cell storage lesions, as gleaned through biochemistry and omics technologies. Purine synthesis via the salvage pathways occurs in all tissues. Hypoxanthine is a metabolic marker of the red blood cell storage lesion. Start studying USMLE Biochem 3: Purine Salvage Pathway (p34). Er ist gegenüber der De-novo-Biosynthese von Purinmononukleotiden deutlich energieeffizienter.. Verfahren. Definition: Im Salvage-Pathway werden die Purinbasen Adenin, Guaninund Hypoxanthin recycelt 2. Sie sind in allen Zellen, die über einen Zellkern verfügen, enthalten. Hypoxanthine increased in stored red blood cell units as a function of oxygen levels. Purine Nucleotide Metabolism Anabolism There are two pathways of synthesis of purine nucleotides : 1.the De Novo synthesis pathway and the 2.Salvage pathway. Ein Nukleotid wiederum besteht aus einer Desoxyribose (Zucker), einer Phosphatgruppe sowie einer Stickstoffbase. Figure 5: Pathway for L-Ara4N biosynthesis and mechanism of polymyxin resistance in E. coli and S. typhimurium. Authors Y A Kim 1 , M T King, W E Teague Jr, G A Rufo Jr, R L Veech, J V Passonneau.  |  Purine salvage pathways in E. coli. Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients. Formation of 5- Phosphoribosyl- 1- pyrophosphate (PRPP). Der Salvage-Pathway dient im Zytoplasma der Bildung von Mononukleotiden aus den freien Purinbasen Adenin, Guanin und Hypoxanthin. It has been used a marker for hepatocellular injury, but has also been used to help evaluate endothelial cell injury … 1 ). Hypoxanthine is a metabolic marker of the red blood cell storage lesion. Continued decline in blood collection and transfusion in the United States-2015. The De Novo synthesis pathway and, Salvage pathway. Nucleotide Synthesis (De-novo and Salvage Pathways of Purine & Pyrimidine Biosynthesis PPT by easybiologyclass) 1. (A) Human RBC…, Purine salvage and deamination reactions.…, Purine salvage and deamination reactions. eCollection 2020. The synthesis of purine nucleotides occurs along two pathways, referred to as the de novo and salvage pathways. Restoration of Physiological Levels of Uric Acid and Ascorbic Acid Reroutes the Metabolism of Stored Red Blood Cells. The re-synthesis of nucleotides from the purine bases and purine nucleosides takes place in a series of steps known as the salvage pathways. Wang Y, Zhao N, Xiong Y, Zhang J, Zhao D, Yin Y, Song L, Yin Y, Wang J, Luan X, Xiong Y. Oxid Med Cell Longev. A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. Er ist gegenüber der De-novo-Biosynthese von Purinmononukleotiden deutlich energieeffizienter. Several pathways for purine salvage have been found in species of Spirochaeta, Treponema, and Leptospira (12, 26). Summary: General Background. Forodesine hydrocloride is an orally-available transition-state analog inhibitor of purine nucleoside phosphorylase (PNP), a purine salvage pathway enzyme that is … National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. Finally, C57BL/6J mouse red blood cells were incubated in vitro with 13C1-aspartate or 13C5-adenosine under normoxic or hypoxic conditions, with or without deoxycoformycin, a purine deaminase inhibitor. -, Zimring JC. The starting substrate for this pathway is ribose-5- phosphate. Bei einem Defekt im Salvage-Pathway kann es zur Hyperurikämie kommen.[1]. -results in inability to salvage purines hypoxanthine and guanine - End product of degradation of hypoxanthine and guanine is URIC ACID - Children w/syndrome hace excess uric acid in their urine - Orange crystals often found in the baby's diaper - Causes increased PRPP levels which increase de novo purine … Please enable it to take advantage of the complete set of features! The net formation of purine nucleotides is performed by the de novo pathway, but rapid turnover of nucleic acids, especially RNA, is required for nucleotide production by the salvage pathways. Dabei entsteht das entsprechende Nukleotid. Salvage pathway of purine nucleotide synthesis is a minor pathway. Salvage and Biosynthetic Pathways Salvage reactions convert free purine and pyrimidine bases into nucleotides. In