Source:http://linkedlifedata.com/resource/pubmed/id/20839774
Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
42
|
| pubmed:dateCreated |
2010-10-19
|
| pubmed:abstractText |
The enzymes in the nucleotide pyrophosphatase/phosphodiesterase (NPP) family have various substrates such as nucleotides, phospholipids, and sphingolipids. The substrate specificity in relation to their structures is largely unknown because no mammalian NPP complex has been crystallized. NPP7, also called alkaline sphingomyelinase (alk-SMase), is a NPP family member that may have important implications in carcinogenesis and cholesterol absorption. The sequence of NPP7 is 36% similar to that of the closest NPP member, but NPP7 has no activity against nucleotides. In this work, we predict the three-dimensional structure of NPP7 by homology modeling using a recently crystallized NPP from bacteria. Using the model, we studied the substrate specificity of the enzyme by docking. The model generated explains the functional changes in previous mutagenesis studies and rationalizes the structural basis for the lack of activity toward nucleotides. An effort to shift the substrate specificity from sphingomyelin (SM) to nucleotide was not successful but revealed a site-directed mutation that increased activity toward SM. In conclusion, this is the first study to predict the structure of a mammalian NPP and its substrate specificity by molecular modeling. The information may be helpful in understanding the functional differences of NPP members.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
1520-4995
|
| pubmed:author | |
| pubmed:issnType |
Electronic
|
| pubmed:day |
26
|
| pubmed:volume |
49
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
9096-105
|
| pubmed:meshHeading |
pubmed-meshheading:20839774-Amino Acid Sequence,
pubmed-meshheading:20839774-Animals,
pubmed-meshheading:20839774-Base Sequence,
pubmed-meshheading:20839774-Catalytic Domain,
pubmed-meshheading:20839774-Cattle,
pubmed-meshheading:20839774-Computer Simulation,
pubmed-meshheading:20839774-DNA Primers,
pubmed-meshheading:20839774-Humans,
pubmed-meshheading:20839774-Molecular Dynamics Simulation,
pubmed-meshheading:20839774-Molecular Sequence Data,
pubmed-meshheading:20839774-Mutagenesis, Site-Directed,
pubmed-meshheading:20839774-Protein Conformation,
pubmed-meshheading:20839774-Recombinant Proteins,
pubmed-meshheading:20839774-Sequence Alignment,
pubmed-meshheading:20839774-Sequence Homology,
pubmed-meshheading:20839774-Sequence Homology, Amino Acid,
pubmed-meshheading:20839774-Sphingomyelin Phosphodiesterase,
pubmed-meshheading:20839774-Static Electricity,
pubmed-meshheading:20839774-Substrate Specificity
|
| pubmed:year |
2010
|
| pubmed:articleTitle |
Understanding the molecular activity of alkaline sphingomyelinase (NPP7) by computer modeling.
|
| pubmed:affiliation |
Schro?dinger GmbH, Dynamostrasse 13, 681 61 Mannheim, Germany. jianxin.duan@schrodinger.com
|
| pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
|