Information on EC 3.2.1.46 - galactosylceramidase

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The expected taxonomic range for this enzyme is: Euarchontoglires

EC NUMBER
COMMENTARY
3.2.1.46
-
RECOMMENDED NAME
GeneOntology No.
galactosylceramidase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
D-galactosyl-N-acylsphingosine + H2O = D-galactose + a ceramide
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of O-glycosyl bond
-
-
-
-
hydrolysis of O-glycosyl bond
-
-
hyrolysis of O-glycosyl bond
-
-
PATHWAY
KEGG Link
MetaCyc Link
Metabolic pathways
-
Sphingolipid metabolism
-
SYSTEMATIC NAME
IUBMB Comments
D-galactosyl-N-acylsphingosine galactohydrolase
cf. EC 3.2.1.62 glycosylceramidase.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
beta-galactocerebrosidase
-
-
-
-
beta-galactocerebrosidase
-
-
beta-galactosylceramidase
-
-
-
-
ceramidase, galacatosyl-
-
-
-
-
ceramide galactosidase
-
-
-
-
cerebroside beta-galactosidase
-
-
-
-
cerebroside galactosidase
-
-
-
-
galactoceramidase
-
-
-
-
galactocerebrosidase
-
-
-
-
galactocerebrosidase
-
-
galactocerebroside beta-galactosidase
-
-
-
-
galactocerebroside galactosidase
-
-
-
-
galactocerebroside-beta-D-galactosidase
-
-
-
-
Galactosylceramidase
-
-
-
-
Galactosylceramidase
-
-
galactosylceramidase I
-
-
-
-
galactosylceramide beta-galactosidase
-
-
-
-
galactosylcerebrosidase
-
-
-
-
galcerase
-
-
-
-
GM1 ganglioside beta-galactosidase
-
similar enzyme, hydrolyzes galactosylceramide in presence of sodium cholate
lactosylceramidase
-
-
-
-
lactosylceramidase I
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
9027-89-8
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
Lesch-Nyhan cells
-
-
Manually annotated by BRENDA team
mutant enzyme /Krabbe disease
-
-
Manually annotated by BRENDA team
mutant enzyme /Krabbe disease; normal enzyme
-
-
Manually annotated by BRENDA team
LMTK-cells
-
-
Manually annotated by BRENDA team
twi +/i C57BL6 mice and wild-type mice
-
-
Manually annotated by BRENDA team
twitcher mouse
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
physiological function
-
lysosomal galactocerebrosidase GALC, which is defective in globoid cell leukodystrophy, is involved in the maintenance of a functional hematopoietic stem/progenitor cell niche by contributing to the control of the intracellular content of key sphingolipids. Both insufficient and supraphysiologic GALC activity by inherited genetic deficiency or forced gene expression in patients' cells and in the disease model induce alterations of the intracellular content of the bioactive GALC downstream products ceramide and sphingosine, and thus affect hematopoietic stem/progenitor cell survival and function and the functionality of the stem cell niche
physiological function
-
lysosomal galactocerebrosidase GALC is involved in the maintenance of a functional hematopoietic stem/progenitor cell niche by contributing to the control of the intracellular content of key sphingolipids. Both insufficient and supraphysiologic GALC activity by inherited genetic deficiency or forced gene expression induce alterations of the intracellular content of the bioactive GALC downstream products ceramide and sphingosine, and thus affect hematopoietic stem/progenitor cell survival and function and the functionality of the stem cell niche
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
4-methylumbelliferyl beta-galactoside + H2O
methylumbelliferone + beta-D-galactose
show the reaction diagram
-
-
-
-
?
4-methylumbelliferyl beta-galactoside + H2O
methylumbelliferone + beta-D-galactose
show the reaction diagram
-
-
-
-
?
4-methylumbelliferyl-beta-D-galactopyranoside + H2O
4-methylumbelliferone + beta-D-galactopyranose
show the reaction diagram
-
pH 4.0, 30 min, 37°C
-
-
?
5-bromo-3-chloro-beta-galactopyranoside + H2O
?
show the reaction diagram
-
-
-
?
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside + H2O
6-hexadecanoylamino-4-methylbelliferone + beta-D-galactopyranose
show the reaction diagram
-
-
-
-
?
