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J J Marr

Publications and source records attributed to J J Marr.

At least 55 records · Page 3Linked to original sources
PubMed1983

Pyrazolopyrimidine metabolism in the pathogenic trypanosomatidae.

Pyrazolopyrimidines are purine analogues. These compounds are metabolized by the pathogenic hemoflagellates and other members of the family Trypanosomatidae as though they were purines. This metabolic sequence does not exist in man or other mammals. In the hemoflagellates, the pyrazolopyrimidine base, of which allopurinol is the paradigm, undergoes ribosylphosphorylation to the ribonucleotide. This ribonucleotide may remain as such or be aminated to the amino analogue and further converted to the aminopyrazolopyrimidine ribonucleoside triphosphate. The latter is incorporated into RNA. This metabolic sequence has been demonstrated in the genera Leishmania and Trypanosoma.

Allopurinol↗
PubMed1983

Purine metabolism in Leishmania donovani amastigotes and promastigotes.

Purine metabolism in Leishmania donovani amastigotes was found to be similar to that of promastigotes with the exception of adenosine metabolism. Adenosine kinase activity in amastigotes is approximately 50-fold greater than in promastigotes. Amastigotes deaminate adenosine to inosine through adenosine deaminase, an enzyme not present in promastigotes. Inosine is cleaved to hypoxanthine and phosphoribosylated by hypoxanthine-guanine phosphoribosyltransferase. Promastigotes cleave adenosine to adenine and deaminate adenine to hypoxanthine via adenase, an enzyme not present in amastigotes. Hypoxanthine is phosphoribosylated by hypoxanthine-guanine phosphoribosyltransferase.

Adenosine↗
PubMed1983

Cutaneous leishmaniasis in an infant.

Cutaneous leishmaniasis (CL) in the United States is unusual. We report an infant who developed CL after returning from an endemic area. A skin biopsy yielded Leishmania organisms within 48 hours. The cutaneous lesions resolved with scarring after several months.

Humans↗
PubMed1982

Purine metabolism in the bloodstream forms of Trypanosoma gambiense and Trypanosoma rhodesiense.

Bloodstream forms of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense are incapable of de novo purine synthesis. Purine bases are converted directly to ribonucleotides and with the exception of guanine, are stable. Guanine is incorporated directly into ribonucleotides and also deaminated to xanthine. Purine ribonucleosides are hydrolyzed rapidly; these reactions may limit their incorporation since purine bases label the nucleotide pools more efficiently than do ribonucleosides. The apparent order of salvage efficiency for ribonucleosides is adenosine greater than inosine greater than guanosine greater than xanthosine for both organisms. T. b. gambiense salvages purine bases in the same order, while T. b. rhodesiense salvages purine bases in the order hypoxanthine greater than adenine greater than guanine greater than xanthine.

Animals↗
PubMed1982

Antileishmanial action of 4-thiopyrazolo (3.4-d) pyrimidine and its ribonucleoside. Biological effects and metabolism.

Thiopurinol [4-thiopyrazolo(3.4-dyprimidine, TPP] and its ribonucleoside (TPPR) were effective in vitro against the intracellular and extracellular forms of L. braziliensis and L. mexicana. They also inhibited the transformation of the amastigote of L. donovani to the promastigote. These thio-analogues had about the same activity as allopurinol [4-hydroxypyrazolo(3.4-d)pyrimidine, HPP] and its ribonucleoside (HPPR). the thiopyrazolopyrimidines were converted primarily to the ribonucleoside-5' -phosphate (TPPR-MP) and to an unidentified metabolite, but not to any of the adenine ribonucleoside analogues previously shown to be formed from allopurinol and its ribonucleoside. There was an antagonism between the growth-inhibitory effects of allopurinol and thiopurinol. This is consistent with the findings that the intracellular concentrations of TPP and TPPR-MP are sufficient to inhibit the conversion of allopurinol to allopurinol ribonucleotide (HPPR-MP) by the hypoxanthine-guanine phosphoribosyltransferase by 30 per cent and the amination of HPPR-MP by adenylosuccinate synthetase by 50 per cent respectively. Consequently, the incorporation of the aminated product (aminopyrazolopyrimidine) into RNA was substantially decreased. The difference in metabolism between the thio- and hydroxypyrazolopyrimidines suggests a difference in their mechanisms of action against the pathogenic leishmania.

Allopurinol↗
PubMed1982

Adenylosuccinate synthetase and adenylosuccinate lyase from Trypanosoma cruzi, Specificity studies with potential chemotherapeutic agents.

Adenylosuccinate (succino-AMP) synthetase and succino-AMP lyase isolated from epimastigotes of Trypanosoma cruzi by chromatography on phosphocellulose. The synthetase was capable of catalyzing the condensation of aspartic acid with IMP and several IMP analogs. The reaction with allopurinol ribonucleotide is of potential chemotherapeutic interest. This analog was slowly converted to its corresponding succino-AMP analog with a Km' of 140 micrometers (cf. IMP at 10 micrometers) and a Vmax' of 0.3 per cent the rate with IMP. The comparable reaction with this analog does not occur with succino-AMP synthetase from a representative mammalian source [T. Spector and R. L. Miller, Biochim. biophys. Acta 455, 509 (1976)]. The protozoal succino-AMP lyase had a broad substrate which was characteristic of this enzyme from many sources. It catalyzed the rapid and efficient cleavage of all the succino-AMP analogs that were produced by succino-AMP synthetase. Thus, these two enzymes appear to be responsible for the selective amination of allopurinol ribonucleotide in T. cruzi. The metabolically produced AMP analog may be the agent or a precursor of the agent that accounts for the anti-growth activity of allopurinol in these organisms. Similar selective amination was observed previously with these enzymes from Leishmania donovani [T. Spector, T. E. Jones and G. B. Elion, J. biol. Chem. 254, 8422 (1979)]. Thiopurinol ribonucleotide was not a substrate of succino-AMP synthetase from T. cruzi, but it was an inhibitor with a K1 = 33 micrometers. Therefore, the weakness of thiopurinol's anti-growth activity with T. cruzi is not due to its inability to inhibit this enzyme.

