Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to purine synthesis inhibitors and/or methionine starvation. We reported previously that the MTAP gene is deleted in adult T cell leukemia (ATL) cells. In the present study, we expanded our series and used a real-time quantitative PCR assay for accurate diagnosis of the deletion and nine of 65 primary ATL samples (13.8%) were MTAP negative. In spite of this low incidence, ATL cells showed significantly higher sensitivity to L-alanosine, an inhibitor of de novo adenosine monophosphate (AMP) synthesis, than normal lymphocytes, suggesting that the MTAP gene is inactivated not only by deletion but also by other mechanisms. Indeed, a real-time quantitative RT-PCR assay disclosed that primary ATL cells had significantly lower MTAP mRNA expression than normal lymphocytes. Since MTAP-negative ATL cell lines also showed much higher sensitivity to L-alanosine than MTAP-positive ATL cell lines, we used these cell lines to investigate whether it is possible to develop selective therapy targeting MTAP deficiency. A substrate of MTAP, methylthioadenosine (MTA) or its substitutes rescued concanavalin A (Con A)-activated normal lymphocyte proliferation from L-alanosine toxicity. All the compounds except 5'-deoxyadenosine, however, also caused the undesirable rescue of MTAP-negative ATL cell lines. 5'-Deoxyadenosine had the desired ability to rescue hematopoietic progenitor cells without rescuing ATL cell lines. These results support the rationale for a chemotherapy regimen of L-alanosine combined with 5'-deoxyadenosine rescue in MTAP-deficient ATL.
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PMID:Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL). 1220 Jun 96

In this paper, we report that cells undergoing metabolic stress conditions may use the ribose moiety of nucleosides as energy source to slow down cellular damage. In fact, the phosphorolytic cleavage of the N-glycosidic bond of nucleosides generates, without energy expense, the phosphorylated pentose, which through pentose phosphate pathway and glycolysis, can be converted to energetic intermediates. In this respect, nucleosides may be considered as energy source, alternative or supplementary to glucose, which may become of primary importance especially in conditions of cellular stress. In accordance with the role of these compounds in energy repletion, we also show that the uptake of nucleosides is increased when the energetic demand of the cell is enhanced. As cell model, we have used a human colon carcinoma cell line, LoVo, and the depletion of ATP, with a concomitant fall in the cell energy charge, has been induced by exclusion of glucose from the medium and pre-incubation with oligomycin, an inhibitor of oxidative phosphorylation. In these conditions of energy starvation, we show that the uptake of 2'-deoxyadenosine in LoVo cells is significantly enhanced, and that the phosphorylated ribose moiety of inosine can be used for energy repletion through anaerobic glycolysis. Our data support previous reports indicating that the phosphorylated ribose stemming from the intracellular catabolism of nucleosides may be used in eukaryots as energy source, and advance our knowledge on the regulation of the uptake of nucleosides in eukaryotic cells.
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PMID:Uptake and utilization of nucleosides for energy repletion. 1569 39