A nonhydrolyzable analogue of phosphotyrosine, and related aryloxymethano- and aryloxyethano-phosphonic acids as motifs for inhibition of phosphatases.
Nonhydrolyzable analogues of both stereoisomers of phosphotyrosine, and a series of related aryloxy (or thio) methyl and aryloxy (or thio) ethyl phosphonic acids of the general formula RX-(CH(2))(n)-PO(3)H(2) (where X=O or S and n=1 or 2), have been tested as nonhydrolyzable mimetics of phosphatase substrates. These compounds were tested against a panel of phosphatases (two alkaline phosphatases, a protein-tyrosine phosphatase, and two serine/threonine phosphatases) with different active site motifs. The compounds exhibit competitive inhibition toward all enzymes tested, with the best inhibition expressed toward the Ser/Thr phosphatases. The stereoisomers of the phosphotyrosine analogues exhibited an unexpected difference in their inhibitory properties toward the protein-tyrosine phosphatase from Yersinia. The K(i) for the d isomer is 33-fold lower than that of the l isomer, and is more than an order of magnitude lower than the reported K(m) of the substrate l-phosphotyrosine.
Iyer
Subashree
S
Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322-0300, USA.
Younker
Jarod M
JM
Czyryca
Przemyslaw G
PG
Hengge
Alvan C
AC
D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019000:Phosphotyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D063065:Organophosphonates; D011480:Protease Inhibitors; D019000:Phosphotyrosine; D010749:Phosphoprotein Phosphatases