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Biomedical subjects

J Barankiewicz

Publications and source records attributed to J Barankiewicz.

At least 37 records · Page 2Linked to original sources
PubMed1987

Impairment of nucleotide metabolism by iron-chelating deferoxamine.

The effect of deferoxamine on nucleotide metabolism in HL-60 leukemic cells was studied to explore the mechanism of its antiproliferation activity. It was found that in intact cells deferoxamine markedly inhibited the ribonucleotide reduction and incorporation of bases (adenine, hypoxanthine), ribonucleosides (inosine, guanosine) and deoxyribonucleosides (thymidine, deoxyadenosine, deoxyguanosine) into nucleic acids. Although deferoxamine did not inhibit thymidine and uridine incorporation into free nucleotides, inhibition of hypoxanthine and adenine incorporation into nucleotides as well as inhibition of nucleotide biosynthesis de novo was found. Nucleotide catabolism, protein synthesis, and intracellular levels of ribonucleotides were not affected significantly by deferoxamine. These results showed that deferoxamine selectively affects several specific reactions of nucleotide metabolism. Inhibition of ribonucleotide reduction, inhibition of ribonucleotide and deoxyribonucleotide incorporation into nucleic acids, as well as inhibition of purine biosynthesis, may alter significantly cellular physiology and, therefore, contribute significantly to the antiproliferative activity of deferoxamine.

Cell Division↗
PubMed1987

Purine nucleotide metabolism in phytohemagglutinin-induced human T lymphocytes.

The comprehensive studies of purine nucleotide metabolism were done in nonstimulated and phytohemagglutinin (PHA)-stimulated human peripheral blood T lymphocytes. Nonstimulated lymphocytes synthesize nucleotides in two alternative pathways: via biosynthesis de novo and salvage pathways. Although synthesis of triphosphonucleosides in unstimulated lymphocytes was the predominant pathway, interconversion of monophosphonucleosides was also active. Exposure of cells to PHA affects differently various pathways of nucleotide metabolism. The most marked changes observed were rapid activation of purine salvage within minutes after exposure to PHA, and significant increase of 5-phosphoribosyl-1-pyrophosphate levels. In addition, significant increases were found in de novo purine biosynthesis, nucleotide interconversions, and RNA and DNA synthesis, whereas catabolism of nucleotides remained unchanged. These results indicate that PHA activation of T lymphocytes causes a rapid synthesis of nucleotides which may be required immediately for increases in energy metabolism and later as the precursors of nucleic acid synthesis.

Adenine↗
PubMed1986

Selective protection of tubercidin toxicity by nitrobenzyl thioinosine in normal tissues but not in human neuroblastoma cells.

Tubercidin, an adenosine analogue, is toxic to human neuroblastoma cell lines, to peripheral blood mononuclear cells (PBMCs), and to myeloid colony-forming cells (CFU-C) as tested by a short-term labeled precursor uptake and by a clonogenic assay. When it was co-administered with a potent purine transport inhibitor, nitrobenzyl thioinosine (NBTI), the cytotoxic effect of tubercidin was abolished in PBMCs but not in neuroblastoma cells. Studies of nucleoside transport in neuroblastoma cells demonstrate that although [3H]NBTI binds to the plasma membrane of these cells, the transport of thymidine into the cells is only partially inhibited in the presence of excess NBTI. These data imply that neuroblastoma cells contain a nucleoside transport mechanism which is insensitive to NBTI. "Host protection" with a nucleoside transport inhibitor such as NBTI, may allow effective therapy with otherwise toxic dosages of tubercidin and other cytotoxic nucleosides in patients with neuroblastoma.

Biological Transport↗
PubMed1986

Modification of ribonucleotide and deoxyribonucleotide metabolism in interferon-treated human B-lymphoblastoid cells.

