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PubMed1977

The effect of formycin on the processing of transfer RNA precursors in the posterior silk gland of Bombyx mori.

Formycin, an adenosine analog, was used in studies of RNA synthesis by silk glands of silkworms in organ culture. Formycin has been shown to inhibit preferentially the incorporation of [3H]uridine into low molecular weight RNA in the cytoplasm. When silk glands were pulse-chase labeled with [3H]uridine in the presence of formycin, the synthesis of 4.5S tRNA precursors was not affected, as determined by gel electrophoresis. However, the accumulation of mature 4S tRNA was greatly reduced in the formycin-treated system, although the precursors synthesized disappeared from the 4.5S region on chase at the same rate as in the control system. [14C]Formycin was incorporated into the 4.5S precursors but not into 4S tRNA. These findings suggest that the inhibition of tRNA synthesis by formycin is due to the existence of some degradation mechanisms of formycin-containing 4.5S precursor RNA's and the failure to process them into normal 4S tRNA.

Animals↗

PubMed1989

Theoretical study of the protonation and tautomerization of adenosine, formycin, and their 2-NH2 and 2-F derivatives: functional implications in the mechanism of reaction of adenosine deaminase.

A quantum chemical study of adenosine, formycin, and their 2-NH2 and 2-F derivatives is performed. The tautomerism of neutral and protonated species as well as the protonation of adenosine, formycin, and their derivatives are theoretically studied using semiempirical MNDO and AM1, as well as ab initio STO-3G methods. Calculations have been performed on a reduced model, in which the ribose moiety has been substituted by a hydroxy-methyl group. Results indicate that adenosine is mainly protonated at the N1 atom, whereas formycin can be protonated on N1 or N3, depending on the tautomeric form (N8-H or N7-H). The quantum chemical study of the N1-protonated molecules shows that a second protonation of adenosine is mainly on the N3 atom, whereas formycin can be protonated on N8 or N3, depending on the tautomeric form. On the other hand, results indicate that the protonation of formycin and its derivatives at the N1 atom leads to a change in their tautomeric preference from N7-H to N8-H. The importance of both tautomerism and protonation reactions in the mechanism of action of adenosine deaminase is studied by means of a quantitative structure activity relationships strategy. Significant correlations were found between several electronic parameters and the logarithm of the maximum rate of deamination (log Vm) of the studied compounds. For formycin and its derivatives, it was necessary to consider their N8-H tautomeric forms. The electronic parameters giving good correlations were as follows: energy of the minimum of the ab initio molecular electrostatic potential on N1, net charge over purine (pyrazolo-pyrimidine) and pyrimidine rings, and the N1 protonation energy. It must be noted that all these parameters are informative in relation to a proton attack. Adenosine and purine ribosides have been studied largely because of their high biological relevance. They are constituents of nucleic acids, intermediates in secondary metabolism, neuromodulators, and neurohormones. Their analogues have been extensively used because of their wide range of pharmacological effects (1). Formycin A (Fig. 1) is one of the most studied analogues of adenosine. It is a natural product extracted from Nocardia interforma (2) with proven antiviral (3-5), antibiotic (2), immunodepressant (6), antitumor (6), and antimetabolic (5) activities.

Adenosine↗

PubMed1984

Monophosphates of formycin B and allopurinol riboside. Interactions with leishmanial and mammalian succino-AMP synthetase and GMP reductase.

Formycin B 5'-monophosphate (Form B-MP) and allopurinol riboside 5'-monophosphate ( HPPR -MP) are isomers of IMP that are metabolically produced when Leishmania spp. are incubated with the antileishmanial agents formycin B and allopurinol or allopurinol riboside. The interactions of Form B-MP with succino -AMP synthetase and GMP reductase from both leishmanial and mammalian sources were compared with the data of earlier studies with HPPR -MP. Both analogs could substitute for IMP as a substrate for succino -AMP synthetase isolated from Leishmania donovani. The V'max values of Form B-MP and HPPR -MP were about 1% of the V'max of IMP. Only Form B-MP (and not HPPR -MP) could serve as an alternative substrate for mammalian succino -AMP synthetase. The V'max of Form B-MP was 40% that of IMP. The corresponding analogs of AMP, ADP and ATP were produced when Formycin B was incubated with mouse L cells. The Formycin A residue was incorporated into the cellular RNA. The amount of Formycin A-TP produced (relative to ATP) in mouse L cells was considerably less than that produced in Leishmania spp. Both Form B-MP and HPPR -MP were inhibitors of partially purified GMP reductase from L. donovani. The binding of Form B-MP and HPPR -MP to human GMP reductase was 40- and 100-fold weaker, respectively, than the binding to leishmanial GMP reductase. Pretreatment of promastigotes of L. donovani with either allopurinol or Formycin B resulted in greater than 95% reduction of the incorporation of the radiolabel from [14C]xanthine into ATP and greater than 80% reduction of the incorporation of the label into GTP. The HPPR -MP and Form B-MP present in these cells may have inhibited the leishmanial succino -AMP synthetase and GMP reductase. The analogs had little or no effect on the pool sizes of ATP and GTP of either mouse L cells or L. donovani.

