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
Biochemical Pharmacology, ISSN: 0006-2952, Vol: 38, Issue: 2, Page: 335-342
1989
- 72Citations
- 26Captures
Metric Options: Counts1 Year3 YearSelecting the 1-year or 3-year option will change the metrics count to percentiles, illustrating how an article or review compares to other articles or reviews within the selected time period in the same journal. Selecting the 1-year option compares the metrics against other articles/reviews that were also published in the same calendar year. Selecting the 3-year option compares the metrics against other articles/reviews that were also published in the same calendar year plus the two years prior.
Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
Citation Benchmarking is provided by Scopus and SciVal and is different from the metrics context provided by PlumX Metrics.
Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
Citation Benchmarking is provided by Scopus and SciVal and is different from the metrics context provided by PlumX Metrics.
Metrics Details
- Citations72
- Citation Indexes72
- 72
- CrossRef53
- Captures26
- Readers26
- 26
Article Description
CH 2 -H 4 PteGlu and H 4 PteGlu exist in human colon adenocarcinoma xenografts predominantly in the form of polyglutamate species at concentrations of < 3 μM. The interaction of polyglutamates of [6 R ]CH 2,-H 4 PteGlu in the formation and stability of [6- 3 H]FdUMP-thymidylate synthase-CH 2 -H 4 PteGlu n 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. [6 R ]CH 2 -H 4 PteGlu 3–6 (0.9 to 1.6 μM) were >200-fold and [6 R ]CH 2 -H 4 PteGlu 2 (18.2 μm) was 18-fold more effective than [6 R ]CH 2 -H 4 PteGlu 1 (335 μM) at stabilizing ternary complexes for a T12 for dissociation of 100 min. Polyglutamylation of CH 2 -H 4 PteGlu also increased the affinity of binding of [6- 3 H]FdUMP to thymidylate synthase as determined by Scatchard analysis at folate concentrations of 10 μM, where the K d in the presence of [6 R ]CH 2 -H 4 PteGlu 1 was in the order of 4.0 × 10 −8 M, and for [6 R ]CH 2 -H 4 PteGlu 3–5 was between 3.7 and 5.5 × 10 −9 M. To examine whether this effect was due to differences in the rates at which [6- 3 H]FdUMP was bound ( k on ) or dissociated ( k off ) from the enzyme, the apparent rate of [6- 3 H]FdUMP binding was determined in the presence of [6 R ]CH 2 H 4 PteGlu 1, [6 R ]CH 2 -H 4 PteGlu 3 and [6 R ]CH 2 -H 4 PteGlu 4. The k on values were similar and were in the range of 1.7 to 2.3 × 10 6 M −1 min −1 for 10 or 20 μM folate concentrations. Differences in binding affinity determined for [6 R ]CH 2 -H 4 PteGlu 1 and longer polyglutamate forms of [6 R ]CH 2 -H 4 PteGlu were thus due to differences in k off. The V max for the initial velocity of [6- 3 H]FdUMP binding was achieved at 10 μM folate. Consequently, at concentrations of CH 2 -H 4 PteGlu polyglutamates present in tumors, inhibition of thymidylate synthase by FdUMP in vivo would be expected to be transient, based upon the concentration of [6 R ]CH 2 -H 4 PteGlu n required for maximal formation and stability of the covalent ternary complex. It would be advantageous for modulation of CH 2 -H 4 PteGlu n pools to increase the concentrations of the longer polyglutamate species (n ≥ 3) to maximize the interaction between FdUMP, thymidylate synthase and CH2-H 4 PteGlu.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/0006295289900464; http://dx.doi.org/10.1016/0006-2952(89)90046-4; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0024578676&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/2914018; https://linkinghub.elsevier.com/retrieve/pii/0006295289900464; http://dx.doi.org/10.1016/0006-2952%2889%2990046-4; https://dx.doi.org/10.1016/0006-2952%2889%2990046-4
Elsevier BV
Provide Feedback
Have ideas for a new metric? Would you like to see something else here?Let us know