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside + H2O
6-hexadecanoylamino-4-methylbelliferone + beta-D-galactopyranose
show the reaction diagram
-
fluorogenic substrate
-
-
?
D-galactosyl-alkyl-acyl-glycerol + H2O
?
show the reaction diagram
-
a precursor of the seminolipid
-
-
?
D-galactosyl-N-acylsphingosine + H2O
D-galactose + N-acylsphingosine
show the reaction diagram
-
-
-
-
?
D-galactosyl-N-acylsphingosine + H2O
D-galactose + N-acylsphingosine
show the reaction diagram
-
-
-
-
?
D-galactosyl-N-acylsphingosine + H2O
D-galactose + N-acylsphingosine
show the reaction diagram
-
-
-
-
?
D-galactosyl-N-acylsphingosine + H2O
D-galactose + N-acylsphingosine
show the reaction diagram
-, O02791
-
-
-
?
D-galactosyl-N-acylsphingosine + H2O
?
show the reaction diagram
-
-
-
-
-
D-galactosyl-N-acylsphingosine + H2O
?
show the reaction diagram
-
-
-
-
-
D-galactosyl-N-acylsphingosine + H2O
?
show the reaction diagram
-
-
-
-
-
D-galactosyl-N-acylsphingosine + H2O
?
show the reaction diagram
-, O02791
-
-
-
-
D-galactosylceramide + H2O
D-galactose + ceramide
show the reaction diagram
-
-
-
-
?
D-galactosylsphingoside + H2O
D-galactose + sphingosine
show the reaction diagram
-
i.e. psychosine
-
-
?
galactocerebroside + H2O
D-galactose + N-acylceramide
show the reaction diagram
-
-
-
-
?
galactocerebroside + H2O
D-galactose + N-acylceramide
show the reaction diagram
-
-
-
-
?
galactocerebroside + H2O
D-galactose + N-acylceramide
show the reaction diagram
-
-
-
-
?
galactocerebroside + H2O
D-galactose + N-acylceramide
show the reaction diagram
-, O02791
-
-
-
?
galactosylceramide + H2O
D-galactose + N-acylceramide
show the reaction diagram
-
-
-
-
?
galactosylceramide + H2O
D-galactose + N-acylceramide
show the reaction diagram
-
-
-
-
?
galactosylceramide + H2O
D-galactose + N-acylceramide
show the reaction diagram
-, O02791
-
-
-
-
GM1 ganglioside + H2O
D-galactose + N-acylceramide
show the reaction diagram
-
-
-
-
?
GM1 ganglioside + H2O
D-galactose + N-acylceramide
show the reaction diagram
-
-
-
-
?
lactosylsphingosine + H2O
lactose + sphingosine
show the reaction diagram
-
-
-
-
?
N-stearoyl psychosine + H2O
D-galactose + N-stearoylsphingosine
show the reaction diagram
-
-
-
-
?
psychosine + H2O
D-galactose + sphingosine
show the reaction diagram
-
-
-
-
-
psychosine + H2O
D-galactose + sphingosine
show the reaction diagram
-
-
-
-
?
psychosine + H2O
D-galactose + sphingosine
show the reaction diagram
-
galactosylsphingosine
-
-
?
lactosylsphingosine + H2O
lactose + sphingosine
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
the enzyme is required for normal sperm maturation and function, enzyme deficiency leads to degeneration of oligodendrocytes, severe demyelination, and causes sperm abnormalities in the mouse model of human globoid cell leukodystrophy or Krabbe disease, mutant twitcher mice show reduced size of testis and sperm acrosomal membrane which is redundant, detached from the nucleus and folded over
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
D-galactosyl-N-acylsphingosine + H2O
D-galactose + N-acylsphingosine
show the reaction diagram
-
-
-
-
?
D-galactosyl-N-acylsphingosine + H2O
?
show the reaction diagram
-
-
-
-
-
D-galactosyl-N-acylsphingosine + H2O
?
show the reaction diagram
-
-
-
-
-
D-galactosyl-N-acylsphingosine + H2O
?
show the reaction diagram
-
-
-
-
-
D-galactosyl-N-acylsphingosine + H2O
?
show the reaction diagram
-, O02791
-
-
-
-
D-galactosylceramide + H2O
D-galactose + ceramide
show the reaction diagram
-
-
-
-
?
