title: Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease.
abstract: Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann-Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients.
authors.affiliation: Protein Engineering Department, Biologics Research, Sanofi, Framingham, Massachusetts 01701, USA.
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry &Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts 01003, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Metcalf
authors.affiliation: Department of Biochemistry &Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts 01003, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Garman
authors.affiliation: Protein Engineering Department, Biologics Research, Sanofi, Framingham, Massachusetts 01701, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Edmunds
authors.affiliation: Protein Engineering Department, Biologics Research, Sanofi, Framingham, Massachusetts 01701, USA.
authors.forename: Huawei
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Protein Engineering Department, Biologics Research, Sanofi, Framingham, Massachusetts 01701, USA.
authors.forename: Ronnie R
authors.initials: RR
authors.lastname: Wei
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009542:Niemann-Pick Diseases / Q000201:enzymology*; D010767:Phosphorylcholine / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D000072417:Protein Domains; D049231:Saposins / Q000737:chemistry; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D015032:Zinc / Q000378:metabolism
chemical_list: D049231:Saposins; D010767:Phosphorylcholine; D011392:Proline; D013108:Sphingomyelin Phosphodiesterase; D015032:Zinc