Literature DB >> 12825924

Dihydrofolate reductase mutant with exceptional resistance to methotrexate but not to trimetrexate.

Pamela Pineda1, Aaron Kanter, R Scott McIvor, Stephen J Benkovic, Andre Rosowsky, Carston R Wagner.   

Abstract

Two double (F31A/F34A, I60A/L67G) and one quadruple (F31A/F34A/I60A/L67G) mutant murine dihydrofolate reductases were constructed and evaluated for their ability to impart antifolate resistance. Both I60A/L67G and F31A/F34A/I60A/L67G were found to be unstable and devoid of catalytic activity. The K(i) values for F31A/F34A, methotrexate (MTX), bis-MTX, and PT-523 were found to be 10100-, 4410-, and 617-fold higher than the wild-type enzyme, respectively, but only 13.5-fold higher for trimetrexate (TMTX). These findings suggest that F31A/F34A could be used for gene therapy to render normal cells resistant to MTX but sensitive to TMTX.

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Year:  2003        PMID： 12825924     DOI： 10.1021/jm034057i

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  5 in total

1.  Self-assembly of antibodies by chemical induction.

Authors:  Qing Li; David Hapka; Hua Chen; Daniel A Vallera; Carston R Wagner
Journal:  Angew Chem Int Ed Engl       Date:  2008       Impact factor: 15.336

2.  Chemically self-assembled antibody nanostructures as potential drug carriers.

Authors:  Adrian Fegan; Sidath C Kumarapperuma; Carston R Wagner
Journal:  Mol Pharm       Date:  2012-10-16       Impact factor: 4.939

3.  Ligand binding modulates the mechanical stability of dihydrofolate reductase.

Authors:  Sri Rama Koti Ainavarapu; Lewyn Li; Carmen L Badilla; Julio M Fernandez
Journal:  Biophys J       Date:  2005-08-12       Impact factor: 4.033

4.  A trimethoprim derivative impedes antibiotic resistance evolution.

Authors:  Madhu Sudan Manna; Yusuf Talha Tamer; Ilona Gaszek; Nicole Poulides; Ayesha Ahmed; Xiaoyu Wang; Furkan C R Toprak; DaNae R Woodard; Andrew Y Koh; Noelle S Williams; Dominika Borek; Ali Rana Atilgan; John D Hulleman; Canan Atilgan; Uttam Tambar; Erdal Toprak
Journal:  Nat Commun       Date:  2021-05-19       Impact factor: 14.919

5.  Structural analysis of a holoenzyme complex of mouse dihydrofolate reductase with NADPH and a ternary complex with the potent and selective inhibitor 2,4-diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine.

Authors:  Vivian Cody; Jim Pace; Andre Rosowsky
Journal:  Acta Crystallogr D Biol Crystallogr       Date:  2008-08-13
  5 in total

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