D-galactosylsphingoside + H2O
D-galactose + sphingosine
show the reaction diagram
-
i.e. psychosine
-
-
?
additional information
?
-
-
the enzyme is required for normal sperm maturation and function, enzyme deficiency leads to degeneration of oligodendrocytes, severe demyelination, and causes sperm abnormalities in the mouse model of human globoid cell leukodystrophy or Krabbe disease, mutant twitcher mice show reduced size of testis and sperm acrosomal membrane which is redundant, detached from the nucleus and folded over
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Cl-
-
activating
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
2-hydroxydecanoyl DL-erythro-3-phenyl-2-amino-1,3-propanediol
-
2-hydroxy fatty acid amides of phenylaminopropanediol, noncompetitive
2-hydroxydodecanoyl DL-erythro-3-phenyl-2-amino-1,3-propanediol
-
2-hydroxy fatty acid amide of phenylaminopropanediol, noncompetitive
2-hydroxyhexadecanoyl DL-erythro-3-phenyl-2-amino-1,3-propanediol
-
2-hydroxy fatty acid amides of phenylaminopropanediol, noncompetitive
2-hydroxyoctadecanoyl DL-erythro-3-phenyl-2-amino-1,3-propanediol
-
2-hydroxy fatty acid amides of phenylaminopropanediol, noncompetitive
2-hydroxytetradecanoyl DL-erythro-3-phenyl-2-amino-1,3-propanediol
-
2-hydroxy fatty acid amides of phenylaminopropanediol, noncompetitive
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside
-
competitive
-
Galactonolactone
-
-
galactonyl hydrazide
-
-
-
lactosyl ceramide
-
-
N-(6-aminohexyl)-D-galactoside
-
-
-
N-decanoyl psychosine
-
competitve and noncompetitive
N-dodecanoyl psychosine
-
competitve and noncompetitive
N-ethyl psychosine
-
competitve and noncompetitive
N-hexyl psychosine
-
competitve and noncompetitive
N-octanoyl psychosine
-
competitve and noncompetitive
taurocholate
-
high concentrations, above 0.3% w/v
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
Activator protein
-
purified from normal spleen
-
phosphatidylcholine
-
from 0.02 mg to 0.1 mg
phosphatidylinositol
-
from 0.02 mg to 0.05 mg
phosphatidylserine
-
at 0.02 mg
phosphatidylserine
-
in absence of sodium taurocholate
Sulfatide
-
from 0.02 mg to 0.05 mg
Sulfatide
-
-
taurocholate
-
-
taurocholate
-
in combination with oleic acid
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.47
-
4-methylumbelliferyl-beta-D-galactopyranoside
-
-
0.017
-
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside
-
cholate system
-
0.03
-
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside
-
taurocholate and oleic acid activated, in leukocytes
-
0.04
-
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside
-
taurocholate and oleic acid activated, in fibroblasts
-
0.045
-
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside
-
taurocholate system
-
0.15
-
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside
-
taurocholate and oleic acid activated
-
0.005
-
galactocerebroside
-
taurocholate system
0.025
-
galactocerebroside
-
cholate system
0.02
-
galactosylceramide
-
normal enzyme
0.1
-
galactosylceramide
-
taurocholate activated
0.165
-
galactosylceramide
-
mutant enzyme
0.2
-
galactosylceramide
-
phosphatidylserine activated
0.11
-
galactosylsphingosine
-
without taurocholate
0.67
-
galactosylsphingosine
-
with taurocholate
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.000008
-
-
GALC enzyme activity in the posterior part of the brain of single intracerebroventricular-GALC injected mice
0.0000087
-
-
GALC enzyme activity in the anterior part of the brain of single intracerebroventricular-GALC injected mice
0.12
-
-
-
70
-
-
with plasmid encoding GALC-TMH transfected 293T cell, GALC units per mg of cell extract
120
-
-
with plasmid encoding GALC-MH transfected 293T cell, GALC units per mg of cell extract
130
-
-
with plasmid encoding unmodified GALC transfected 293T cell, GALC units per mg of cell extract
additional information
-
-
electrospray ionization mass spectrometry for assay, detection limits are comparable to those from assays using radioactive labels
additional information
-
-
economical and fast histochemical way to distinguish neural cells expressing galactocerebrosidase from thoses that are deficient, using 5Br-3Cl-beta-galactopiranoside in the presence of taurodeoxycholic and oleic acids
additional information
