Structure and function of sphingomyelinase

Abstract

Bacillus cereus is one that causes of opportunistic human infections. Sphingomyelinase produced by B. cereus is assumed a virulence factor for the infection. Sphingomyelinase from Bacillus cereus (Bc-SMase) is Mg 2+-containing metalloenzyme. Bc-SMase is a family of neutral SMase (nSMase) and mimics the actions of the endogenous mammalian nSMase in causing differentiation, development, and apoptosis. Bc-SMase may be a good model for the poorly characterized mammalian nSMase. Activation of Bc-SMase by divalent metal ions was in the order Co2+>,Mn2+>,Mg 2+≫ Ca2+>,Sr2+. Crystal structure analysis of Bc-SMase bound to Co2+, Mg2+, or Ca 2+ revealed that the water-bridged double divalent metal ions at the center of the cleft in both the Co2+- and Mg2+-bound forms is the catalytic architecture required for sphingomyelinase activity. In contrast, the architecture of Ca2+ binding at the site showed only one binding site. A further single metal-binding site existed at one side edge of the cleft. Based on the highly conserved nature of amino acid residues of the binding sites, the crystal structure of Bc-SMase with Mg2+ or Co2+ provided a common structural framework applicable to phosphohydrolases belonging to the DNase I-like folding superfamily. In addition, our analysis provided evidence that β-hairpin containing the aromatic amino acid residues and the metal ion of the side-edge participate in binding to sphinogmyelin and membranes containing sphingomyelin. This article summarized current knowledge of characteristics and mode of action of Bc-SMase. © 2009 The Pharmaceutical Society of Japan.