Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatic mutations in the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene are rare occurrences in T-lymphocytes of normal individuals. Lacking pathogenic significance, these events can serve as reporters for assessing environmental genotoxicity. The present molecular analyses of hprt mutations arising spontaneously in normal children show that 30-35% of the genomic hprt changes in children under 5 years of age have approximately 20 Kb deletions encompassing exons 2 and 3. The frequency of these specific changes are dramatically decreased in older children. Sequence analysis of these deletion breakpoint and joining regions reveal the molecular hallmarks of V(D)J recombinase-mediated recombination events. This early childhood hprt mutational spectrum is quite distinct from the adult background spectrum but similar to that reported previously for newborns, as determined in lymphocytes from placental cord blood. The present study also demonstrates that definition of sequences in the hprt deletion joining regions that are analogous to the N-nucleotide insertion hypervariable regions of rearranged T-cell receptor genes allows the same identification of in vivo clonality of mutants as does analysis of the T-cell receptor gene rearrangements themselves. These methods reveal an in vivo clonal amplification of a V(D)J recombinase-mediated hprt mutant clone in one child in the present study. This newly found age-frequency distribution of V(D)J recombinase-mediated hprt mutations correlates with the age-frequency distribution of childhood acute lymphocytic leukemia. A significant number of these malignancies, including acute T-cell leukemia, are also characterized by V(D)J recombinase-mediated recombinations but in critical regions of the genome. hprt, therefore, captures a pathogenic mutagenic mechanism as a harmless mistake which, when it occurs in other genetic regions, may result in malignancy.
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PMID:V(D)J recombinase-mediated HPRT mutations in peripheral blood lymphocytes of normal children. 864 Aug 32

The thiopurine antimetabolite 6-mercaptopurine (6MP) is an important chemotherapeutic drug in the conventional treatment of childhood acute lymphoblastic leukemia (ALL). 6MP is mainly catabolized by both hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and xanthine oxidase (XOD) to form thioinosinic monophosphate (TIMP) (therapeutically active metabolite) and 6-thiouric acid (6TUA) (inactive metabolite), respectively. The activity of both the enzymes varies among ALL patients governing the active and the inactive metabolite profile within the immature lymphocytes. Therefore, an attempt was made to study the kinetic nature of the branched bi-enzyme system acting on 6MP and to quantitate TIMP and 6TUA formed when the two enzymes are present in equal and variable ratios. The quantification of the branched kinetics using spectrophotometric method presents problem due to the closely apposed lambda(max) of the substrates and products. Hence, employing an HPLC method, the quantification of the products was done with the progress of time. The limit of quantification (LOQ) of substrate was found to be 10nM and for products as 50 nM. The limit of detection (LOD) was found to be 1 nM for the substrate and the products. The method exhibited linearity in the range of 0.01-100 microM for 6MP and 0.05-100 microM for both 6TUA and TIMP. The amount of TIMP formed was higher than that of 6TUA in the bi-enzyme system when both the enzymes were present in equivalent enzymatic ratio. It was further found that enzymatic ratios play an important role in determining the amounts of TIMP and 6TUA. This method was further validated using actively growing T-ALL cell line (Jurkat) to study the branched kinetics, wherein it was observed that treatment of 50 microM 6MP led to the generation of 12 microM TIMP and 0.8 microM 6TUA in 6 h at 37 degrees C.
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PMID:Application of HPLC to study the kinetics of a branched bi-enzyme system consisting of hypoxanthine-guanine phosphoribosyltransferase and xanthine oxidase--an important biochemical system to evaluate the efficiency of the anticancer drug 6-mercaptopurine in ALL cell line. 1708 13