6-Azauridine, an Inhibitor of the Purine Salvage Pathway

Abstract Purine nucleoside phosphorylase (PNP), the enzyme schematically next to adenosine deaminase in the purine salvage pathway, has been demonstrated cytochemically in peripheral blood lymphocytes of healthy subjects and chronic lymphocytic leukemia (CLL) patients. The enzyme activity is confined to the cytosol. In healthy subjects the majority of lymphocytes are strongly reactive for PNP, whereas the rest are devoid of cytochemically demonstrable activity. The percentage of PNP- positive cells largely corresponds to the number of E rosette-forming cells and is inversely proportional to the number of Ig-bearing cells. In six of seven CLL patients studied only a minor percentage of the lymphocytes showed strong PNP activity, whereas the large majority (88%- -98%) possessed trace activity. Such patients have a high number of Ig- bearing cells and a low number of E rosette-forming cells. A different pattern of markers was found in the lymphocytes of the seventh CLL patient: 66% were strongly reactive for PNP, an important number formed E rosettes, and a minor percentage were Ig bearing. These data indicate that PNP can be useful as a “nonmembrane” marker in the differentiation of the B and T cell origin in CLL and deserves to be studied in other lymphoproliferative disorders.

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Identification of a novel putative inhibitor of the Plasmodium falciparum purine nucleoside phosphorylase: exploring the purine salvage pathway to design new antimalarial drugs

Molecular Diversity ◽

10.1007/s11030-017-9745-8 ◽

2017 ◽

Vol 21 (3) ◽

pp. 677-695 ◽

Cited By ~ 8

Author(s):

Luciano Porto Kagami ◽

Gustavo Machado das Neves ◽

Ricardo Pereira Rodrigues ◽

Vinicius Barreto da Silva ◽

Vera Lucia Eifler-Lima ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Purine Nucleoside Phosphorylase ◽

Antimalarial Drugs ◽

Purine Nucleoside ◽

Salvage Pathway ◽

Purine Salvage ◽

Nucleoside Phosphorylase

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Transport of purines and purine salvage pathway inhibitors by the Plasmodium falciparum equilibrative nucleoside transporter PfENT1

Molecular and Biochemical Parasitology ◽

10.1016/j.molbiopara.2009.10.001 ◽

2010 ◽

Vol 169 (1) ◽

pp. 40-49 ◽

Cited By ~ 23

Author(s):

Paul M. Riegelhaupt ◽

María B. Cassera ◽

Richard F.G. Fröhlich ◽

Keith Z. Hazleton ◽

Jonathan J. Hefter ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Nucleoside Transporter ◽

Salvage Pathway ◽

Purine Salvage ◽

Equilibrative Nucleoside Transporter

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Inhibitors of the Purine Salvage Pathway: A Valuable Approach for Antiprotozoal Chemotherapy?

Current Medicinal Chemistry ◽

10.2174/092986710791556023 ◽

2010 ◽

Vol 17 (23) ◽

pp. 2456-2481 ◽

Cited By ~ 54

Author(s):

M. Berg ◽

P. Van der Veken ◽

A. Goeminne ◽

A. Haemers ◽

K. Augustyns

Keyword(s):

Salvage Pathway ◽

Purine Salvage

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New Strategy That Delays Progression of Amyotrophic Lateral Sclerosis in G1H-G93A Transgenic Mice: Oral Administration of Xanthine Oxidoreductase Inhibitors That Are Not Substrates for the Purine Salvage Pathway

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlw088 ◽

2016 ◽

Vol 75 (12) ◽

pp. 1124-1144 ◽

Cited By ~ 4

Author(s):

Shinsuke Kato ◽

Masako Kato ◽

Teruo Kusano ◽

Takeshi Nishino

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Transgenic Mice ◽

Oral Administration ◽

Xanthine Oxidoreductase ◽

Salvage Pathway ◽

Purine Salvage ◽

New Strategy ◽

Lateral Sclerosis ◽

G93a Transgenic Mice

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Molecular mechanism of regulation of the purine salvage enzyme XPRT by the alarmones pppGpp, ppGpp, and pGpp

10.1101/2020.03.04.977603 ◽

2020 ◽

Author(s):

Brent W. Anderson ◽

Aili Hao ◽

Kenneth A. Satyshur ◽

James L. Keck ◽

Jue D. Wang

Keyword(s):

Binding Sites ◽

Bacterial Species ◽

Evolutionary Conservation ◽

Differential Regulation ◽

Hill Coefficient ◽

Binding Motif ◽

Salvage Pathway ◽

Purine Salvage ◽

Starvation Response ◽

Dimer Interface

ABSTRACTThe alarmones pppGpp and ppGpp mediate starvation response and maintain purine homeostasis to protect bacterial species. Xanthine phosphoribosyltransferase (XPRT) is a purine salvage enzyme that produces the nucleotide XMP from PRPP and xanthine. Combining structural, biochemical and genetic analyses, we show that pppGpp and ppGpp, as well as a third putative alarmone pGpp, all directly interact with XPRT and inhibit XPRT activity by competing with its substrate PRPP. Structural analysis reveals that ppGpp binds the PRPP binding motif within the XPRT active site. This motif is present in another (p)ppGpp target, the purine salvage enzyme HPRT, suggesting evolutionary conservation in different enzymes. However, XPRT oligomeric interaction is distinct from HPRT in that XPRT forms a symmetric dimer with two (p)ppGpp binding sites at the dimer interface. This results in two distinct regulatory features. First, XPRT cooperatively binds (p)ppGpp with a Hill coefficient of 2. Also, XPRT displays differential regulation by the alarmones as it is potently inhibited by both ppGpp and pGpp, but only modestly by pppGpp. Lastly, we demonstrate that the alarmones are necessary for protecting GTP homeostasis against excess environmental xanthine in Bacillus subtilis, suggesting that regulation of XPRT is key for regulating the purine salvage pathway.

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