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<p>Ectonucleotide pyrophosphatase/phosphodiesterase 7 (ENPP7) is an alkaline sphingomyelinase that degrades sphingomyelin to ceramide and phosphocholine in the colon. It is closely related to the tumorigenesis of colorectal cancer (CRC). Although numerous naturally occurring mutant variations of this protein have been found in CRC patients, it is still unclear how the mutation affects the protein’s overall structure and activity. In this study, mutagenesis to the wild-type ENPP7 sequence (designated <b>1</b>) was carried out according to the data on natural mutant variations obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, producing nine altered protein sequences (<b>2</b>–<b>10</b>). Results show that the theoretical isoelectric point and instability index of mutant <b>3</b> (V346I) and <b>8</b> (E89K) differ from those of wild-type protein <b>1</b>. While all proteins have four identical motifs, the transmembrane region of mutant <b>8</b> has a lower random coil and a higher alpha-helix abundance than <b>1</b>. All protein structures were then homologically built using the PDB: 5UDY crystal structure as a reference. Molecular docking and dynamics simulation showed that mutant <b>8</b> and phosphocholine (the ligand) had the lowest binding affinity between each other, and the mutation deteriorated the thermodynamic feasibility, nonbonded interactions, and overall binding stability with its ligand. All these results suggested that the E89K mutation (represented by mutant <b>8</b>) negatively impacted the protein structure and activity, which could directly contribute to the tumorigenesis and severity of CRC.</p>

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Sequence analysis, homology modeling, and molecular docking studies of the effects of point mutations on the ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7) in colorectal cancer

  • 期刊论文

  • 发表日期：

    2025年11月28日

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  • Chun Hoe Tan,
  • Hiba Ahmed Hassan

摘要

Ectonucleotide pyrophosphatase/phosphodiesterase 7 (ENPP7) is an alkaline sphingomyelinase that degrades sphingomyelin to ceramide and phosphocholine in the colon. It is closely related to the tumorigenesis of colorectal cancer (CRC). Although numerous naturally occurring mutant variations of this protein have been found in CRC patients, it is still unclear how the mutation affects the protein’s overall structure and activity. In this study, mutagenesis to the wild-type ENPP7 sequence (designated 1) was carried out according to the data on natural mutant variations obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC) database, producing nine altered protein sequences (2–10). Results show that the theoretical isoelectric point and instability index of mutant 3 (V346I) and 8 (E89K) differ from those of wild-type protein 1. While all proteins have four identical motifs, the transmembrane region of mutant 8 has a lower random coil and a higher alpha-helix abundance than 1. All protein structures were then homologically built using the PDB: 5UDY crystal structure as a reference. Molecular docking and dynamics simulation showed that mutant 8 and phosphocholine (the ligand) had the lowest binding affinity between each other, and the mutation deteriorated the thermodynamic feasibility, nonbonded interactions, and overall binding stability with its ligand. All these results suggested that the E89K mutation (represented by mutant 8) negatively impacted the protein structure and activity, which could directly contribute to the tumorigenesis and severity of CRC.