Adenylosuccinate Lyase↗
PubMed1982

Purine and pyrimidine salvage pathways in Leishmania donovani.

Leishmania donovani, grown in culture, salvaged radiolabeled purine bases which were distributed into adenine and guanine ribonucleotides and into the RNA of these cells. De novo synthesis of purines in L. donovani does not occur [J. J. Marr, R. L. Berens and D. J. Nelson, Biochim. biophys. Acta 544, 360 (1978)]. [8-14C]Adenine was rapidly deaminated to hypoxanthine via the action of an adenine aminohydrolase (EC 3.5.4.2). [8-14C]Guanine was also rapidly deaminated by guanase (EC 3.5.4.3) to form zanthine in these cells. Therefore, the formation of nucleotides of hypoxanthine and xanthine are the first committed steps of purine salvage in L. donovani. While purines are efficiently conserved by this parasite, the salvage of pyrimidines is not so dramatic. [2-14C]Orotic acid was converted to OMP and then incorporated into the pyrimidine nucleotides and into RNA, indicating the existence of the later steps of de novo pyrimidine synthesis. [6-14C]Thymidine was salvaged by L. donovani, being incorporated into the thymine deoxyribonucleotides and into DNA. The major pathway of thymidine metabolism in this parasite, however, was cleavage of the deoxyriboside linkage to form thymine, probably via the action of a thymidine phosphorylase (EC 2.4.2.4).

Animals↗
PubMed1982

Effect of allopurinol on Trypanosoma cruzi: metabolism and biological activity in intracellular and bloodstream forms.

Allopurinol (4-hydroxypyrazolo [3,4-d]pyrimidine) is an effective agent in vitro against Trypanosoma cruzi. The important forms of this parasite, with respect to the pathogenesis of Chagas' disease in man, are the bloodstream (trypomastigote) and the intracellular forms. Experiments with radiolabeled allopurinol and analysis of the metabolic products of this compound by high-performance liquid chromatography showed that both the bloodstream and the intracellular forms of T. cruzi metabolize allopurinol in the same manner as has been shown for the epimastigotes in vitro. The metabolic pathways for pyrazolopyrimidines in the pathogenic forms were demonstrated with organisms isolated from infected animals and a tissue culture system infected with T. cruzi. Treatment of infected tissue culture with allopurinol eradicated the infection. This investigation implies that allopurinol may be useful in chemotherapy of T. cruzi infections, a supposition which has been borne out in one animal study.

Allopurinol↗
PubMed1981

Sterilization of Ommaya reservoir by instillation of vancomycin.

We describe the management of a patient with a Staphylococcus epidermidis infection of an Ommaya reservoir that was being used for the treatment of carcinomatous meningitis. Intravenous vancomycin failed to eradicate the organism. We treated our patient successfully with parenteral antibiotics and local instillation of vancomycin (25 micrograms/ml) without removing the reservoir. The patient tolerated the intraventricular vancomycin well. We recommend this approach in the treatment of infected Ommaya reservoirs in patients who have diseases with extremely poor prognoses and who wish to be discharged from the hospital early.

Adult↗
PubMed1981

Purine metabolism in Trypanosoma cruzi.

Culture forms of Trypanosoma cruzi are incapable of synthesizing purines de novo from formate, glycine, or serine and require an exogenous purine for growth. Adenine, hypoxanthine, guanine, xanthine and their respective ribonucleosides are equal in their abilities to support growth. Radiolabeled purine bases, with the exception of guanine, are stable and are converted to their respective ribonucleotides directly by phosphoribosyltransferase activity. Guanine is both converted to its ribonucleotide and deaminated to xanthine. Purine nucleosides are not hydrolysed to any extent but are converted to their respective ribonucleotides. This conversion may involve a rete-limiting ribonucleoside cleaving activity or a purine nucleoside kinase or phosphotransferase activity. The apparent order of salvage efficiency for the bases and their respective ribonucleosides is adenine greater than hypoxanthine greater than guanine greater than xanthine.

Adenine↗
PubMed1981

Rapid drug-susceptibility testing of Mycobacterium tuberculosis.

Three methods for rapidly determining the susceptibility of Mycobacterium Tuberculosis isolates to isoniazid, rifampin, ethambutol, streptomycin, and para-aminosalicylic acid were evaluated in a large-scale, blind study. Two of the methods measured evolution of CO2 from radio-labeled substrate (14CO2), and one method measured incorporation of 3H-uracil into ribonucleic acid. Rapid indirect drug-susceptibility test results for nearly 300 isolates were compared with those obtained using a standard modified proportion technique. The 3H-uracil uptake method proved to be unacceptable. Over-all, the results obtained using the 14CO2 methods and the standard method were similar. In general, there was greater agreement between the 14CO2 and proportion techniques with drug-susceptible strains than with drug-resistant strains. Among drug-resistant strains, both 14CO2 methods were more reliable for determining resistance to rifampin than to other drugs. This study demonstrates that large-scale, blind evaluations of new laboratory procedures are valuable. Our results indicate that methods relying o the enzymatic release of 14CO2 should be further refined and evaluated.

Aminosalicylic Acid↗