Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur

J Med Chem. 2019 Jan 24;62(2):987-992. doi: 10.1021/acs.jmedchem.8b01723. Epub 2018 Dec 19.

Abstract

Human acid ceramidase (AC) is a lysosomal cysteine amidase, which has received a great deal of interest in recent years as a potential target for the development of new therapeutics against melanoma and glioblastoma tumors. Despite the strong interest in obtaining structural information, only the structures of the apo-AC enzyme in its zymogen and activated conformations are available. In this work, the crystal structure of AC in complex with the covalent carmofur inhibitor is presented. Carmofur is an antineoplastic drug containing an electrophilic carbonyl reactive group that targets the catalytic cysteine. This novel structural data explains the basis of the AC inhibition, provides insights into the enzymatic properties of the protein, and is a great aid toward the structure-based drug design of potent inhibitors for AC, providing the detailed mechanism, which has eluded the scientific community for more than 30 years, of carmofur's mysterious 5-fluorouracil-independent antitumor activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Ceramidase / antagonists & inhibitors*
  • Acid Ceramidase / genetics
  • Acid Ceramidase / metabolism
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Fluorouracil / analogs & derivatives*
  • Fluorouracil / chemistry
  • Fluorouracil / metabolism
  • Humans
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification

Substances

  • Antineoplastic Agents
  • Recombinant Proteins
  • Acid Ceramidase
  • 1-hexylcarbamoyl-5-fluorouracil
  • Fluorouracil