5UDY

Human alkaline sphingomyelinase (alk-SMase, ENPP7, NPP7)

Summary for 5UDY

• Entry DOI: 10.2210/pdb5udy/pdb
• Descriptor: Ectonucleotide pyrophosphatase/phosphodiesterase family member 7, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: sphingomyelinase, sphingomyelin, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 53346.49

Authors

Gorelik, A.,Liu, F.,Illes, K.,Nagar, B. (deposition date: 2016-12-28, release date: 2017-03-22, Last modification date: 2024-10-30)

Primary citation

Gorelik, A.,Liu, F.,Illes, K.,Nagar, B.
Crystal structure of the human alkaline sphingomyelinase provides insights into substrate recognition.
J. Biol. Chem., 292:7087-7094, 2017

PubMed Abstract: Absorption of dietary sphingomyelin (SM) requires its initial degradation into ceramide, a process catalyzed by the intestinal enzyme alkaline sphingomyelinase (alk-SMase, NPP7, ). 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.

PubMed: 28292932
DOI: 10.1074/jbc.M116.769273

Experimental method

X-RAY DIFFRACTION (2.6 Å)