Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-Acetylserotonin (compound 1) and N-acetyldopamine (compound 7) inhibit bovine adrenal medullary sepiapterin reductase in a manner competitive with the pterin substrate and have Ki values of 0.12 and 0.4 microM, respectively. Molecular modeling suggests that the phenyl rings of the two compounds bind in the pyrimidine pocket of the enzyme with the 3-hydroxyl of dopamine or the 5-hydroxyl of serotonin aligned at the pyrimidine 4-position. Further, the acetyl moieties of the two inhibitors appear to mimic the substrate side chain. Consistent with this analysis, N-acetyl-m-tyramine (compound 13) is also an excellent competitive inhibitor (Ki = 0.13 microM), whereas N-acetyltryptamine (compound 2), N-acetyl-p-tyramine (compound 14) and N-acetylphenylethylamine (compound 15) all bind poorly. Interestingly, restricted-rotation analogs of N-acetyldopamine and N-acetyl-m-tyramine are noncompetitive inhibitors of the enzyme. Modification of N-acetyldopamine to N-chloroacetyldopamine (compound 10) or of N-acetylserotonin to the N-chloroacetyl (5) or N-methoxyacetyl (compound 6) analogs results in greatly increased competitive affinity, with Ki = 0.014 microM for the dopamine analog and 0.006 and 0.008 microM, respectively, for the serotonin analogs. In MOLT-4 T-cell leukemia and MCF-7 breast adenocarcinoma in culture, 0.1 mM N-methoxyacetylserotonin depleted tetrahydrobiopterin by greater than or equal to 97 and greater than 50%, respectively, with no effect upon cell growth. In both cell lines, the GTP cyclohydrolase inhibitor, 2,4-diamino-6-hydroxypyrimidine at 1-5 mM also depleted tetrahydrobiopterin greater than or equal to 97%. In this case, however, modest growth inhibition did occur. Since the growth inhibition could not be reversed upon tetrahydrobiopterin repletion, inhibition was due to other effects of the inhibitor rather than to tetrahydrobiopterin depletion. The results show that there is no effect on cell growth when at least 97% of the tetrahydrobiopterin in these cell lines is depleted. Since the sepiapterin reductase inhibitor depleted tetrahydrobiopterin with fewer nonspecific effects than the cyclohydrolase inhibitor, it will be useful for determining metabolic effects of tetrahydrobiopterin depletion.
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PMID:New inhibitors of sepiapterin reductase. Lack of an effect of intracellular tetrahydrobiopterin depletion upon in vitro proliferation of two human cell lines. 154 33

The cellular origin and the control of neopterin release associated with immune stimulation was studied in cell cultures. Using purified human mononuclear cells, the intracellular change in concentrations of GTP and pterins was measured under various kinds of stimulation. Three enzymes involved in tetrahydrobiopterin biosynthesis, i.e. GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase, were also determined. Human macrophages stimulated with culture supernatant from activated T-lymphocytes were the main producers of neopterin. In these cells, GTP cyclohydrolase I activity was elevated due to high GTP levels and therefore neopterin accumulated. Human macrophages lack 6-pyruvoyl tetrahydropterin synthase activity. Exogenous tetrahydrobiopterin added to the culture medium of stimulated T cells and macrophages suppressed the elevation of GTP cyclohydrolase I activity and neopterin concentration, but not the elevation of intracellular GTP. Stimulation of macrophages with recombinant human interferon-gamma and neutralization of the effect of T cell supernatants by addition of a monoclonal antibody specific for human interferon-gamma showed that immune interferon induced the alterations in GTP cyclohydrolase I activity and neopterin concentration. In the human macrophage line U-937 and in the leukemia line HL-60, no GTP cyclohydrolase I activity or intracellular pterins were detected, but high levels of GTP. In mouse mononuclear cells, no neopterin was detected, but biopterin and pterin. After stimulation, biopterin was elevated in the same way as neopterin in human mononuclear cells. This is explained by the different regulation of the rate-limiting steps of tetrahydrobiopterin biosynthesis in man and in mouse. These results suggest that neopterin is an unspecific marker for the activation of the cellular immune system.
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PMID:Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse. 330 38