Synthesis and catabolism of galactosylceramide and sulfatide

CGT catalyzes the synthesis of GalCer by adding a galactose molecule to ceramide (A). Ceramide with a hydroxy group at the two position (dashed circle) is a more efficient CGT substrate than nonhydroxyceramide. CST catalyzes the sulfation of GalCer to generate both non-hydroxy and 2-hydroxy-sulfatide (B). GalCer and sulfatide are degraded in the lysosome by the enzymes GALC and ARSA, which are deficient in KD and MLD, respectively (C, D). GALC and ARSA deficiency results in lysosomal accumulation of these glycolipids and their subsequent deacylation into the toxic byproducts psychosine and lysosulfatide by acid ceramidase (E). Previous substrate reduction approaches using L-cycloserine targets a reaction upstream from ceramide synthesis (F).

Abbreviations: ARSA, arylsulfatase A; CGT, ceramide galactosyltransferase; CST, cerebroside sulfotransferase; FA2H, fatty acid 2-hydroxylase; GALC, galactosylceramidase; GalCer, galactosylceramide; KD, Krabbe disease; MLD, metachromatic leukodystrophy.

(Souce: Babcock MC, Mikulka CR, Wang B, et al. Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor. Sci Rep 2021;11[1]:14486. Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0.)