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Licensed Unlicensed Requires Authentication Published by De Gruyter May 1, 2015

The molecular medicine of acid ceramidase

Michael Frohbergh, Xingxuan He and Edward H. Schuchman
From the journal Biological Chemistry

Abstract

Acid ceramidase (N-acylsphingosine deacylase, EC 3.5.1.23; AC) is the lipid hydrolase responsible for the degradation of ceramide into sphingosine and free fatty acids within lysosomes. The enzymatic activity was first identified over four decades ago and is deficient in two rare inherited disorders, Farber lipogranulomatosis (Farber disease) and spinal muscular atrophy with myoclonic epilepsy (SMA-PME). Importantly, AC not only hydrolyzes ceramide into sphingosine within acidic compartments, but also can synthesize ceramide from sphingosine at neutral pH, suggesting that the enzyme may have diverse functions depending on its subcellular location and the local pH. Within cells, AC exists in a complex with other lipid hydrolases and requires a polypeptide cofactor (saposin D) for full hydrolytic activity. Recent studies also have shown that AC is overexpressed in several human cancers, and that inhibition of this enzyme may be a useful cancer drug target. Aberrant AC activity has also been described in several other common diseases. The cDNA and gene (ASAH1) encoding AC have been isolated, several mouse models of AC deficiency have been constructed, and the recombinant enzyme is currently being manufactured for the treatment of Farber disease and SMA-PME. Current information concerning the biology of this enzyme and its role in human disease is reviewed within.


Corresponding author: Edward H. Schuchman, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA, e-mail:

Acknowledgments

Dr. Schuchman acknowledges all of his current and past collaborators who have contributed to the work on acid ceramidase. In particular, he acknowledges Professors Konrad Sandhoff and Shimon Gatt for mentorship and close collaboration over the years. Work described in this review was supported in part by NIH grant R01 DK 54830, and by a research grant from Plexcera Therapeutics.

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Received: 2014-12-1
Accepted: 2015-1-7
Published Online: 2015-5-1
Published in Print: 2015-6-1

©2015 by De Gruyter

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