Adenylosuccinate Synthase↗

PubMed1989

RNA synthesis in starfish embryos: developmental consequences of its inhibition by formycin.

Embryos of the starfish Asterina pectinifera were examined with regard to their ability to undergo the early events of embryonic development in the presence of formycin, an analogue of adenosine and a reported inhibitor of RNA synthesis. It was shown that in normal embryos the pool of ribonucleoside 5'-triphosphates increased during the period of blastula formation. The increase of the UTP pool was blocked nearly completely by 25 micrograms/ml formycin, and that of the CTP pool was inhibited partially by the same concentration of the drug. On the other hand, the pools of ATP and GTP were the same for both control and formycin-treated embryos. The development of embryos cultured in the presence of 25 micrograms/ml formycin stopped at the early blastula stage. Addition of 100 micrograms/ml each of uridine and cytidine to cultures of embryos that had been placed in 25 micrograms/ml formycin at the onset of blastulation allowed gastrulation to occur, suggesting that the developmental arrest produced by formycin is due primarily to the inhibition of pyrimidine nucleotide biosynthesis.

Animals↗

PubMed1994

Electrostatic potential surface analysis of the transition state for AMP nucleosidase and for formycin 5'-phosphate, a transition-state inhibitor.

AMP nucleosidase hydrolyzes the N-glycosidic bond of AMP to yield adenine and ribose 5-phosphate. Kinetic isotope effects have been used to establish an experimentally based transition-state structure for the native enzyme and a Vmax mutant [Mentch, F., Parkin, D. W., & Schramm, V. L. (1987) Biochemistry 26, 921-930; Parkin, D. W., Mentch, F., Banks, G. A., Horenstein, B. A., & Schramm, V. L. (1991) Biochemistry 30, 4586-4594]. The transition states are characterized by weak reaction coordinate bonds to C1' and substantial carbocation character in the ribose ring. The N9-C1' bond to the leaving group is nearly broken and the adenine ring is protonated at the transition state. Formycin 5'-phosphate and other purine nucleoside 5'-phosphate analogues with syn-glycosyl torsion angles bind better than substrate, supporting a syn configuration in the enzyme-substrate complex and presumably in the transition state [Giranda, V. L., Berman, H. M., & Schramm, V. L. (1988) Biochemistry 27, 5813-5818]. Access to a geometric model of the transition state permits the analysis of its molecular electrostatic potential surface as enforced by the enzyme. Comparison of the molecular electrostatic potential surfaces for AMP, formycin 5'-phosphate, and the transition state reveals a striking similarity in the surface charges of formycin 5'-phosphate and the transition state. The enzyme-stabilized transition state for AMP hydrolysis is characterized by new positive electrostatic potential in the adenine ring as a result of protonation by the enzyme. This is closely matched by the protonated pyrazole ring of formycin 5'-phosphate. The molecular electrostatic potential surfaces of formycin 5'-phosphate and the transition state for AMP are similar and are likely to be a factor in the Km/Ki value of > 10(3) for formycin 5'-phosphate as a transition-state inhibitor of AMP nucleosidase.

Electricity↗

PubMed1991

Formycin A resistant mutants due to defect in adenosine transport system in Vibrio parahaemolyticus.

An antibiotic formycin A inhibited growth of Vibrio parahaemolyticus under certain conditions, which suggested that formycin A was taken up by cells under these conditions. We found that formycin A was transported via the adenosine transport system which we previously reported as a Na(+)-coupled cotransport system. We isolated many formycin A resistant mutants, and about half of them grew very poorly on adenosine as a sole source of carbon. Judging from their reversion frequencies, these mutants seemed to have single mutations. Respiration driven uptake of 14C-adenosine was not observed in such mutants; also, Na+ uptake induced by the addition of adenosine or formycin A to a cell suspension was completely abolished in them. Thus we conclude that these mutants possess a defect in the Na+/adenosine cotransport system, and have become formycin A resistant.