The effect of recombinant interferon-alpha 2 (IFN-alpha 2) (50 U/ml) on the cell cycle, nucleotide metabolism, and protein and nucleic acid synthesis was studied in human B-lymphoblastoid (Daudi) cells. Cell cycle analysis showed that IFN treatment resulted in G0/G1 arrest (69%) as compared to control cells (42% at G0/G1). IFN inhibited the incorporation of radioactive thymidine and uridine into DNA and RNA, respectively, but had only slight effect on incorporation of radioactive threonine, leucine, or valine into proteins. IFN inhibited ribonucleotide biosynthesis by de novo and salvage pathways and decreased level of the P-ribose-PP. Both pathways of deoxyribonucleotide biosynthesis, ribonucleotide reduction and deoxyribonucleoside salvage, were also markedly inhibited by IFN., In contrast, ribonucleotide catabolism was significantly increased in the presence of IFN. No changes in ribonucleotide interconversion were found. Intracellular concentrations of both ribonucleotides and deoxyribonucleotides were markedly diminished by IFN. These results suggest that inhibition of both ribonucleotide and deoxyribonucleotide biosynthesis, together with increased rate of nucleotide catabolism, may significantly decrease intracellular nucleotide availability. Decrease of the supply of nucleic acid precursors, as well as limitation of nucleotides for energy metabolism and other processes, may result in the inhibition of cell multiplications.

B-Lymphocytes↗
PubMed1985

Evidence for distinct catabolic pathways for deoxy-GTP and GTP in purine-nucleoside phosphorylase-deficient mouse T lymphoblasts.

The catabolism of deoxy-GTP and GTP was compared in purine-nucleoside phosphorylase-deficient mouse T lymphoblasts. It was found that guanine ribonucleotides and deoxyribonucleotides are degraded by distinct pathways in cells cultured under both physiological and induced catabolic conditions. In T lymphoblasts, cultured under physiological conditions, 50% of the GMP formed during GTP catabolism was dephosphorylated and 50% was deaminated, whereas in the presence of the catabolic inducer deoxyglucose 90% of the GMP formed was dephosphorylated and only 10% was deaminated. These results indicate that GTP catabolism in lymphoblasts proceeds by alternative pathways, either via GMP dephosphorylation or via GMP reductive deamination, and physiological conditions determine with pathway will be used. In contrast, deoxy-GTP catabolism proceeds exclusively via deoxy-GMP dephosphorylation under both physiological and induced catabolic conditions. The lack of deoxy-GMP deamination may contribute to the accumulation of cytotoxic levels of deoxyguanosine found in purine-nucleoside phosphorylase-deficient patients.

Animals↗
PubMed1985

Purine nucleotide metabolism in resident and activated rat macrophages in vitro.

The overall purine metabolism was studied in detail in resident peritoneal macrophages (M phi) and in thioglycolate elicited peritoneal M phi in vitro. The salvage of purine bases (adenine, hypoxanthine and guanine) was active in both M phi populations, whereas purine biosynthesis de novo was low. Purine nucleosides (inosine, guanosine and adenosine) were efficiently degraded to uric acid and only adenosine was directly salvaged into nucleotides. Purine salvage was markedly increased in elicited M phi as compared to resident M phi whereas purine degradation pathways were enhanced only slightly. These results clearly indicate that salvage of purine bases is the main source for purine nucleotide biosynthesis in M phi, but nucleotide catabolism is the predominant pathway.

Adenine↗
PubMed1985

Catabolic pathways of purine ribonucleotides and deoxyribonucleotides in lymphocytes.

