Crystal structure of alkaline phosphatase from human placenta at 1.8 A resolution - Implication for a substrate specificity

Human placental alkaline phosphatase (PLAP) is one of three tissue-specific human APs extensively studied because of its ectopic expression in tumors. The crystal structure, determined at 1.8-Angstrom resolution, reveals that during evolution, only the overall features of the enzyme have been conser ved with respect to Escherichia coli. The surface is deeply mutated with 8% residues in common, and in the active site, only residues strictly necessa ry to perform the catalysis have been preserved. Additional structural elem ents aid an understanding of the allosteric property that is specific for t he mammalian enzyme (Hoylaerts, M. F., Manes, T., and Millan, J. L. (1997) J. Biol. Chem. 272, 22781-22787). Allostery is probably favored by the qual ity of the dimer interface, by a long N-terminal alpha -helix from one mono mer that embraces the other one, and similarly by the exchange of a residue from one monomer in the active site of the other. In the neighborhood of t he catalytic serine, the orientation of Glu-429, a residue unique to PLAP, and the presence of a hydrophobic pocket close to the phosphate product, ac count for the specific uncompetitive inhibition of PLAP by L-amino acids, c onsistent with the acquisition of substrate specificity. The location of th e active site at the bottom of a large valley flanked by an interfacial cro wn-shaped domain and a domain containing an extra metal ion on the other si de suggest that the substrate of PLAP could be a specific phosphorylated pr otein.