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8/19/2019 Metabolism of Sphingolipids and Glycosphingolipids
1/21
METABOLISMMETABOLISMOF THEOF THE
SPHINGOLIPIDS ANDSPHINGOLIPIDS ANDGLYCOSPHINGOLIPIDSGLYCOSPHINGOLIPIDS
Floro B. Madarcos, MDFloro B. Madarcos, MD
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I. GENERAL STRUCTUREI. GENERAL STRUCTURE
OF SPHINGOLIPIDSOF SPHINGOLIPIDS
HH
II
CHCH33 – CH – CH!!""#!#! $ C % C $$ C % C $
II
HH
HH
II
CC33II
OHOH
HH
II
CC!! – – CC##HH!!OHOH
II
NHNH!!
HH
II
H –H – CC
II
OHOH
HH
II
33 – C – C!! – – CC##HH!!OHOH
II
OHOH
Gl&c'rolGl&c'rol
S()*+os*+'S()*+os*+'
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II. MA-OR TYPES OFII. MA-OR TYPES OF
SPHINGOLIPIDSSPHINGOLIPIDS
• S()*+o&'l*+S()*+o&'l*+
• Gl&cos()*+ol*(*dsGl&cos()*+ol*(*ds
– C'r'/ros*d'sC'r'/ros*d's
• Galac0oc'r'/ros*d'sGalac0oc'r'/ros*d's
• Gl1coc'r'/ros*d'Gl1coc'r'/ros*d'
– S1l2a0*d'sS1l2a0*d's
– Glo/os*d'sGlo/os*d's
– Ga+l*os*d'sGa+l*os*d's
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II. SYNTHESIS OF SPHINGOLIPIDSII. SYNTHESIS OF SPHINGOLIPIDS
AND GLYCOSPHINGOLIPIDS A"AND GLYCOSPHINGOLIPIDS A"
OO
IIII
CHCH33$ CH$ CH!!""##$ C$CoA$ C$CoA
COOCOO$$
II
HH33N$C$HN$C$H
II
CHCH!!OHOH
44
Pal*0o&l CoAPal*0o&l CoA
S'r*+'S'r*+'
OO
IIII
CHCH33$CH$CH!!""##$C$$C$ CC!!H$CH$C##HH!!OHOH
II NHNH!!3$5'0od*)&dros()*+os*+'3$5'0od*)&dros()*+os*+'
COCO!!
PLPPLP
M+M+4!4!
CoASHCoASH
Serine palmitoyl transferaseSerine palmitoyl transferase
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II. SYNTHESIS OF SPHINGOLIPIDSII. SYNTHESIS OF SPHINGOLIPIDS
AND GLYCOSPHINGOLIPIDS B"AND GLYCOSPHINGOLIPIDS B"
OO
IIII
CHCH33$CH$CH!!""##$$CC$ C$ C!!H$CH$C##HH!!OHOH
II
NHNH!!
S()*+a+*+'S()*+a+*+' D*)&dros()*+os*+'"D*)&dros()*+os*+'"
CHCH33$CH$CH!!""#!#!$CH$CH!!$ CH$ CH!!$$ CH $CH $
II
OHOH
3$5'0od*)&dros()*+os*+'3$5'0od*)&dros()*+os*+'
CH$CHCH$CH!!OHOH
II
NHNH!!
NADPHNADPH
4 H4 H44 NADPHNADPH
3-ketosphinganine3-ketosphinganine
reductasereductase
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II. SYNTHESIS OF SPHINGOLIPIDSII. SYNTHESIS OF SPHINGOLIPIDS
AND GLYCOSPHINGOLIPIDS C"AND GLYCOSPHINGOLIPIDS C"
CHCH33$CH$CH!!""#!#!$CH$CH!!$ CH$ CH!!$ CH $$ CH $
II OHOH
CH$CHCH$CH!!OHOH
II NHNH!!S()*+a+*+'S()*+a+*+'
D*)&dros()*+os*+'"D*)&dros()*+os*+'"OO
IIII
CHCH33$CH$CH!!""!6!6$C$SCoA$C$SCoA
B')'+&l CoAB')'+&l CoACoACoA
CHCH33$CH$CH!!""#!#!$C$C77HH!!$C$CHH!!$CH$CH33$$ II
OHOH
CC!!H$CH$C##HH!!OHOHII
NHNH
II
C$CHC$CH!!""!6!6$CH$CH33IIII
OO
D*)&droc'ra*d'D*)&droc'ra*d'
CC!!H$CH$C##HH!!OHOH
II
NHNH
II
C$CHC$CH!!""!6!6
$CH$CH33
IIII
OO
HH
II
CHCH33$CH$CH!!""#!#!$C$C77%C%C$C$C33H$H$
I II I
H OHH OH
C'ra*d'C'ra*d'
FADFAD
FADHFADH!!
