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Crystal structure of human acid ceramidase in covalent complex with carmofurCrystal structure of human acid ceramidase in covalent complex with carmofur
Structural highlights
Publication Abstract from PubMedHuman 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. Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur.,Dementiev A, Joachimiak A, Nguyen H, Gorelik A, Illes K, Shabani S, Gelsomino M, Ahn EE, Nagar B, Doan N J Med Chem. 2019 Jan 24;62(2):987-992. doi: 10.1021/acs.jmedchem.8b01723. Epub, 2018 Dec 19. PMID:30525581[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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