Title : Crystal structure of the human
alkaline sphingomyelinase provides insights into substrate recognition
Abstract :
- Absorption of dietary sphingomyelin ( SM ) requires its initial degradation into ceramide, a process catalyzed by the intestinal enzyme alkaline sphingomyelinase (alk-SMase , NPP7 , ENPP7 )
- alk-SMase belongs to the nucleotide pyrophosphatase/phosphodiesterase (NPP) family, the members of which hydrolyze nucleoside phosphates, phospholipids, and other related molecules
- NPP7 is the only paralog that can cleave SM , and its activity requires the presence of bile salts, a class of physiological anionic detergents
- To elucidate the mechanism of substrate recognition, we determined the crystal structure of human alk-SMase in complex with phosphocholine, a reaction product
- Although the overall fold and catalytic center are conserved relative to other NPPs , alk-SMase recognizes the choline moiety of its substrates via an NPP7-specific aromatic box composed of tyrosine residues
- Mutational analysis and enzymatic activity assays identified features on the surface of the protein-a cationic patch and a unique hydrophobic loop-that are essential for accessing SM in bile salt micelles
- These results shed new light on substrate specificity determinants within the NPP enzyme family
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):