Metabolism of sphingomyelin, cerebrosides, sulphatides and gangliosides

1. Metabolism of Sphingolipids
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India

3. The sphingolipids are of two types:
Phospho-
sphingolipids
Glyco-
sphingolipids
The only phosphosphingolipid is
sphingomyelin
Glycosphingolipids include the cerebro-
sides, sulphatides and gangliosides

5. The prosthetic group is phosphoryl choline
in sphingomyelin
It is carbohydrate(s) in glycosphingolipids

7. Sphingolipids are components of all
membranes
They are particularly abundant in the
myelin sheath

8. Synthesis of sphingolipids begins with
the synthesis of ceramide
Ceramide is acyl sphingosine (fatty
acyl group bonded to sphingosine)
Sphingosine is released from ceramide,
and can form different sphingolipids
Synthesis of sphingolipids

9. Ceramide is formed on the outer surface
of endoplasmic reticulum
The first reaction occurs between serine
and palmitoyl CoA
Serine is decarboxylated
CoA is released from palmitoyl CoA

10. The product of the first reaction is 3-keto-
dihydrosphingosine
This is the rate-limiting reaction of sphingo-
lipid synthesis
The reaction is catalysed by serine
palmitoyltransferase (SPT)
SPT is a pyridoxal phosphate-dependent
enzyme

12. 3-Ketodihydrosphingosine is also known
as 3-ketosphinganine
It is reduced to dihydrosphingosine
(sphinganine)
The enzyme is NADPH-dependent
3-ketodihydrosphingosine reductase

14. Ceramide synthase adds a fatty acyl
group to dihydrosphingosine
The product is dihydroceramide
There are six different ceramide
synthases in human beings
They add fatty acids of different chain
lengths to dihydrosphingosine

16. Two hydrogen atoms are removed from
dihydroceramide forming a double bond
Dihydroceramide is converted into
ceramide
The reaction is catalyzed by
dihydroceramide Δ4-desaturase

18. After synthesis of ceramide, sphingosine
is released from it by ceramidase
Different ceramide synthases add different
fatty acids to sphingosine
This results in the formation of different
species of ceramide

20. Ceramide has to be moved from one
compartment to another
Being insoluble in water, it can be moved
by vesicular transport
Or it is transported by ceramide transfer
protein (CERT)

21. Ceramide transfer protein is a cytosolic
protein
It transfers ceramide from endoplasmic
reticulum to the Golgi apparatus
Various sphingolipids are synthesized
from ceramide in the Golgi apparatus

22. Sphingomyelin is not a single species
There are different sphingomyelins
differing in the fatty acid component
The main fatty acids in sphingomyelins
are palmitic acid and stearic acid
Synthesis of sphingomyelin

23. Sphingomyelins are synthesized from:
Ceramide Phosphatidyl choline
Synthesis of sphingomyelins occurs:
In Golgi apparatus On cell membrane

24. Phosphoryl choline is transferred from
phosphatidylcholine to ceramide
Phosphoryl choline is converted into
diacylglycerol
Ceramide is converted into sphingomyelin

26. Sphingomyelins are hydrolysed into
phosphoryl choline and ceramide by
sphingomyelinase
Apart from being components of cell
membrane, sphingomyelins act as a
reservoir of ceramide
Catabolism of sphingomyelins

28. Glycosphingolipids are made up of
ceramide and some carbohydrate group
The carbohydrate group may be mono-
or oligo-saccharide
The main glycosphingolipids are cerebro-
sides, sulphatides and gangliosides
Synthesis of glycosphingolipids

29. Cerebrosides have a monosaccharide
linked to ceramide
Sulfatides are sulphuric acid esters of
cerebrosides
Gangliosides contain an oligosaccharide
including N-acetyl neuraminic acid (NANA)
The carbohydrate group is attached to
carbon 1 of sphingosine

30. The usual monosaccharide in
cerebrosides is galactose
Cerebrosides having galactose are
called galactocerebrosides
Galactocerebrosides are components
of neuronal cell membranes