-
-
distribution of recombinant GALC activity in COS-7 cells: GALC-MH, 41.2% activity in cell extract, 58.8% released into cell culture medium, GALC-TMH, 27.5% to 72.5%
additional information
-
-
0.14 mU/mg, from Krabbe fibroblasts; 0.31 mU/mg; 0.884 mU/mg, from Krabbe lymphocytes; 1.65 mU/mg, neural presursor cells, after transduction with lentiviral GALC vectors; 3.2 mU/mg, monocytic U937 cells, after transduction with lentiviral GALC vector; 4.32 mU/mg, from healthy fibroblasts; 5.24 mU/mg, from healthy lymphocytes
additional information
-
-
0.31 mU/mg; 0.65 mU/mg for hematopoetic stem cells from wild-type mice; 0.6 mU/mg for hematopoetic stem cells, after transduction with lentiviral GALC vector; 2.33 mU/mg for neural precursor cells, after transduction with lentiviral GALC vector
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
3.75
-
-
without taurocholate
4.1
-
-
-
4.2
-
-
taurocholate activated
4.2
-
-
-
4.4
-
-
-
4.4
-
-
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside, cholate system
4.5
-
-
taurocholate and oleic acid activated
4.6
-
-
galactocerebroside, cholate system
4.7
-
-
phosphatidylserine activated
5.2
-
-
6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside, cholate system
5.4
-
-
with taurocholate
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
3.5
5.3
-
pH 3.5: about 10% of maximal activity, pH 5.3: about 40% of maximal activity
3.5
6
-
-
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
-
assay at
37
-
-
GALC substrate cleavage assay
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
level of activity in umbilical cord blood is comparable ro that in adult blood
Manually annotated by BRENDA team
-
hippocampal pyramidal neuron, cerebellar neuron
Manually annotated by BRENDA team
-
Lesch-Nyhan cells
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
30000
-
-
gel filtration, SDS-PAGE, N-terminal sequencing
50000
-
-
urine, gel filtration, SDS-PAGE, N-terminal sequencing
70000
-
-
gel filtration, SDS-PAGE, N-terminal sequencing
77000
-
-
amino acid analysis
80000
-
-
brain, placenta, gel filtration, SDS-PAGE, N-terminal sequencing
80000
-
-
recombinant protein
80000
-
-
determined by SDS-PAGE and Western Blot analysis
90000
-
-
gel filtration, SDS-PAGE, N-terminal sequencing
121000
-
-
gel filtration, monomer
640000
-
-
gel filtration chromatography
750000
-
-
gel filtration, SDS-PAGE, mutant and normal protein
760000
-
-
gel filtration, hexamer
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
dimer
-
2 * 125000, aggregation from monomer to dimer, from dimer to tetramer or hexamer, SDS-PAGE
hexamer
-
6 * 125000, active form in vivo, SDS-PAGE
monomer
-
1 * 125000, aggregation from monomer to dimer, from dimer to tetramer or hexamer, SDS-PAGE
tetramer
-
4 * 125000, aggregation from monomer to dimer, from dimer to tetramer or hexamer, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
glycoprotein
-
-
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
crystal structures of GALC and the GALC-D-galactose product complex, to 2.1 and 2.4 A resolution, respectively. The overall fold comprises a central triosephosphate isomerase barrel, a beta-sandwich domain, and a lectin domain. The overall fold of GALC is unchanged upon galactose binding, the core of the binding pocket being formed by the long loops on the C-terminal face of the TIM barrel. Loops from both the beta-sandwich and lectin domains also contribute to the substrate-binding pocket, and mutations involved in Krabbe's disease are widely distributed throughout the protein
P54818
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
52
-
-
35 min, 50% loss of activity, normal enzyme; 4 min, 50% loss of activity, mutant enzyme
54
-
-
10 min, 45% inactivation
54
-
-
20 min, 45% inactivation
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
bovine serum albumin for stabilization
-
urea, 50% loss of activity of the mutant enzyme at 1.3 M urea, 50% loss of activity of the normal enzyme at 5.6 M urea
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
partially
-
to homogeneity, Krabbe disease
-
partially
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expression in CHO cells
-
expression in lentiviral GALC vectors
-
nonsense mutation in Krabbe disease
-
