A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase.
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 (approximately 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 SN2-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.
Seto
Marian
M
Department of Biophysics, Berlex Biosciences, Richmond, California 94804, USA.
Whitlow
Marc
M
McCarrick
Margaret A
MA
Srinivasan
Subha
S
Zhu
Ying
Y
Pagila
Rene
R
Mintzer
Robert
R
Light
David
D
Johns
Anthony
A
Meurer-Ogden
Janet A
JA
D000135:Acid Phosphatase / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D051381:Rats; D016415:Sequence Alignment; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry*; D040681:Structural Homology, Protein
D006023:Glycoproteins; C091137:purple acid phosphatase; D000135:Acid Phosphatase; D013108:Sphingomyelin Phosphodiesterase