Mechanism-based inhibition of human folylpolyglutamate synthetase: design, synthesis, and biochemical characterization of a phosphapeptide mimic of the tetrahedral intermediate

Archives of Biochemistry and Biophysics
T TsukamotoJames K Coward

Abstract

Folylpolyglutamate synthetase (FPGS) catalyzes anATP-dependent ligation reaction that results in the synthesis of poly(gamma-glutamate) metabolites of folates and some antifolates. We have synthesized and characterized the prototype of a new class of mechanism-based FPGS inhibitor in which a phosphonate moiety mimics the tetrahedral intermediate formed during the ligation reaction. This phosphonate, 4-amino-4-deoxy-10-methyl-pteroyl-L-glutamyl-gamma-[Psi¿P(O)(OH)-O¿] glutarate (4-NH2-10-CH3-Pte-L-Glu-gamma-[Psi¿P(O)(OH)-O¿]glutarate), is not a substrate for human FPGS, but is a linear, competitive inhibitor (Kis = 46 nM) with respect to methotrexate as the variable substrate. Inhibition is not time-dependent and preincubation of FPGS with this phosphonate does not increase the degree of inhibition, suggesting that it is not a slow, tight-binding inhibitor involving a time-dependent isomerization, EI --> EI*. Substructures containing the phosphonate moiety but lacking the pterin are much less inhibitory to FPGS, indicating that a significant portion of the inhibitor binding energy is derived from the pterin moiety, a feature also observed in substrate binding. 4-NH2-10-CH3-Pte-L-Glu-gamma-[Psi¿P(O)(OH)-O¿]glutarate is also an an...Continue Reading

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Citations

Jul 14, 2011·Leukemia & Lymphoma·Rebecca J WattersThomas P Loughran
Aug 29, 2006·Journal of Molecular Biology·Clyde A Smith
Aug 15, 2001·Journal of Molecular Biology·X SunC A Smith
Jul 12, 2002·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Alun Bermingham, Jeremy P Derrick
Jul 26, 2005·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Jun Hiratake
Feb 11, 2005·Chemical Reviews·Ivan M KompisRudolf L Then
Jul 20, 2002·Bioorganic & Medicinal Chemistry Letters·Takashi TsukamotoJames K Coward
Nov 1, 2002·Journal of Medicinal Chemistry·Aleem GangjeeRoy L Kisliuk
Jul 1, 2009·Archives of Biochemistry and Biophysics·John J McGuireJames K Coward

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