mutation in Krabbe disease
O02791
expression vectors for different fusion-proteins are constructed: GALC, unmodified enzyme, GALC-MH: fusion protein containing a C-terminal myc-tag and six His residues, GALC-TMH: fusion protein containing in addition a Tat-PTD, the protein transduction domain derived from the HIV-1 Tat protein
-
exression in lentiviral GALC vectors
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
E114K
P54818
residue in TIM barrel, mutation is likely to result in severe misfolding, crystallization data
E215K
P54818
residue is exposed on the surface of the TIM barrel, mutation confers an opposite charge on the same face as the substrate-binding pocket, crystallization data
G537R
P54818
resiude in lectin domain, mutation is likely to result in severe misfolding, crystallization data
GALCdelta-MH
-
mutant containing a C-terminal myc-tag and six His residues with the last 11 amino acids at the C-terminus of GALC deleted
L364R
P54818
resiude in beta-sandwich, mutation is likely to result in severe misfolding, crystallization data
L629R
P54818
resiude in lectin domain, mutation is likely to result in severe misfolding, crystallization data
S257F
P54818
resiude in TIM barrel, mutation is likely to result in severe misfolding, crystallization data
W410G
P54818
resiude in beta-sandwich, mutation is likely to result in severe misfolding, crystallization data
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
-
enzymatic diagnosis
medicine
-
enzyme deficiency in globoid cell leucodystrophy or Krabbe disease
medicine
-
electrospray mass spectrometry combined with the use of biotinylated substrate conjugates and bioaffinity purification represents a new approach for the diagnosis of lysosomal storage disease, Krabbe disease
medicine
-
diagnosis of Krabbe disease
medicine
-
lysosomal galactocerebrosidase GALC, which is defective in globoid cell leukodystrophy, is involved in the maintenance of a functional hematopoietic stem/progenitor cell niche by contributing to the control of the intracellular content of key sphingolipids. Both insufficient and supraphysiologic GALC activity by inherited genetic deficiency or forced gene expression in patients' cells and in the disease model induce alterations of the intracellular content of the bioactive GALC downstream products ceramide and sphingosine, and thus affect hematopoietic stem/progenitor cell survival and function and the functionality of the stem cell niche
medicine
O02791
enzyme deficiency in globoid cell leucodystrophy or Krabbe disease
medicine
-
twitcher mouse, a model for globoid cell leucodystrophy
medicine
-
enzymatic diagnosis
medicine
-
economical and fast histochemical way to distinguish neural cells expressing galactocerebrosidase from thoses that are deficient. This method enables the assessment of enzyme activity in virally-transduced cells as well as the biodistribution of galactocerebrosidase activity in Twitcher mice under gene or cell therapy
medicine
-
globoid cell leukodystrophy, GLD or Krabbe disease, is caused by loss-of-fuction mutations in the GALC gene, injection of GALC improves the survival of the mouse model of GLD
medicine
-
findings could lead to an improved therapy for globoid cell leukodystrophy, GLD, or Krabbe disease
medicine
-
diagnosis of Krabbe disease
medicine
P54818
mutations involved in Krabbe's disease are widely distributed throughout the protein. Mutations that are likely to result in severe misfolding include E114K and S257F in the TIM barrel, L364R and W410G in the beta-sandwich domain, and G537R and L629R in the lectin domain. Mutation E215K is exposed on the surface of the TIM barrel. The mutation confers an opposite charge on the same face as the substrate-binding pocket suggesting that the mechanism of disease for this mutation will involve the perturbation of a binding face for an activating factor. Residue P302 that is found on the surface of GALC very close to the substrate-binding pocket is mutated to arginine in Krabbe's disease. The beta-sandwich domain of a long loop forms an integral part of the substrate-binding site. R380 at the tip of this loop directly binds the galactose molecule in the active site, its mutation to tryptophan or leucine leads to severe infantile Krabbe's disease