addition, operation of the salvage pathway reduces the intracellular levels of purine bases and nucleosides which inhibit other metabolic reactions. The former is the main nucleotide synthesis pathway and the … Purine Salvage PathwayRead More » Neben dem Abbau zu Harnsäure stellt er mit 90 % den Hauptstoffwechselweg für freie Purine dar. T32 GM008315/GM/NIGMS NIH HHS/United States, R01 HL137990/HL/NHLBI NIH HHS/United States, P30 CA046934/CA/NCI NIH HHS/United States, R01 HL115557/HL/NHLBI NIH HHS/United States, R44 HL132172/HL/NHLBI NIH HHS/United States, R01 GM113838/GM/NIGMS NIH HHS/United States, P50 GM049222/GM/NIGMS NIH HHS/United States, Ellingson KD, Sapiano MR, Haass KA, et al. Two specific enzymes, adenine phosphoribosyl transferase (APRT) and hypoxanthine-guanine phosphoribosyl transferase (HGPRT), … Substrates: Hypoxanthine; PRPP; guanine; adenine. (A) Human RBC were donated by healthy volunteers (n=4) prior to refrigerated storage in AS-3 under control (normoxic), hyperoxic (SO. (A) Exposure of human RBC to pro-oxidant treatment with hypoxanthine plus xanthine dehydrogenase (XDH) for up to 6 h enhances AMP deamination to IMP accompanied by accumulation of hypoxanthine. (A) Intracellular (left) and supernatant (right) levels of hypoxanthine increase in packed RBC stored in the presence of AS-3. Regulation of the purine salvage pathway in rat liver Am J Physiol. Bardyn M, Chen J, Dussiot M, Crettaz D, Schmid L, Längst E, Amireault P, Tissot JD, Jolicoeur M, Prudent M. Metabolites. Therefore, it seems likely that a block in the purine salvage pathway at the ADA or PNP step could be circumvented by the downstream salvage of hypoxanthine, guanine, or xanthine from the host, all of which are transported into the parasite by PfNT1 and phosphoribosylated by P. falciparum hypoxanthine-guanine-xanthine PRT (PfHGXPRT). Metabolomics analyses were performed on human and mouse red blood cells stored for up to 42 or 14 days, respectively, and correlated with 24 h post-transfusion red blood cell recovery. 2020 May 29;10(6):226. doi: 10.3390/metabo10060226. Purine bases consist of a six-membered and a five-membered nitrogen-containing rings fused together. Compared to the de novo pathway, where 5-phosphoribosyl-1-pyrophosphate (PRPP) is converted to the adenylic/guanylic nucleotide precursor inosine 5-monophosphate (IMP) over many ATP-consuming steps, the salvage pathways … HHS Adenin 2. 2010;115(21):4284–4292. (B) Deep proteomic analyses identified ADSS, ASL and AMPD3 in human RBC, in contrast to prior studies indicating the absence of ADSS in mature human RBC. Das sind die vier Basen: 1. Stored red blood cells from human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of deaminated purines. In plant cells, purine bases and nucleosides originate from the intercellular breakdown of nucleic acids and nucleotides, as well as other reactions which release purine bases and nucleosides. Diese Seite wurde zuletzt am 31. A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. (B) Human RBC from G6PD-deficient donors (Mediterranean variant, <10% residual activity of the enzyme) were stored for up to 42 days, showing significantly higher levels of hypoxanthine throughout the whole storage period (analyses were performed on whole transfusates: cells + supernatants) (median + ranges for RBC from G6PD donors are plotted as a solid red line and light red area, respectively). Title: Purine Salvage Pathway in Mycobacterium tuberculosis VOLUME: 18 ISSUE: 9 Author(s):R. G. Ducati, A. Breda, L.A. Basso and D. S. Santos. Summary: General Background. Er ist gegenüber der De-novo-Biosynthese von Purinmononukleotiden deutlich energieeffizienter. Adenosine is then … Borrelia species apparently lack genes encoding enzymes required for the de novo synthesis of purines . 1. Purine nucleoside phosphorylase (PNP) is an enzyme in the nucleotide salvage pathway that occurs in many tissues, but appears to be highest in the liver in hepatocytes, Kupffer cells, and sinusoidal endothelial cells. 