Adenosine↗

PubMed1983

Leishmania donovani: oral efficacy and toxicity of formycin B in the infected hamster.

Formycin B, a structural analog of inosine, was evaluated as an orally administrable antileishmanial agent. Against Leishmania donovani in hamsters, it achieved an 85-92% reduction in numbers of parasites in livers of infected animals after oral administration at 13 mg/kg/day for 4 days. Its efficacy by oral administration was approximately four to eight times that by intramuscular administration and four times that of the positive control drug Glucantime by intramuscular administration. The levels of formycin B in serum after the final oral administration of 26 mg/kg/day were 1.4 micrograms/ml at 1 hr and 0.3 microgram/ml at 2 hr. The concentration in liver was greater (9.0 micrograms/ml at 1 hr) and declined more slowly. With this latter dosage or with 104 mg/kg/day there was no acute toxicity of formycin B to bone marrow or formed elements of the blood. The only statistically significant toxicity to the liver was a doubling of serum total bilirubin levels. Comparison of the in vivo efficacy of formycin B against L. donovani to the mild acute toxicity of the drug suggests that formycin B has potential as an oral agent against visceral leishmaniasis.

Administration, Oral↗

PubMed1995

Dual effect of formycin A upon the hydrolysis of phosphoinositides in perifused pancreatic islets.

Formycin A (1.0 mM) caused a rapid, sustained and rapidly reversible inhibition of effluent radioactivity in rat pancreatic islets prelabelled with myo-[2-3H]inositol and perifused in the presence of 8.3 mM D-glucose. This coincided with a progressive decrease in islet ATP content and transient inhibition of insulin release. Thereafter, however, formycin A increased glucose-induced insulin release. Moreover, in islets that were preincubated with myo-[2-3H]inositol and then exposed during perifusion to a rise in D-glucose concentration from 2.8 to 16.7 mM, the release of insulin and 3H fractional outflow rate at both the low and high hexose concentrations were much higher when both the preincubation and perifusion were conducted in the presence, rather than absence, of formycin A. It is concluded that formycin A first inhibits and later enhances both the hydrolysis of phosphoinositides and release of insulin, these effects being possibly related to changes in the islet cell content of adenosine and/or formycin A triphosphates.

Adenosine Diphosphate↗

PubMed1985

In vitro and in vivo activities of formycin B against Trypanosoma cruzi.

The inosine analog formycin B was examined for in vitro and in vivo activities against Trypanosoma cruzi. concentration of formycin B as low as 0.1 microgram/ml markedly inhibited intracellular multiplication of T. cruzi strains both in macrophages and in L929 cells. Mice infected with 10(5) blood form trypomastigotes of the highly virulent strain Y of T. cruzi were completely protected against death by treatment with 11.8 or 5.9 mg of formycin B per kg administered intraperitoneally each day for 19 days. Four different strains of T. cruzi were used, and each was susceptible to formycin B administered either intraperitoneally or orally. Parasitological cure, however, was not achieved with any of the treatments used, including prolonged treatment for up to 10 weeks. Formycin B has a remarkable capacity for inhibiting the in vitro intracellular replication of T. cruzi and protecting mice against death due to the acute infection with the organism. It does not appear, however, to be able to completely eliminate T. cruzi from infected mice.

Animals↗

PubMed1980

Formycin B, purine nucleoside phosphorylase and lymphocyte function.

A genetic deficiency of purine nucleoside phosphorylase (NP) is associated with immune dysfunctin that specifically affects T cells. An absence of adenosine deaminase (ADA), the preceding enzyme in the pathway of purine recycling, is associated with failure of both T and B lymphocyte function. Formycin B, an analogue of inosine and an inhibitor of purine nucleosidase phosphorylase, was used in cell culture systems to stimulate deficiency of this enzyme. The cells used were normal circulating lymphocytes and lymphoblastoid cell lines (LCL) with T and B cell characteristics. Formycin B inhibited the growth of these cells, but its primary effect was found to be due to a mechanism other than purine nucleoside phosphorylase inhibition. The possibility that formycin B was inhibiting adenosine deaminase, for which it is a product analogue, was studied by the analysis of reaction progress curves using the integrated rate equation. The molecular structure of formycin B, whilst preventing its phosphorylytic cleavage by purine nucleoside phosphorylase, could enable this compound to function as a substrate for adenosine kinase. The resultant formation of formycin B nucleotide probably causes the observed inhibition of growth in cultured cells.

Adenosine Deaminase↗

PubMed1975

Influence of formycin B on polyadenosine diphosphoribose synthesis in vitro and in vivo.

