Zhang, Y., Desharnais, J., Marsilje, T.H., Li, C.L., Hedrick, M.P., Gooljarsingh, L.T., Tavassoli, A., Benkovic, S.J., Olson, A.J., Boger, D.L. and Wilson, I.A.
Rational design, synthesis, evaluation, and crystal structure of a potent inhibitor of human GAR tfase: 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid
Biochemistry, 42, (20), . (doi:10.1021/bi034219c).
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Glycinamide ribonucleotide transformylase (GAR Tfase) has been the target of anti-neoplastic intervention for almost two decades. Here, we use a structure-based approach to design a novel folate analogue, 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid (10-CF3CO-DDACTHF, 1), which specifically inhibits recombinant human GAR Tfase (Ki = 15 nM), but is inactive (Ki > 100 ?M) against other folate-dependent enzymes that have been examined. Moreover, compound 1 is a potent inhibitor of tumor cell proliferation (IC50 = 16 nM, CCRF-CEM), which represents a 10-fold improvement over Lometrexol, a GAR Tfase inhibitor that has been in clinical trials. Thus, this folate analogue 1 is among the most potent and selective inhibitors known toward GAR Tfase. Contributing to its efficacious activity, compound 1 is effectively transported into the cell by the reduced folate carrier and intracellularly sequestered by polyglutamation. The crystal structure of human GAR Tfase with folate analogue 1 at 1.98 A resolution represents the first structure of any GAR Tfase to be determined with a cofactor or cofactor analogue without the presence of substrate. The folate-binding loop of residues 141-146, which is highly flexible in both Escherichia coli and unliganded human GAR Tfase structures, becomes highly ordered upon binding 1 in the folate-binding site. Computational docking of the natural cofactor into this and other apo or complexed structures provides a rational basis for modeling how the natural cofactor 10-formyltetrahydrofolic acid interacts with GAR Tfase, and suggests that this folate analogue-bound conformation represents the best template to date for inhibitor design.
|Digital Object Identifier (DOI):
||functional complementation, biological evaluation, 10-trideazafolic acid, glycinamide ribonucleotide transformylase, selective-inhibition, oral, kinetic mechanism, folic-acid, folate-binding-protein, active-site, escherichia-coli, 8, 10-formyl-5
||31 Jul 2008
||16 Apr 2017 17:47
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