1. Sphingolipid Disorders
2/23/2019
Sphingolipid Disorders
Sphingolipids (phospho- or glycolipids) S
General Structure
Cer PC Sm
GlcCb (neutral GL)
S: sphingosine Cer: ceramide Sm: sphinglmyelin
PC: phosphocholine Glu: glucose
GL: glycolipid Lac: lactose
Gb: globoside (two or more sugars plus GalNAc)
Gan: ganglioside (contains NANA) Cb: cerebroside (single sugars)
LacCer (Gb)
Gan
Eric Niederhoffer
SIU-SOM

2. b-glucosylceramidase b-galactosylceramidase
2/23/2019
Gangliosidoses
neuraminidase
(sialidase)
Cer
Gal
Glu
NANA
GalNAc b
Generalized gangliosidosis
b-galactosidase
GD1
Cer
Gal
Glu
NANA
GalNAc b
GM1
Cer
Gal
Glu
NANA
GalNAc b
Tay-Sachs disease
b-hexosaminidase A
GM2 activator
GM2
Cer
Gal
Glu
NANA b
Sialidosis
neuraminidase
(sialidase)
SAP-B
GM3
Cer
Gal
Glu b
Fabry’s disease
a-galactosidase A
SAP-B
b-galactosidase
SAP-B, SAP-C
Cer
Gal
Glu a b
NANA: N-acetylneuraminic acid (sialic acid)
Cer: ceramide Glu: glucose Gal: galactose
GalNAc: N-acetylgalactosamine G: ganglioside
D1: dineuraminic acid + Gal-GalNAc-Gal-Glc-Cer
M1: neuraminic acid + Gal-GalNAc-Gal-Glc-Cer
M2: neuraminic acid + GalNAc-Gal-Glc-Cer
M3: neuraminic acid + Gal-Glc-Cer
SAP: sphingolipid activator protein (saposin)
Cer-Glu-Gal: lactosylceramide Cer-Glu: glucosylceramide
S: sphingosine FA: fatty acid
Cer-Glu-Gal-Gal-GalNAc: globoside Cer-Glu-Gal-Gal: globotriaosylceramide
PC: phosphocholine Cer-PC: sphingomyelin
Cer-Gal-SO3H: sulfatide Cer-Gal: galactosylceramide
Cer
Glu b
Sandhoff’s disease
b-hexosaminidase A&B
b-glucosylceramidase
SAP-C
Cer
Cer
Gal
Glu
GalNAc a b
Gaucher’s disease
Krabbe’s disease
Cerezyme
b-galactosylceramidase
SAP-A, SAP-C
Cer
Gal b
Cer PC
sphingomyelinase
S + FA
Metachromatic leukodystrophy
Niemann-Pick disease
arylsulfatase A
SAP-B
Cer
Gal
SO3H b

3. Targeting of Lysosomal Enzymes to Lysosomes
2/23/2019
Targeting of Lysosomal Enzymes to Lysosomes
Addition of M6P to lysosomal enzymes
Recognition by MPRs
M6P independent pathways
M6P: mannose-6-phosphate
MPR: mannose-6-phosphate receptor

4. 2/23/2019
Review Questions
How do you interpret ganglioside names (G, D, M, 1, 2, 3)?
What do the different lysosomal enzyme names mean in the context of removing saccharides?
Where does ganglioside degradation occur?