Salvage pathways as targets of chemotherapy

Weber, George; Jayaram, Hiremagalur N.; Pillwein, Konrad; Natsumeda, Yutaka; Reardon, Melissa A.; Yong, Zhen

doi:10.1016/0065-2571(87)90022-7

Cited by 36 publications

(17 citation statements)

References 14 publications

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“…In contrast, the reserve capacity of de novo synthesis for changing its metabolic rate was relatively high, and could be attained through several regulatory mechanisms including the allosteric activation or inhibition of ATase activity (29,30), the cell cycle-dependent expression of the ATase gene (31), and the relatively short half-life of the ATase protein. 2 Resting human T lymphocytes were reported to meet their metabolic demands via the salvage pathway except during cell growth, while intact de novo synthesis is essential for the proliferation of phetohemagglutinin-stimulated T lymphocytes (32). The large capacity of de novo synthesis has been shown in patients with LeschNyhan's syndrome (complete deficiency of HPRT) and in cultured cells from patients with this syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…key enzyme of the purine salvage pathway, was reported to be more active than that catalyzed by ATase, the presumed ratelimiting enzyme of the de novo pathway, in many tissues and malignant cells (1,2). The increased metabolic rate via the de novo pathway and ATase activity are, however, more strongly linked with cell growth and malignant transformation than the metabolic rate via the salvage pathway and HPRT activity (1,(3)(4)(5)(6)(7).…”

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confidence: 99%

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Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Yamaoka

Kondo

Honda

et al. 1997

Journal of Biological Chemistry

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Factors controlling relative flux rates of the de novo and salvage pathways of purine nucleotide biosynthesis during animal cell growth are not fully understood. To examine the relative role of each pathway for cell growth, three cell lines including CHO K1 (a wild-type Chinese hamster ovary fibroblast cell line), CHO ade ؊ A (an auxotrophic cell line deficient of amidophosphoribosyltransferase (ATase), a presumed rate-limiting enzyme of the de novo pathway), and CHO ade ؊ A transfected with human ATase cDNA ( ؊ A؉hATase) resulting in 30 -350% of the ATase activity of CHO K1, were cultured in purine-rich or purine-free media. Based on the enzyme activities of ATase and hypoxanthine phosphoribosyltransferase, the metabolic rate of the de novo and salvage pathways, the rate of cell growth (growth rate) in three cell lines under various culture conditions, and the effect of hypoxanthine infusion on the metabolic rate of the de novo pathway in rat liver, we concluded the following. 1) In ؊ A؉hATase transfectants, ATase activity limits the rate of the de novo pathway, which is closely linked with the growth rate. 2) Purine nucleotides are synthesized preferentially by the salvage pathway as long as hypoxanthine, the most essential source of purine salvage, can be utilized, which was confirmed in rat liver in vivo by hypoxanthine infusion. The preferential usage of the salvage pathway results in sparing the energy expenditure required for de novo synthesis.3) The regulatory capacity of the de novo pathway (about 200%) was larger than that of the salvage pathway (about 20%) with constant hypoxanthine phosphoribosyltransferase activity.Purine nucleotides synthesized via de novo and salvage pathways are indispensable for cell growth through DNA and RNA syntheses and for the ATP energy supply. Interference of purine metabolism has thus been the target of antineoplastic drugs. However, it is unclear which of the two pathways is more important for the supply of purine nucleotides during cell growth. Purine nucleotide synthesis catalyzed by HPRT, 1 the key enzyme of the purine salvage pathway, was reported to be more active than that catalyzed by ATase, the presumed ratelimiting enzyme of the de novo pathway, in many tissues and malignant cells (1, 2). The increased metabolic rate via the de novo pathway and ATase activity are, however, more strongly linked with cell growth and malignant transformation than the metabolic rate via the salvage pathway and HPRT activity (1, 3-7). To interpret this enigma, we investigated the mutual regulation of purine biosynthesis between the de novo and salvage pathways. The cDNA cloning of rat and human ATase (hATase) in our laboratory (8, 9), an ATase-deficient auxotrophic Chinese hamster ovary fibroblast cell line of CHO ade Ϫ A, and CHO ade Ϫ A transfected with hATase cDNA driven by the cytomegalovirus promoter ( Ϫ AϩhATase) enabled us to explore the rate-limiting property of ATase and to study the relationship between the two pathways in three cell lines in two purine-free or two purine-...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Yamaoka

Kondo

Honda

et al. 1997

Journal of Biological Chemistry

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“…1). Salvage enzymes have a greater affinity for PRPP than does the initial PRPP-requiring enzyme of de novo synthesis [36][37][38], and preferred utilization of PRPP by the salvage pathway would thereby limit de novo synthesis.…”

Section: Discussionmentioning

confidence: 99%

Hypoxanthine Regulation of Oocyte Maturation in the Mouse: Insights Using Hypoxanthine Phosphoribosyltransferase-Deficient Animals1

