| 19563773 |
McGuire JJ, Bartley DM, Tomsho JW, Haile WH, Coward JK: Inhibition of human folylpolyglutamate synthetase by diastereomeric phosphinic acid mimics of the tetrahedral intermediate. Arch Biochem Biophys. 2009 Aug 15;488(2):140-5. Epub 2009 Jun 27.
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. |
85(1,1,1,5) |