31. A few cerebrosides contain glucose
They are called glucocerebrosides
Glucocerebrosides are intermediates in
the synthesis or degradation of
gangliosides

34. The galactocerebrosides include
cerebron, nervon, oxynervon, kerasin etc
The fatty acids present in them are very
long-chain (24-carbon) fatty acids

35. The fatty acids in
galactocerebrosides are:
Cerebronic acid in cerebron
Nervonic acid in nervon
Oxynervonic acid in oxynervon
Lignoceric acid in kerasin

36. Sulphatides are synthesized from
galactocerebrosides and activated sulphate
The activated sulphate is phospho-
adenosine phospho-sulphate (PAPS)
The sulphate group is transferred from
PAPS to carbon 3 of galactose
Synthesis of sulphatides

37. Galactosylceramide
sulphotransferase
Galactocerebroside
Sulphatide
Phosphoadenosine
phosphosulphate
Phosphoadenosine
phosphate



39. Synthesis of gangliosides
Gangliosides are synthesized from:
Ceramide
Activated hexoses
Activated hexosamines
N-Acetyl neuraminic acid (NANA)

40. The sugar residues are added one by
one to ceramide by specific glycosyl
transferases
Various gangliosides, e.g. GM3, GM2 and
GM1, are formed at different stages

41. In the name of the gangliosides:
The letter G means ganglioside
This is followed by subscript letter M,
D, T or Q
This indicates the number of NANA
residues (mono, di, tri or quatra)
The subscript numbers 1, 2 and 3
indicate the carbohydrate sequence

44. The sugar residues are split off one by
one by specific glycosidases
The glycosidases are present in the
lysosomes
Catabolism of glycosphingolipids

47. Sphingolipidoses are inborn errors of
sphingolipid metabolism
Some catabolic enzyme is deficient
Sphingolipids accumulate in the body
due to decreased breakdown
Sphingolipidoses

48. The sphingolipids are present in large
amounts in nervous tissue
Therefore, the nervous system bears the
brunt of the disease
There is some accumulation of sphingo-
lipids in all the tissues

49. Major sphingolipidoses are:
Generalized gangliosidosis
Tay-Sachs disease
Gaucher's disease
Krabbe's disease
Metachromatic leukodystrophy
Niemann-Pick disease

50. Generalized gangliosidosis
Deficiency of GM1-b-galactosidase
Breakdown of GM1 ganglioside is impaired
GM1 ganglioside accumulates in the tissues
Causes mental retardation, hepatomegaly
and skeletal deformities

51. Tay-Sachs disease
Deficiency of hexosaminidase A
Accumulation of GM2 ganglioside
Causes mental retardation, blindness,
hypotonia and paralysis
Fatal by 3-4 years of age

52. Gaucher's disease
Deficiency of b-glucosidase
Accumulation of glucosyl ceramide
(glucocerebroside)
Causes mental retardation,
hepatosplenomegaly, hypersplenism and
erosion of bones

53. Krabbe's disease
Deficiency of b-galactosidase
Accumulation of galactosyl ceramide
(galactocerebroside)
Causes mental retardation, blindness,
deafness, hypertonia and hyperirritability

54. Metachromatic leukodystrophy
Deficiency of arylsulphatase A
Accumulation of sulphatides
Causes dementia and progressive
paralysis
Fatal by 3-10 years of age

55. Niemann-Pick disease
Deficiency of sphingomyelinase
Accumulation of sphingomyelin
Causes mental retardation, motor
disturbances, growth failure and
hepatosplenomegaly
Fatal by four years of age

56. Antenatal diagnosis of sphingolipidoses is
possible
Abnormal sphingolipids can be detected
in foetal cells present in amniotic fluid

57. Inheritance of sphingolipidoses is
autosomal recessive
The disease occurs only in homozygotes
Heterozygotes can transmit the defect to
their offsprings