Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur

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.