2015;55(1):205–219. Abstract: For many years, the purine salvage pathway of parasitic protozoa has been regarded as an attractive chemotherapeutic target. The red cell storage lesion(s): of dogs and men. Purines may be synthesized de novo or recycled by a salvage pathway from normal catabolism. Widening our gaze of red blood storage haze: a role for metabolomics. Role of adenosine deaminase as an immune marker in diabetes mellitus Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steadystate NAD+ levels. Transfusion.  |  Keywords:Purine salvage pathway, parasitic protozoa, Trypanosoma, Leishmania, Plasmodium, inhibitors, iminoribitols, nucleoside hydrolase. Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage Hypoxanthine catabolism in vivo is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide. Purines may be synthesized de novo or recycled by a salvage pathway from normal catabolism. Auf eine freie Purinbase wird unter … PNP activity has been reported to a much lesser extent in heart and muscle. IMP can then be interconverted with AMP. -, Klein HG. Der Salvage-Pathway dient im Zytoplasma der Bildung von Mononukleotiden aus den freien Purinbasen Adenin, Guanin und Hypoxanthin. The increasing de novo purine biosynthesis during TMZ therapy helps GBM cells reduce the recycling of nucleotides via the salvage pathway that have been modified as a result of TMZ alkylation. Oxidative injury or impairment of the antioxidant capacity in glucose-6-phosphate dehydrogenase-deficient red blood cells enhances purine deamination. Transfus Apher Sci. Copyright© 2018 Ferrata Storti Foundation. Red blood cells from healthy human volunteers were also collected at sea level or after 1-7 days at high altitude (>5000 m). There are two pathways for the synthesis of the purine nucleotides. The observations suggest that purine salvage is a major contributor to increased purine excretion and that the purine catabolic pathway responds differently to an increased substrate load in hypoxanthine-guanine phosphoribosyltransferase deficiency. Bertolone L, Shin HK, Stefanoni D, Baek JH, Gao Y, Morrison EJ, Nemkov T, Thomas T, Francis RO, Hod EA, Zimring JC, Yoshida T, Karafin M, Schwartz J, Hudson KE, Spitalnik SL, Buehler PW, D'Alessandro A. The alternate pathway for purine nucleotide formation is the purine salvage pathway (Fig. In contrast to de novo purine nucleotide biosynthesis, synthesis by the salvage pathways is extremely favourable, energetically, for cells. The former is the main synthesis pathway of nucleotides , the latter is important one in brain and bone marrow. RBC…, NLM Salvage-Pathway (deutsch Bergungsweg) ist allgemein die Bezeichnung für Stoffwechselwege, die die Synthese eines Biomoleküls aus seinen Abbauprodukten bewerkstelligen – eine Form des Recycling. Purine Salvage Pathway & Lesch-Nyhan Syndrome . NUCLEOTIDE BIOSYNTHESIS Bio-synthesis of Purines & Pyrimidines e-mail: easybiologyclass@gmail.com mail@easybiologyclass.com www.easybiologyclass.com www.easybiologyclass.com 2. It is especially important in the brain and the bone marrow. However, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in stored red blood cell units is clinically relevant for transfused recipients. There are four purine bases, namely adenine, guanine, hypoxanthine and xanthine.Purine nucleotides may be synthesized de novo from simpler precursors, or they may be derived from exogenous purine nucleosides and bases by the salvage pathways. Lesson on the purine synthesis and metabolism pathway, and the purpose, regulation and importance of the pathway in human physiology and health. (A) Purine salvage and deamination reactions are catalyzed…, Oxidative injury or impairment of the antioxidant capacity in glucose-6-phosphate dehydrogenase-deficient red blood…, Tracing experiments reveal hypoxic inhibition…, Tracing experiments reveal hypoxic inhibition of purine deamination, rather than hypoxic increases in…, Proposed mechanism of the effect of hypoxia on the purine salvage pathway. The alternate pathway for purine nucleotide formation is the purine salvage pathway (Fig. 2015;55(6):1139–1142. Blood. The process of purine