Formycin B inhibited growth of L5178Y mouse leukemia cells in concentrations of less than twice the concentration that inhibits cell proliferation at 50% by cytostasis; at higher concentrations (more than twice the 50% concentration mentioned), the cells were killed. In cells treated with the concentration that inhibits cell proliferation at 50%, the average cell volume did not change. The formycin B inhibitory effect on cell proliferation was reduced by coincubation with nicotinamide adenine diphosphate or adenosine. The biosyntheses of DNA,RNA, and protein in whole cells were sensitively inhibited by formycin B as checked by incorporation studies with radioactive precursors. In addition, the formation of polyadenosine diphosphoribose was reduced even with higher sensitivity; in particular the extent of adenosine diphosphate ribosylation of histone subfraction H1 was reduced. Formycin B has been shown to be an inhibitor for the polyadenosine diphosphoribose polymerase, isolated from oviduct nuclei of quails. Both the chromatin-bound and the soluble enzyme are inhibited competitively; the relative affinity (Ki/Km) of formycin B to the polyadenosine diphosphoribose polymerase is 1.5.

Adenosine↗

PubMed1995

Deleterious effect of formycin A on tumor islet cells.

The adenosine analogue formycin A was recently introduced as a potent insulin secretagogue in normal pancreatic islet cells. In the present study, formycin A was found to inhibit insulin release and to exert a cytotoxic effect in tumor islet cells of the RINm5F line. The latter effect was concentration-related in the 10-100 microM range of formycin A concentrations, not rapidly reversed, and not reproduced by adenosine. This study thus reveals that formycin A may display cytotoxic potential in the same range of concentrations in which it causes a progressive increase of glucose-stimulated insulin secretion in normal pancreatic islets.

Adenoma, Islet Cell↗

PubMed1990

Na(+)-dependent, active and Na(+)-independent, facilitated transport of formycin B in mouse spleen lymphocytes.

Na(+)-dependent, active and Na(+)-independent facilitated nucleoside transport were characterized in mouse spleen cells using rapid kinetic techniques and formycin B, a metabolically inert analog of inosine, as substrate. The Michaelis-Menten constants for formycin B transport by the two transporters were about 30 and 400 microM, respectively. The first-order rate constant for Na(+)-dependent transport was about 4-times higher than that for facilitated formycin B transport. The Na(+)-dependent carrier is specific for uridine and purine nucleosides and accumulates formycin B concentratively in an unmodified form. Concentrative accumulation was inhibited by ATP depletion and gramicidin and ouabain treatment of the cells. Our data indicate a single Na(+)-binding site on the Na(+)-dependent nucleoside carrier and a Michaelis-Menten constant for Na+ of about 10 mM. This transporter was not significantly inhibited by dipyridamole and nitrobenzylthioinosine, inhibitors of the facilitated transporter. The Na(+)-independent, facilitated nucleoside transporter of spleen cells exhibits properties comparable to those of the carriers present in mammalian cells in general. The B lymphocytes remaining after depletion of spleen cell populations of T lymphocytes by incubation with a combination of T-cell specific monoclonal antibodies plus complement exhibited about the same activities of active and facilitated nucleoside transport as the original suspension.

Adenosine Triphosphate↗

PubMed1991

Mycoplasma contamination greatly enhances the apparent transport and concentrative accumulation of formycin B by mammalian cell culture.

S49 mouse leukemia cells exhibit both equilibrative and Na(+)-dependent, concentrative formycin B transport. The latter represents only a minor nucleoside transport component and is detectable only when equilibrative nucleoside transport is inhibited by dipyridamole or another transport inhibitor. Thus in uncontaminated S49 cells formycin B accumulated only to slightly above the intracellular-extracellular equilibrium level. In contrast, in suspensions of S49 cells contaminated with mycoplasma, formycin B accumulated in the intracellular water space in unmodified form to 40-50-times the extracellular concentration in a dipyridamole-independent manner during 90 min of incubation at 37 degrees C. The mycoplasma active formycin B transport system was inhibited by all nucleosides tested, including thymidine and deoxycytidine, which are not substrates for the concentrative nucleoside transporter of S49 cells. Mycoplasma contamination was detected by the presence of cell-associated adenosine phosphorylase activity.

Animals↗

PubMed1985

Inhibition of Rous sarcoma virus production by formycin.

