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 the inherited
lipid storage disorder,
Farber Lipogranulomatosis (
Farber disease). Importantly, AC not only hydrolyzes
ceramide into
sphingosine, but also can synthesize
ceramide from
sphingosine and
free fatty acids in vitro and in situ. This "reverse" enzymatic activity occurs at a distinct pH from the hydrolysis ("forward") reaction (6.0 vs. 4.5, respectively), suggesting that the
enzyme may have diverse functions within cells dependent on its subcellular location and the local pH. Most information concerning the role of AC in human disease stems from work on
Farber disease. This
lipid storage disease is caused by mutations in the gene encoding AC, leading to a profound reduction in enzymatic activity. Recent studies have also shown that AC activity is aberrantly expressed in several human
cancers, and that the
enzyme may be a useful
cancer drug target. For example, AC inhibitors have been used to slow the growth of
cancer cells, alone or in combination with other established, anti-oncogenic treatments. Aberrant AC activity also has been described in
Alzheimer's disease, and overexpression of AC may prevent
insulin resistant (Type II) diabetes induced by
free fatty acids. Current information concerning the biology of this
enzyme and its role in human disease is reviewed within.