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A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase

¹ Departments of Biophysics, ² System Biology, ³ Cardiovascular, ⁴ Molecular Pharmacology, and ⁵ Antibody Technology, Berlex Biosciences, Richmond, California 94804, USA
⁶ Department of Medicinal Chemistry, Celgene Corp., San Diego, California 92121, USA
⁷ Jivan Biologics Inc., Berkeley, California 94710, USA

(RECEIVED July 1, 2004; FINAL REVISION August 23, 2004; ACCEPTED August 24, 2004)

Sequence profile and fold recognition methods identified mammalian purple acid phosphatase (PAP), a member of a dimetal-containing phosphoesterase (DMP) family, as a remote homolog of human acid sphingomyelinase (ASM). A model of the phosphoesterase domain of ASM was built based on its predicted secondary structure and the metal-coordinating residues of PAP. Due to the low sequence identity between ASM and PAP (~15%), the highest degree of confidence in the model resides in the metal-binding motifs. The ASM model predicts residues Asp 206, Asp 278, Asn 318, His 425, and His 457 to be dimetal coordinating. A putative orientation for the phosphorylcholine head group of the ASM substrate, sphingomyelin (SM), was made based on the predicted catalysis of the phosphorus–oxygen bond in the active site of ASM and on a structural comparison of the PAP–phosphate complex to the C-reactive protein–phosphorylcholine complex. These complexes revealed similar spatial interactions between the metal-coordinating residues, the metals, and the phosphate groups, suggesting a putative orientation for the head group in ASM consistent with the mechanism considerations. A conserved sequence motif in ASM, NX₃CX₃N, was identified (Asn 381 to Asn 389) and is predicted to interact with the choline amine moiety in SM. The resulting ASM model suggests that the enzyme uses an S_N2-type catalytic mechanism to hydrolyze SM, similar to other DMPs. His 319 in ASM is predicted to protonate the ceramide-leaving group in the catalysis of SM. The putative functional roles of several ASM Niemann-Pick missense mutations, located in the predicted phosphoesterase domain, are discussed in context to the model.

Keywords: acid sphingomyelinase; phosphoesterase; purple acid phosphatase; threading; structure predictions

Abbreviations: ASM, acid sphingomyelinase • CRP, C-reactive protein • DMP, dimetal-containing phosphoesterase • HMM, hidden Markov model • LDL, low-density lipoproteins • MM1–MM5, predicted phosphatase metal-coordinating motifs 1 through 5 • PAP, purple acid phosphatase • RMSD, root mean square deviation • SM, sphingomyelin • TRAP, tartrate-resistant acid phosphatase

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04966204.

Reprint requests to: Janet A. Meurer-Ogden, Department of Molecular Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA; e-mail: Janet_Meurer{at}Berlex.com; fax: (510) 262-7844.

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