The effect of formycin, an adenosine analog, on the growth of chick embryo fibroblasts and on Rous sarcoma virus (RSV) production was studied. An adverse effect on cell proliferation was observed in the presence of 10 microM formycin. Treatment with 5 microM formycin for 24 hr reduced by a factor of about 1000 the yield of infections progeny whereas the cell growth remained unaltered. Moreover the few particles released in the presence of formycin showed a markedly decreased ability to synthesize viral cDNA. This impairment was shown to be related to a nonfunctional primer tRNA.

Animals↗

PubMed1990

Purine nucleoside phosphorylase: purification using an ether-linked formycin B/sepharose 6B resin with unusual properties.

Formycin B [9-deazainosine] was reacted with epoxy-activated Sepharose 6B to form an affinity resin for purine nucleoside phosphorylase (PNPase). This resin had a large capacity (7,600 units/ml) for the enzyme from Escherichia coli. Enzyme retention was dependent on high ionic strength. Although this property is reminiscent of hydrophobic interaction chromatography, analogous resins prepared with pseudouridine or monoethanolamine instead of with formycin B, did not retain the enzyme even at high ionic strength. Furthermore, hypoxanthine facilitatted elution of the enzyme from the resin. It appeared, therefore, that the enzyme was not bound simply by hydrophobic interactions. A simple two-step purification procedure for PNPase from Escherichia coli was devised using this resin. Overall recovery was 50%, and purity of the final preparation was greater than 95%. This resin was also useful in the purification of PNPase from human erythrocytes. The ether linkage between formycin B and Sepharose 6B, together with the carbon-to-carbon linkage between the pentose and heterocyclic moieties of formycin B, provided stability to both chemical and enzymatic degradation. After 5 years of use and exposure to a variety of biological preparations, the resin showed no detectable decrease in its ability to bind PNPase.

Electrophoresis, Polyacrylamide Gel↗

PubMed1983

Formycin B-resistant mutants of Chinese hamster ovary cells: novel genetic and biochemical phenotype affecting adenosine kinase.

Stable mutants which are approximately three- and eightfold resistant to the pyrazolopyrimidine nucleosides formycin A and formycin B (FomR) have been selected in a single step from mutagenized Chinese hamster ovary cells. In cell extracts, the two FomR mutants which were examined were both found to contain no measurable activity of the enzyme adenosine kinase (AK). However, cross-resistance studies with other adenosine analogs such as toyocamycin and tubercidin show that these mutants are distinct from toyocamycin or tubercidin resistant (Toyr) mutants which also contain no measurable AK activity in cell extracts. Studies on the uptake and incorporation of [3H]adenosine and [3H]tubercidin by various mutants and parental cell lines show that unlike the Toyr mutants, which are severely deficient in the phosphorylation of these compounds, the FomR mutants possess nearly normal capacity to phosphorylate these compounds and incorporate them into cellular macromolecules. These results suggest that the FomR mutants contain normal levels of AK activity in vivo. In cell hybrids formed between FomR X FomS cells and FomR X Toyr cells, the formycin-resistant phenotype of both of the FomR mutants behaved codominantly. However, the extracts from these hybrid cells contained either congruent to 50% (FomR X FomS) or no measurable (FomR X Toyr) AK activity, indicating that the lesion in these mutants neither suppresses the wild-type AK activity nor complements the AK deficiency of the Toyr mutants. The presence of AK activity in the FomR mutants in vivo, but not in their cell extracts, along with the codominant behavior of the mutants in hybrids, indicates that the lesions in the FomR mutant are of a novel nature. It is suggested that the genetic lesion in these mutants affects AK activity indirectly and that it may involve an essential cellular function which exists in a complex form with AK. Some implications of these results regarding the mechanism of action of formycin B are discussed.

Adenosine↗

PubMed1980

Effects of a new adenosine deaminase inhibitor, isocoformycin, on toxicity, antitumor activity and tissue distribution of formycin A and 9-beta-D-arabinofuranosyladenine.

Single intraperitoneal and intravenous injections of isocoformycin at 1,200 mg/kg did not cause the death of mice. Isocoformycin which inhibited adenosine deaminase enhanced significantly the toxicity of formycin A and ara-A at various combination ratios. Isocoformycin potentiated antitumor activity of formycin A and ara-A against L1210 leukemia. Formycin A and ara-A disappeared rapidly from the blood and tissues and could not be found in any tissues even 0.5 hour after a single intraperitoneal injection. However, when used in combination with isocoformycin both were detected in the blood and tissues, especially at high concentration in liver and kidney. These indicate that the deamination of formycin A and ara-A is blocked by isocoformycin in vivo.

Adenosine Deaminase Inhibitors↗