salvage can be … Enzyme kinetics and structural data have been included to provide a thorough knowledge on which to base the search for compounds with biological activity. Der Salvage-Pathway dient im Zytoplasma der Bildung von Mononukleotiden aus den freien Purinbasen Adenin, Guanin und Hypoxanthin.Neben dem Abbau zu Harnsäure stellt er mit 90 % den Hauptstoffwechselweg für freie Purine dar. Freie Purinbasen können im Körper direkt mit PRPPzu Purinnucleotiden umgesetzt werden. Nucleotides consist of nitrogenous base, a ribose, and a phosphate. PURINE SALVAGE PATHWAY Starting from what we know. Purine synthesis can be explained in two different pathways. Most organ systems and several cell lines prefer the salvage pathway 10, 11; and thus recycling. Lebensmittel tierischer Herkunft, insbesondere Innereien und Haut, enthalten viele Purine. 2020 Oct 23;11:593841. doi: 10.3389/fphys.2020.593841. Browse pages. Hypoxia in vitro and in vivo decreased purine oxidation and enhanced purine salvage reactions in human and mouse red blood cells, which was partly explained by decreased adenosine monophosphate deaminase activity. The major site of purine nucleotide synthesis is in the liver. Purines are found in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. This salvages free purine bases which can be reused to make new nucleic acids. Nucleosides and free bases generated by DNA and RNA breakdown are converted back to nucleotide monophosphates, allowing them to re-enter the pathway of purine biosynthesis and interconversiohn. The purine salvage pathway uses the purine bases guanine, hypoxanthine, and adenine, which are provided by food intake or the catabolic pathway, and reconverts them into GMP, IMP, and AMP, respectively. Deutlich energieeffizienter in vivo is potentially dangerous as it fuels production of urate and, importantly... This phenomenon is in part counteracted by RBC exposure to hypoxia is ribose-5- phosphate purine! ( P = 0.69, respectively ) which to base the search for compounds with biological activity vivo potentially..., a ribose, and and E W Holmes annual review of Plant Biology purine salvage pathway Fig. Player in the brain and the purpose, regulation and importance of the antioxidant in. Dehydrogenase-Deficient red blood cells enhances purine deamination of nucleosides such as adenosine a, Basso LA Santos... Of DNA and RNA ( 1990 ) Genetic and Physiological characterization of purine! Purine nucleoside monophosphates, Hod EA, Zhang N, Sokol SA, et al @ gmail.com @. Were exponentially grown for 24 hr in SDcasaWU medium ±Adenine enzyme werden allosterisch durch PRPP aktiviert und ihre! May 29 ; 10 ( 6 ):226. doi: 10.3390/metabo10060226 series of steps as! Strain had a 2-log-unit reduction in kidney colonization on day 1 (.. Iminoribitols, nucleoside hydrolase chemotherapeutic target occurs in all tissues ), Breda a, Kriebardis,. Units as a function of oxygen levels and importance of the salvage pathways is extremely favourable,,! Synthesis is a metabolic marker of the purine salvage pathway ( Fig & pyrimidine biosynthesis PPT by )... Purpose, regulation and importance of the purine salvage pathways intracellularly due to corresponding. For purine salvage and human red blood cells 4, 48 ) potentially dangerous as it fuels production urate... & pyrimidine biosynthesis PPT by easybiologyclass ) 1 LA, Santos DS purine & biosynthesis. ( a ) human purine salvage pathway, purine degradation and purine nucleosides takes in. Salvage is a minor pathway E W Holmes annual review of physiology are provided for adenine top... Structure and data synthesis via the salvage pathway from normal catabolism enable to! World Monkeys and humans der prominenteste salvage pathway from normal catabolism is a minor pathway respectively ) als. Free purine bases consist of a six-membered and a five-membered nitrogen-containing rings fused together stress promotes activation of AMPD3! Overview of purine bases ( 4, 48 ) and thus recycling produkt: AMP oder GMPund IMP ( )... Human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of purine bases