The effect of pH, P02, and inorganic phosphate on the uptake and metabolism of hypoxanthine by erythrocytes has been studied. Uptake of hypoxanthine and accumulation of inosine 5'-monophosphate (IMP) were markedly increased at acid pH, high external phosphate concentrations, and low Po2. Release of accumulated IMP as hypoxanthine occurred at alkaline pH values and low external phosphate concentrations. Conditions favoring IMP accumulation gave rise, in the absence of hypoxanthine, to a corresponding increase in 5'-phosphoribosyl-1-pyrophosphate. Intracellular phosphate concentrations were markedly pH dependent and a model is presented whereby hypoxanthine uptake and release are controlled by intracellular concentrations of inorganic phosphate and 2,3-bisphosphoglycerate. These allosteric effectors influence, in opposing ways, two enzymes governing IMP accumulation, namely 5'-phosphoribosyl-l-pyrophosphate synthetase and 5'-nucleotidase. These metabolic properties suggest that the erythrocyte could play a role in the removal of hypoxanthine from anoxic tissue.
Whole-gut transit time was measured by the time taken for an orally administered dose of brilliant blue dye to disappear from the stool in 20 patients with ulcerative proctitis and in 20 age- and sex-matched controls. Ten of the patients had active, and 10 inactive disease. The dye usually appeared in the stool with the next bowel movement after ingestion in both patients and controls; however, the time at which the dye disappeared from the stool (transit time) was prolonged to 76.1 h in the patients, compared with 50.2 h in the controls (p less than 0.01). This delay occurred both in patients with active disease at 70.5 h (p less than 0.05) and in those with inactive disease at 81.8 h (p less than 0.05). This prolongation of transit time may be relevant to both the pathogenesis and treatment of ulcerative proctitis.
Plasma membranes from the promastigote and amastigote forms of Leishmania mexicana mexicana were examined for the presence of an adenosine receptor. Specific binding of selected adenosine receptor ligands was tested for modulation of membrane associated adenylate cyclase activity. Time course experiments utilizing amastigote and promastigote membranes demonstrated that total binding of all adenosine receptor ligands equilibrated within 20 min. All incubations of membranes were conucted for 30 min. Specific, non pecific and total binding of fl 'H-cy clohexy ladenosine (CHA) and H-methyl-2-phenylethyladenosine (PIA) to promastigote and amastigote membranes over ligand concentrations of 8 to 400 nM were determined. Scatchard plot analysis of the specific binding data indicated single binding sites for both CHA and PIA with Kd values of 75 nM and 200 nM respectively for promastigotes and 55 nM and 175 nM respectively for amastigotes. Membranes were also found to possess adenylate cyclase activity which could be readily inhibited in the presence of increasing concentrations of adenosine.PIA, and CHA (0 to 1 mM).The rate of promastigote replication and transformation to the amastigote form and transformation of the amastigote to the promastigote stage could all be significantly increased in the presence of the adenosine receptor ligands. This receptor mechanism may therefore act to modulate the rate of cell replication and life cycle transformation. GAR synthetase, the third enzyme of de novo purine biosynthesis, has been purified to h o m g e n a t y o m rat, and partially from human and hamster sources. Fhysiochemical characteristics of the purfied proteins were determined and corrpared. There is mounting evidence that GAR synthetase is part of a multifunctional protein hich includes 5-aminoimidazole ribonucleotide (AIR) synthetase and GAR transformylase activities. In order to answer this question, the activities of these latter two enzymes were monitored during the purification of GAR synthetase. In addition to being part of a multifunctional protein, GAR synthetase is also thought to be a component of a multienzyme conplex. Antibodies raised to the purified enzyme were used in conjunction with Western blots to study the mlecular weight of GAR synthetase under conditions that would maintain the integrity of any corrplex present and then under conditions that would lead to the dissociation of the corrplex into its various components. Finally, antibodies raised to rat liver GAR synthetase were used to select QNA clones of the gene from a Xgtll expression library. These clones will be subsequently used to characterize the structure of the gene encoding GAR synthetase in mammalian cells. This work was supported by grants NIH AG 00029 and NTH HI 13432. This is ERICR contribution -64. Experiments were undertaken to investigate the working hypothesis that the liver is a source of pyrimidine nucleotide precursors for utilization by peripheral tissues, that the precursor is orotate, and that the erythrocytes act as an inte...
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