Structural origins of L(+)-tartrate inhibition of human prostatic acid phosphatase.
Acid phosphatase activity in the blood serum is usually separated into tartrate-resistant and tartrate-refractory, which is reported as the prostatic acid phosphatase level. Human prostatic acid phosphatase crystals soaked in N-propyl-L-tartramate were used to collect x-ray diffraction data to 2.9 A resolution under cryogenic conditions. Positive difference electron density, corresponding to the inhibitor, was found. The quality of the electron density maps clearly shows the orientation of the carboxylate and N-propyl-substituted amide groups. The hydroxyl group attached to C3 forms two crucial hydrogen bonds with Arg-79 and His-257. Previous crystallographic studies compiled on the tartrate-rat prostatic acid phosphatase binary complex (Lindqvist, Y., Schneider, G., and Vihko, P. (1993) J. Biol. Chem. 268, 20744-20746) erroneously positioned D-tartrate into the active site. Modeling studies have shown that the C3 hydroxyl group on the D(-)-stereoisomer of tartrate, which does not significantly inhibit prostatic acid phosphatase, does not form strong hydrogen bonds with Arg-79 or His-257. The structure of human prostatic acid phosphatase, noncovalently bound in N-propyl-L-tartramate, is used to develop inhibitors with higher specificity and potency than L(+)-tartrate.
LaCount
M W
MW
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, USA.
Handy
G
G
Lebioda
L
L
D000135:Acid Phosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011467:Prostate / Q000201:enzymology*; D013644:Tartrates / Q000494:pharmacology*; D014961:X-Ray Diffraction
D004791:Enzyme Inhibitors; D013644:Tartrates; D000135:Acid Phosphatase