A possible mechanism underlying the ceramide deficiency in atopic dermatitis: expression of a deacylase enzyme that cleaves the N-acyl linkage of sphingomyelin and glucosylceramide.
A deficiency of ordinary ceramides in the stratum corneum is an essential etiologic factor for the dry and barrier-disrupted skin of patients with atopic dermatitis (AD). We have proposed that the mechanism underlying that deficiency involves a novel sphingolipid metabolizing enzyme, termed sphingomyelin (SM) glucosylceramide (GCer) deacylase, which hydrolyzes SM or GCer at the acyl site to yield their lysoforms sphingosylphosphorylcholine (SPC) or glucosylsphingosine (GSP) instead of ceramide, leading to the ceramide deficiency in the AD skin. The enzymic characteristics observed showed a pH dependency of catalytic activity with a peak at pH 5.0 and a molecular weight of 40,000. Analytical isoelectric focusing (IEF) chromatography demonstrated that the pI values of SM deacylase, GlcCDase, SMase and ceramidase were 4.2, 7.4, 7.0 and 5.7, respectively. Those enzymic characteristics of SM-GCer deacylase are completely distinct from ceramidase as well as the other known deacylases. Our enzymic measurements demonstrated that SM-GCer deacylase activity is enhanced more than 5-fold in involved stratum corneum, more than 3-fold in uninvolved stratum corneum and approximately 3-fold in the involved epidermis from patients with AD compared with healthy controls. Our findings suggest that the novel enzyme, SM-GCer deacylase, is expressed in situ at significant levels in the epidermis of AD patients. This results in the production of SPC and GSP, instead of ceramides, which leads in turn to the ceramide deficiency seen in the stratum corneum of those patients. It is likely that the biogenesis of SM-GCer deacylase may be critical to the pathogenesis of AD.
Imokawa
Genji
G
Tokyo University of Technology, School of Bioscience and Biotechnology, Hachioji, Tokyo, Japan. imokawag@dream.ocn.ne.jp
D000581:Amidohydrolases / Q000096:biosynthesis*; D002518:Ceramides / Q000172:deficiency*; D003876:Dermatitis, Atopic / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D005963:Glucosylceramides / Q000378:metabolism; D006801:Humans; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000378:metabolism; D011609:Psychosine / Q000031:analogs & derivatives / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
D002518:Ceramides; D005963:Glucosylceramides; D013109:Sphingomyelins; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D011609:Psychosine; C035742:sphingosyl beta-glucoside; D000581:Amidohydrolases; C109210:sphingomyelin deacylase; D013110:Sphingosine