Abstract
Most biological fluids are supersaturated with calcium salts. A mechanism controlling crystal growth is therefore necessary to prevent excessive precipitation and development of a lithiasis. In pancreatic juice, calcite precipitation is prevented by lithostathine, a glycoprotein that inhibits calcite crystal growth. We describe here the interaction of lithostathine with calcite crystals. Without lithostathine, calcite crystals grew as rhombohedra showing six (104) faces. At low concentration (1 microM), lithostathine already altered crystal growth by generating new (110) faces. At physiological concentrations (3-10 microM), adsorption resulted in a transition from rhombohedral to sub-cubic habits. Immunochemical localization demonstrated that, although all (104) faces are equivalent, lithostathine binding was restricted to the face edges distal to the c axis. Scanning electron microscopy showed that, at the site of lithostathine binding, spreading of new CaCO3 layers during crystal growth was arrested before reaching the crystal diad axis-bearing edges. The successive kinks generated during crystal growth formed the new, striated (110)faces. Similar modifications were observed with the N-terminal undecapeptide of lithostathine that bears the inhibitory activity. With 100 microM lithostathine, (110) faces could reach the c axis outcrop of the former rhombohedron, resulting in an olive-shaped crystal. Finally, the number of crystals increased and their average size decreased when lithostathine concentration increased from 0.1 to 100 microM. Decreased Ca2+ concentration during crystal growth was delayed in the presence of lithostathine. It was concluded that lithostathine controls lithogenesis 1) by triggering germination of numerous calcite crystals and 2) by inhibiting the rate of Ca2+ ion apposition on the nuclei and therefore interfering with the apposition of new layers on calcite. Formation of smaller crystals, whose elimination is easier, is thereby favored.
Highlights
Biological fluids are generally supersaturated with respect to a calcium salt, such as oxalate in urine, phosphate in saliva, and carbonate in bile or pancreatic juice
With lithostathine being the only protein from pancreatic juice with inhibitory activity on CaCO3 crystal growth, these results suggest that it is a key factor in the prevention of stone formation in pancreatic ducts
The same experiments were run with the N-terminal undecapeptide of lithostathine that bears the inhibitory activity on CaCO3 crystal growth [7], except that peptide concentration ranged from 10 M to 10 mM
Summary
(Received for publication, November 13, 1995, and in revised form, May 28, 1996). Sophie Geider‡§, Alain Baronnet¶, Claire Cerini‡§, Serge Nitsche¶, Jean-Pierre Astier¶, Robert Michel‡, Roland Boistelle¶, Yvon Berlandʈ, Jean-Charles Dagorn‡, and Jean-Michel Verdier‡**. Scanning electron microscopy showed that, at the site of lithostathine binding, spreading of new CaCO3 layers during crystal growth was arrested before reaching the crystal diad axis-bearing edges. Biological fluids are generally supersaturated with respect to a calcium salt, such as oxalate in urine, phosphate in saliva, and carbonate in bile or pancreatic juice. Lithostathine is a glycoprotein of 144 amino acids, showing a structural homology with C-type lectins, and synthesized by pancreatic acinar cells [5] It is a powerful inhibitor of CaCO3 crystal nucleation and growth in vitro [6, 7]. With lithostathine being the only protein from pancreatic juice with inhibitory activity on CaCO3 crystal growth, these results suggest that it is a key factor in the prevention of stone formation in pancreatic ducts. Our results led us to propose a model of calcite growth inhibition by lithostathine
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