| pubmed-article:2914018 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:2914018 | lifeskim:mentions | umls-concept:C0086418 | lld:lifeskim |
| pubmed-article:2914018 | lifeskim:mentions | umls-concept:C0338106 | lld:lifeskim |
| pubmed-article:2914018 | lifeskim:mentions | umls-concept:C0522537 | lld:lifeskim |
| pubmed-article:2914018 | lifeskim:mentions | umls-concept:C0040085 | lld:lifeskim |
| pubmed-article:2914018 | lifeskim:mentions | umls-concept:C1280500 | lld:lifeskim |
| pubmed-article:2914018 | lifeskim:mentions | umls-concept:C1167622 | lld:lifeskim |
| pubmed-article:2914018 | lifeskim:mentions | umls-concept:C0048858 | lld:lifeskim |
| pubmed-article:2914018 | lifeskim:mentions | umls-concept:C1998793 | lld:lifeskim |
| pubmed-article:2914018 | pubmed:issue | 2 | lld:pubmed |
| pubmed-article:2914018 | pubmed:dateCreated | 1989-2-28 | lld:pubmed |
| pubmed-article:2914018 | pubmed:abstractText | CH2-H4PteGlu and H4PteGlu exist in human colon adenocarcinoma xenografts predominantly in the form of polyglutamate species at concentrations of less than 3 microM. The interaction of polyglutamates of [6R]CH2-H4PteGlu in the formation and stability of [6-3H]FdUMP-thymidylate synthase-CH2-H4PteGlun ternary complexes has therefore been examined using enzyme purified from a human colon adenocarcinoma xenograft. Dissociation of these complexes was first-order and was dependent upon the concentration of folate. [6R]CH2-H4PteGlu3-6 (0.9 to 1.6 microM) were greater than 200-fold and [6R]CH2-H4PteGlu2 (18.2 microM) was 18-fold more effective than [6R]CH2-H4PteGlu1 (335 microM) at stabilizing ternary complexes for a T1/2 for dissociation of 100 min. Polyglutamylation of CH2-H4PteGlu also increased the affinity of binding of [6-3H]FdUMP to thymidylate synthase as determined by Scatchard analysis at folate concentrations of 10 microM, where the Kd in the presence of [6R]CH2-H4PteGlu1 was in the order of 4.0 x 10(-8) M, and for [6R]CH2-H4PteGlu3-5 was between 3.7 and 5.5 x 10(-9) M. To examine whether this effect was due to differences in the rates at which [6-3H]FdUMP was bound (kon) or dissociated (koff) from the enzyme, the apparent rate of [6-3H]FdUMP binding was determined in the presence of [6R]CH2H4PteGlu1, [6R]CH2-H4PteGlu3 and [6R]CH2-H4PteGlu4. The kon values were similar and were in the range of 1.7 to 2.3 x 10(6) M-1 min-1 for 10 or 20 microM folate concentrations. Differences in binding affinity determined for [6R]CH2-H4PteGlu1 and longer polyglutamate forms of [6R]CH2-H4PteGlu were thus due to differences in koff. The Vmax for the initial velocity of [6-3H]FdUMP binding was achieved at 10 microM folate. Consequently, at concentrations of CH2-H4PteGlu polyglutamates present in tumors, inhibition of thymidylate synthase by FdUMP in vivo would be expected to be transient, based upon the concentration of [6R]CH2-H4PteGlun required for maximal formation and stability of the covalent ternary complex. It would be advantageous for modulation of CH2-H4PteGlun pools to increase the concentrations of the longer polyglutamate species (n greater than or equal to 3) to maximize the interaction between FdUMP, thymidylate synthase and CH2-H4PteGlu. | lld:pubmed |
| pubmed-article:2914018 | pubmed:language | eng | lld:pubmed |
| pubmed-article:2914018 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:2914018 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:2914018 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:2914018 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:2914018 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:2914018 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:2914018 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:2914018 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:2914018 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:2914018 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:2914018 | pubmed:month | Jan | lld:pubmed |
| pubmed-article:2914018 | pubmed:issn | 0006-2952 | lld:pubmed |
| pubmed-article:2914018 | pubmed:author | pubmed-author:HoughtonP JPJ | lld:pubmed |
| pubmed-article:2914018 | pubmed:author | pubmed-author:HoughtonJ AJA | lld:pubmed |
| pubmed-article:2914018 | pubmed:author | pubmed-author:RadparvarSS | lld:pubmed |
| pubmed-article:2914018 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:2914018 | pubmed:day | 15 | lld:pubmed |
| pubmed-article:2914018 | pubmed:volume | 38 | lld:pubmed |
| pubmed-article:2914018 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:2914018 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:2914018 | pubmed:pagination | 335-42 | lld:pubmed |
| pubmed-article:2914018 | pubmed:dateRevised | 2006-11-15 | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:meshHeading | pubmed-meshheading:2914018-... | lld:pubmed |
| pubmed-article:2914018 | pubmed:year | 1989 | lld:pubmed |
| pubmed-article:2914018 | pubmed:articleTitle | Effect of polyglutamylation of 5,10-methylenetetrahydrofolate on the binding of 5-fluoro-2'-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft. | lld:pubmed |
| pubmed-article:2914018 | pubmed:affiliation | Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38101. | lld:pubmed |
| pubmed-article:2914018 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:2914018 | pubmed:publicationType | In Vitro | lld:pubmed |
| http://linkedlifedata.com/r... | pubmed:referesTo | pubmed-article:2914018 | lld:pubmed |
| http://linkedlifedata.com/r... | pubmed:referesTo | pubmed-article:2914018 | lld:pubmed |
