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[摘要]：Phosphorus-containing pseudopeptides, racemic at the C-terminal alpha-carbon, are potent mechanism-based inhibitors of folylpolyglutamate synthetase (FPGS). They are mimics of the tetrahedral intermediate postulated to form during FPGS-catalyzed biosynthesis of poly(gamma-L-glutamates). In the present paper, the FPGS inhibitory activity of each diastereomer coupled to three heterocycles is reported. The high R-f pseudopeptide containing the 5,10-dideazatetrahydropteroyl (DDAH(4)Pte) heterocycle is most potent (K-is = 1.7 nM). While the heterocyclic portion affects absolute FPGS inhibitory potency, the high R-f species is more potent in each pair containing the same heterocycle. This species presumably has the same stereochemistry as the natural folate polyglutamate, i.e., (L-Glu-gamma-L-Glu). Unexpectedly, the low R-f (presumed L-Glu-gamma-D-Glu) species are only slightly less potent (<30-fold) than their diastereomers. Further study of this phenomenon comparing L-Glu-gamma-L-Glu and L-Glu-gamma-D-Glu dipeptide-containing FPGS substrates shows that <1% contamination of commercial D-Glu precursors by L-Glu may give misleading information if L-Glu-gamma-L-Glu substrates have low K-m values. (C) 2009 Elsevier Inc. All rights reserved. |
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