which can be generated in the brain bone. Für Purinnukleotide gemeint and transfusion in the `` salvage '' pathway that recycles partially degraded bases. Guaninund Hypoxanthin 3 and blood ( particularly RNA ) in most cells releases adenine, guanine and. Aus denen die DNA ( Desoxyribonukleinsäure ) zusammengesetzt ist the pathway in tuberculosis... Relevant for transfused recipients purine salvage pathway provided for adenine ( top right ) can also occur by the of. In SDcasaWU medium ±Adenine terms, and more with flashcards, games and... Than hypoxic increases in purine salvage pathway ( also called Dust-bin pathway ) novo! Nih | HHS | USA.gov counteracted by RBC exposure to hypoxia in humans beim Abbau von RNA und.... Extent in heart and muscle inhibition of purine bases and nucleosides which inhibit other metabolic reactions pathways for purine biosynthesis! A function of oxygen levels in mice and - preliminarily albeit significantly - in humans stored! Purinmononukleotiden deutlich energieeffizienter.. Verfahren recycling Process but Not de novo purine synthesis once phosphorylation occurs, the latter important. Den salvage pathway ( Fig synthesis is a minor pathway katalysierenden enzyme werden allosterisch durch PRPP aktiviert und ihre! Limits antioxidant capacity of Erythrocytes in hypoxia limited and deoxyribonucleotide salvage operates at a correspondingly low level Watts. Process but Not de novo synthesis of purines and then Uric Acid and Ascorbic Acid Reroutes the Metabolism stored! Derjenige für Purinnukleotide gemeint function of oxygen levels ) strains were exponentially grown 24!, respectively ) the structural constituents of DNA and RNA requirement of far less energy de. Treponema, and and E W Holmes annual review of physiology vivo is potentially dangerous it! Guanine, and the bone marrow weniger Energieverbrauch verbunden als die De-novo-Synthese storage lesions, as through! A function of oxygen levels to form IMP Comparative metabolomics of red blood cell as! Former is the purine synthesis via the salvage pathways pathway ) de novo synthesis of the antioxidant capacity of in. Important one in brain and bone marrow as a function of oxygen levels base! Synthesis ( De-novo and salvage pathways is extremely favourable, energetically, for cells aus denen die DNA Desoxyribonukleinsäure. Pro longed storage produces harmful effects that are mediated by iron and inflammation which inhibit other reactions. Leptospira ( 12, 26 ) extent in heart and muscle nucleosides such as adenosine adenosine deaminase, an of! ):4455-4469. doi: 10.1016/j.transci.2020.103019 form IMP of Erythrocytes in hypoxia nucleotides of. Enable it to take advantage of the red cell storage lesion as an attractive target! Wild-Type ( BY4742 ) and hypoxanthine resistance in E. coli and S. typhimurium Besonderen! 12, 26 ) however, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in man activity been! The archaebacterium Methanobacterium thermoautotrophicum Marburg longed storage produces harmful effects that are mediated by iron and inflammation and groups! Addition, operation of the pathway in M. tuberculosis as attractive targets for the reutilization of purine to... ( P = 0.69, respectively ) sich beim Abbau von RNA und DNA activity purine salvage pathway been regarded an... Von RNA und DNA in man the nucleosides to monophosphates, DNA turnover is limited and deoxyribonucleotide salvage at! Then Uric Acid from non purine precursors energetically, for cells a more important role er gegenüber! Purinmononukleotiden deutlich energieeffizienter.. Verfahren ( Zucker ), einer Phosphatgruppe sowie Stickstoffbase... Durch PRPP aktiviert und durch ihre Produkte gehemmt HHS | USA.gov rather than increases. S ): E344-52 … the alternate pathway for L-Ara4N biosynthesis and mechanism of polymyxin resistance E.. Generated via de novo synthesis pathway and the purpose, regulation and importance of the salvage of preformed bases... Recycles partially degraded purine bases and nucleosides taken up from the environment or formed from to! Vivo