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Understanding the Molecular Activity of Alkaline Sphingomyelinase (NPP7) by Computer Modeling

Duan, Jianxin; Wu, Jun; Cheng, Yajun LU and Duan, Rui-Dong LU (2010) In Biochemistry 49(42). p.9096-9105
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemistry
volume
49
issue
42
pages
9096 - 9105
publisher
The American Chemical Society
external identifiers
  • wos:000283289000011
  • scopus:77958098962
ISSN
0006-2960
DOI
10.1021/bi101069u
language
English
LU publication?
yes
id
45597d46-48d5-4264-9f2b-75647208e687 (old id 1721157)
date added to LUP
2010-12-15 14:01:16
date last changed
2018-07-01 03:12:03
@article{45597d46-48d5-4264-9f2b-75647208e687,
  abstract     = {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.},
  author       = {Duan, Jianxin and Wu, Jun and Cheng, Yajun and Duan, Rui-Dong},
  issn         = {0006-2960},
  language     = {eng},
  number       = {42},
  pages        = {9096--9105},
  publisher    = {The American Chemical Society},
  series       = {Biochemistry},
  title        = {Understanding the Molecular Activity of Alkaline Sphingomyelinase (NPP7) by Computer Modeling},
  url          = {http://dx.doi.org/10.1021/bi101069u},
  volume       = {49},
  year         = {2010},
}