Deficiency of either one of the subsequent purine catabolic enzymes adenosine deaminase or purine nucleoside phosphorylase results in immunodeficiency disease in humans. However, the mechanism by which impairment of purine metabolism may cause immunodeficiency is unclear. In the present work we have studied the catabolism of purine ribonucleotides and deoxyribonucleotides in T lymphocytes to better understand the role of purine nucleoside phosphorylase and adenosine deaminase in the immune function. It was found that purine deoxyribonucleotides are degraded via catabolic pathways distinctly different from those used for purine ribonucleotide degradation. Thus both adenine and guanine ribonucleotides are deaminated to IMP whereas purine deoxyribonucleotides are exclusively dephosphorylated to the corresponding deoxyribonucleosides. These findings may explain the relatively higher degradation rates of purine deoxyribonucleotides in mammalian cells as compared to purine ribonucleotides. The catabolism of purine nucleotides is tightly linked to the active purine nucleoside cycles which consist of the phosphorolysis of purine nucleosides and deoxyribonucleosides to their corresponding bases, their salvage to monophosphates and back to the corresponding ribonucleosides. The above observations also imply that a possible role of the purine nucleoside cycles is to convert purine deoxyribonucleotides into their corresponding ribonucleotide derivatives. Deficiencies of purine nucleoside phosphorylase or of adenosine deaminase activities, enzymes which participate or lead to the purine nucleoside cycles, thus result in a selective impaired deoxyribonucleotide catabolism and immunodeficiency.

Adenosine Deaminase Inhibitors↗
PubMed1984

Evidence for distinct catabolic pathways of adenine ribonucleotides and deoxyribonucleotides in human T lymphoblastoid cells.

The catabolisms of deoxy-ATP and ATP were compared in cultured human T lymphoblastoid cells incubated under various conditions. It was found that in the presence of deoxycoformycin, an inhibitor of adenosine deaminase, deoxyadenosine was the only product of deoxy-ATP catabolism. In contrast, the main products of ATP catabolism in either the presence or the absence of deoxycoformycin were inosine and hypoxanthine. These results demonstrate that deoxy-ATP catabolism proceeds exclusively via deoxyadenosine deamination, whereas ATP catabolism proceeds mainly via adenylate deamination. These findings thus provide an explanation for the selective deoxynucleotide metabolic abnormalities associated with adenosine deaminase deficiency in humans.

Adenosine↗
PubMed1984

Nucleotide catabolism and nucleoside cycles in human thymocytes. Role of orthophosphate.

The catabolism of GTP and ATP in intact human thymocytes was studied, and the effect of intracellular Pi concentrations on various catabolic reactions was evaluated. Induction of nucleotide catabolism was performed with either NaN3 or deoxyglucose. NaN3 induced an increase in intracellular Pi, whereas deoxyglucose induced a decrease in Pi in human thymocytes. At elevated Pi concentrations, an intracellular accumulation of GMP, IMP and AMP was observed, and the entry of these nucleotides into the nucleoside cycles was diminished. In contrast, at lowered Pi concentrations, there was no accumulation of nucleoside monophosphates, but the production of purine bases and nucleosides was increased as a result of enhanced nucleotide entry into the nucleoside cycles. The dephosphorylation of nucleotides thus seems to be regulated by intracellular Pi concentrations. ATP catabolism proceeded mainly via adenylate deamination at both elevated and lowered Pi concentrations. Guanylate formed during GTP catabolism was mainly dephosphorylated, but significant amounts of GMP were also deaminated to yield IMP.

Adenosine Triphosphate↗
PubMed1984

Guanosine triphosphate catabolism in purine nucleoside phosphorylase deficient human B lymphoblastoid cells.

GTP catabolism induced by sodium azide or deoxyglucose was studied in purine nucleoside phosphorylase (PNP) deficient human B lymphoblastoid cells. In PNP deficient cells, as in control cells, guanylate was both dephosphorylated and deaminated but dephosphorylation was the major pathway. Only nucleosides were excreted during GTP catabolism by PNP deficient cells and the main product was guanosine. The level of nucleoside excretion was largely affected by intracellular orthophosphate (Pi) level. In contrast, normal cells excreted nucleosides only at low Pi level while at high Pi levels, purine bases (guanine and hypoxanthine) were exclusively excreted. PNP deficiency had no effect on the extent of GMP deamination.

Azides↗