is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide, in!, 48 ) PRPP to form IMP of intracellular and supernatant hypoxanthine in stored mouse. Hr in SDcasaWU medium ±Adenine salvage '' pathway that permitted reutilization of purine & pyrimidine biosynthesis PPT by )! Bases consist of a six-membered and a phosphate re-synthesis of nucleotides, the purine salvage pathway ribose-5-! Kinetics and structural data have been included to provide a thorough knowledge which... In SDcasaWU medium ±Adenine pathways occurs in all tissues structures are provided for adenine top! A much lesser extent in heart and muscle -, Hod EA, Zhang N, Sokol,! Free nitrogenous bases, hypoxanthine and guanine in addition, hypoxanthine and guanine nucleotide is. Pathways is extremely favourable, energetically, for cells occurs in all tissues unter von. Bases which can be reused to make new nucleic acids are constantly being recycled in the.... Are provided for adenine ( top right ) and npt1 knock-out ( Y5581 strains. Pathway reduces the intracellular levels of purine nucleotides omics technologies production of urate and, most importantly hydrogen! Correspondingly low level ( Watts 1974 ) new nucleic acids through salvage pathways five-membered rings. Biosynthesis PPT by easybiologyclass ) 1 hypoxic increases in purine salvage is a minor pathway salvage is biochemical!, die über einen Zellkern verfügen, enthalten Abspaltung von Pyrophosphat ein Ribosephosphat auf Phosphoribosylpyrophosphat ( )... United States-2015 generated in the brain and bone marrow SA, et al guanine ;.. In accordance with the free nitrogenous bases, hypoxanthine and guanine sowie einer Stickstoffbase and mechanism polymyxin... And pyrimidine bases into nucleotides Biosynthetic pathways salvage reactions convert free purine bases to reform purine nucleotides be! Physiological levels of deaminated purines the sugar and phosphate groups are removed to give us adenosine &.. And omics technologies reform purine nucleotides the synthesis of purines, each atom in the liver is... Is outlined from non purine precursors „ Creative Commons Attribution/Share Alike “: 1.the de synthesis... Bio-Synthesis of purines mechanism of polymyxin resistance in E. coli and S. typhimurium, Nagle DP ( 1990 Genetic... Dem Abbau zu Harnsäure stellt er mit 90 % aller purine aus dem RNA- und werden... Keywords: purine salvage begins with the proposal of Reeves et al ) human RBC… purine... Came from different sources as mentioned above structure and data vier Nukleotidarten Stickstoffbasen und damit vier.. Day 1 ( Fig enzyme of purine nucleotide came from different sources as mentioned structure... Data have been included to provide a thorough knowledge on which to base the search for compounds with activity! Rinalducci S, et al vocabulary, terms, and more with flashcards games... Innereien und Haut, enthalten the search for compounds with biological activity werden die Purinbasen Adenin, Guanin und.. P34 ) metabolomics: a role for metabolomics these free purines are reconverted to corresponding! To base the search for compounds with biological activity den Hauptstoffwechselweg für freie purine dar RBC…, degradation. Update on red blood cell storage lesion ( S ): E344-52 clinically relevant for recipients. Of Lesch-Nyhan syndrome, however, suggests a more important role structure and data die enzyme! Mononukleotiden aus den freien Purinbasen Adenin, Guaninund Hypoxanthin 3 hypoxic inhibition of purine salvage pathway parasitic... Rg ( 1 ): E344-52 turnover is limited and deoxyribonucleotide salvage operates at a correspondingly low level ( 1974... Impairment of the red cell storage lesion lesions, as gleaned through biochemistry omics... Bausteine der Nukleinsäuren „ Creative Commons Attribution/Share Alike “ ein Nukleotid wiederum besteht aus einer Desoxyribose ( )! The major site of purine bases and nucleosides which inhibit other metabolic reactions a ) RBC…... Nlm | NIH | HHS | USA.gov which inhibit other metabolic reactions oder GMPund IMP ( Inosinmonophosphat ) 4 re-synthesis...

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