Downs

1997

Biology of Reproduction

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In this study the effects of hypoxanthine (HX) on meiotic maturation were compared using oocytes from mice possessing a hypoxanthine phosphoribosyltransferase null mutation (HPRT-) and from the corresponding HPRT-competent background strain (HPRT+). Oocyte-cumulus cell complexes and cumulus cell-enclosed oocytes (oocytes cultured while enclosed by cumulus cells) from HPRT+, but not HPRT-, mice took up HX and contained significant levels of HPRT activity. In addition, FSH increased, and HX suppressed, the de novo synthesis of purines in HPRT+ complexes, whereas de novo synthesis was elevated in HPRT complexes and was unaffected by FSH or HX. After 3 h of HX treatment, lower frequencies of germinal vesicle breakdown (GVB) were observed in cumulus cell-enclosed than in denuded HPRT+ oocytes; however, identical frequencies of maturation were observed in denuded and cumulus cell-enclosed HPRT oocytes. This demonstrates a direct inhibitory action of HX on the oocyte that does not depend on salvage, plus an additional action of the cumulus cells that requires HPRT activity. Nevertheless, cumulus cells from HPRT- mice are capable of exerting an additional inhibitory action of dibutyryl cAMP (dbcAMP) on the oocyte. A kinetics analysis of FSH action on HX-arrested cumulus cell-enclosed HPRT+ and HPRT- oocytes revealed, first, that the inhibitory effect of the cumulus cells is transient and, second, that HPRT activity is not required for FSH induction of GVB in HX-arrested oocytes. When dbcAMP- or HX-arrested oocytes were treated with FSH, GVB was blocked to the same extent in HPRT- oocytes with the purine de novo synthesis inhibitor, azaserine, but this drug was less effective in HX-treated HPRT+ oocytes. These results confirm the importance of the de novo pathway in hormone-induced maturation and also support a role for purine salvage as an alternative source of nucleotide in this process.

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“…45 and 46), respectively. Arginine, dopamine, glucose, norepinephrine, and thiamine were used as substrates for cationic amino acid transporters (13), dopamine transporter (41), glucose transporters (55,49), neurotransmitter transporters (7), and thiamine transporter (15). Because SVCTs are mammalian orthologs of bacterial nucleobase transporters (24), ascorbate was used as a substrate of SVCTs.…”

Section: Inhibitory Effects Of Several Compounds On Nucleobase Uptakementioning

confidence: 99%

Characterization of novel Na⁺-dependent nucleobase transport systems at the blood-testis barrier

Kato¹,

Maeda²,

Akaike³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Kato, Ryo, Tomoji Maeda, Toshihiro Akaike, and Ikumi Tamai. Characterization of novel Na ϩ -dependent nucleobase transport systems at the blood-testis barrier. Am J Physiol Endocrinol Metab 290: E968 -E975, 2006. First published December 20, 2005 doi:10.1152/ajpendo.00160.2005.-In the testis, nucleosides and nucleobases are important substrates of the salvage pathway for nucleotide biosynthesis, and one of the roles of Sertoli cells is to provide nutrients and metabolic precursors to spermatogenic cells located within the blood-testis barrier (BTB). We have already shown that concentrative and equilibrative nucleoside transporters are expressed and are functional in primary-cultured rat Sertoli cells as a BTB model, but little is known about nucleobase transport at the BTB or about the genes encoding specific nucleobase transporters in mammalian cells. In the present study, we examined the uptake of purine ([ 3 H]guanine) and pyrimidine ([ 3 H]uracil) nucleobases by primary-cultured rat Sertoli cells. The uptake of both nucleobases was time and concentration dependent. Kinetic analysis showed the involvement of three different transport systems in guanine uptake. In contrast, uracil uptake was mediated by a single Na ϩ -dependent high-affinity transport system. Guanine uptake was inhibited by other purine nucleobases but not by pyrimidine nucleobases, whereas uracil uptake was inhibited only by pyrimidine nucleobases. In conclusion, it was suggested that there might be purine-or pyrimidine-selective nucleobase transporters in rat Sertoli cells.nucleoside; Sertoli cells; transporter NUCLEOTIDES PLAY A KEY ROLE as precursors of DNA and RNA, as activated intermediates in many biosynthetic processes, and as metabolic regulators. In general, nucleotides are synthesized via two routes, i.e., the de novo pathway and the salvage pathway (6). In de novo biosynthesis of purine nucleotides, the heterocyclic ring is built up from ␤-D-phosphoribosylamine using six different precursors to generate IMP, and then IMP is used for the production of AMP and GMP. The pyrimidine ring is preformed as orotate and then reacts with ␣-D-ribose 5-phosphoribosyl-1-pyrophosphate (PRPP) to give orotidylate. On the other hand, the salvage pathway is advantageous since degradation products of nucleic acids can be recycled rather than destroyed, which is much less costly than the energy-demanding reactions of the de novo pathway. Both nucleobases and nucleosides are used for salvage nucleotide biosynthesis. A part of the salvage route involves the reaction of purine and pyrimidine nucleosides with ribose 1-phosphate. The reaction is catalyzed by a nucleoside phosphorylase, and the resultant ribonucleosides are converted into the corresponding 5Ј-nucleotides by a cellular kinase. On the other hand, purine nucleobases, which are produced by hydrolytic degradation of nucleotides and nucleic acids, react with PRPP to provide the corresponding purine ribonucleotides. Adenine phosphoribosyltransferase is specific for the reaction with adenine, where...

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Salvage pathways as targets of chemotherapy

Cited by 36 publications

References 14 publications

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Hypoxanthine Regulation of Oocyte Maturation in the Mouse: Insights Using Hypoxanthine Phosphoribosyltransferase-Deficient Animals1

Characterization of novel Na⁺-dependent nucleobase transport systems at the blood-testis barrier

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Salvage pathways as targets of chemotherapy

Cited by 36 publications

References 14 publications

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Hypoxanthine Regulation of Oocyte Maturation in the Mouse: Insights Using Hypoxanthine Phosphoribosyltransferase-Deficient Animals1

Characterization of novel Na+-dependent nucleobase transport systems at the blood-testis barrier

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Characterization of novel Na⁺-dependent nucleobase transport systems at the blood-testis barrier