ER enzymeER enzyme
H&drocar/o+ c)a*+H&drocar/o+ c)a*+
H&drocar/o+ c)a*+H&drocar/o+ c)a*+
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II. SYNTHESIS OF SPHINGOLIPIDSII. SYNTHESIS OF SPHINGOLIPIDS
AND GLYCOSPHINGOLIPIDS D"AND GLYCOSPHINGOLIPIDS D"
OHOH
II
CH$C%C$CHCH$C%C$CH!!""#!#!$CH$CH33HH
HH
6II
R#$C$N$CH
I
C#H! $ O
HH OO
IIII
P$O$CHP$O$CH!!CHCH!!NCHNCH33""334
OHOH
II
CH$C%C$CHCH$C%C$CH!!""#!#!$CH$CH33HH
HH66
IIII
RR##$C$N$CH$C$N$CH
II
CHCH!!
HH
O
HH
OO
HH OHOH
HHHOHO
OHOHHH
HOCHHOCH!!
HH
C'ra*d'C'ra*d'
O O $ $
S()*+o&'l*+S()*+o&'l*+
C'r'/ros*d'C'r'/ros*d'
Galac0oc'r'/ros*d'8Galac0oc'r'/ros*d'8a l&cos()*+ol*(*d"a l&cos()*+ol*(*d"
PhosphatidylcholinePhosphatidylcholine
1,2-diacylglycerol1,2-diacylglycerol
UP-galact- UP-galact-
oseose
UPUP
Fatty acid
P)os()o$P)os()o$
c)ol*+'c)ol*+'
Fatty acid Galac0os'Galac0os'
C'ra*d' 0a*lC'ra*d' 0a*l
OHOH
II
CH$C%C$CHCH$C%C$CH!!""#!#!$CH$CH33HH
HH6
II R#$C$N$CH
I
CH!OH
HH
Sphingosine Sphingosine
Fatty acid Fatty acid
#
#
!alactosyl!alactosyl
transferasetransferase
"ER#"ER#
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SYNTHESIS OF GLUCOCEREBROSIDESYNTHESIS OF GLUCOCEREBROSIDE
OHOH
II
CH$C%C$CHCH$C%C$CH!!""#!#!$CH$CH33HH
HH6
II R#$C$N$CH
I
CH!OH
HH
Sphingosine Sphingosine
Fatty acid Fatty acid
#
C'ra*d'C'ra*d'
! l u c o s y l
! l u c o s y l
t r a n s f e r a s e
t r a n s f e r a s e UP-glucoseUP-glucose
HH
OO
HH OHOH
HHHH
OHOHOHOH
HOCHHOCH!!
HH
C'r'/ros*d'C'r'/ros*d'
Gl1coc'r'/ros*d'8Gl1coc'r'/ros*d'8a l&cos()*+ol*(*d"a l&cos()*+ol*(*d"
Gl1cos'Gl1cos'
C'ra*d' 0a*lC'ra*d' 0a*l
#
OHOH
II
CH$C%C$CHCH$C%C$CH!!""#!#!$CH$CH33HH
HH66
IIII
RR##$C$N$CH$C$N$CH
II
CHCH!!
HH
O
UP UP
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III. SYNTHESIS OF OTHERIII. SYNTHESIS OF OTHER
GLYCOSPHINGOLIPIDSGLYCOSPHINGOLIPIDSCERAMIDECERAMIDE
Galac0o$Galac0o$
c'r'/ros*d'c'r'/ros*d'
Glo/os*d'Glo/os*d'
Ga+l*os*d'Ga+l*os*d'
! or or'! or or'
UDP$s1arsUDP$s1ars
CMP$CMP$
NANANANA
CMPCMP
!lycosyl!lycosyl
transferasetransferase
Galac0oc'r'/ros*d'Galac0oc'r'/ros*d'
3$s1l2a0'3$s1l2a0'
S1l2a0*d'"S1l2a0*d'"
P$P P$P
SulfotransferaseSulfotransferase
!alactosyl !alactosyl
transferasetransferase
P$PS P$PS
UDP$UDP$
alalc0os'alalc0os'
UDPUDP
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I9. STRUCTURE OF GALACTOCEREBROSIDEI9. STRUCTURE OF GALACTOCEREBROSIDE
3$SULFATE3$SULFATE
Galac0oc'r'/ros*d' 3$S1l2a0'
Fatty acid Adenine
ring
PentoseCHCH!!OHOH
OHOH
OHOH
OSOOSO$$33
OO
HH
HH
HH
HH
CHCH
IIII
CHCH
II
CH–OHCH–OH II
O%C$HN$CHO%C$HN$CH
II
CHCH
II
OO
OO
IIII
P$O$CHP$O$CH!! II
OO$$
OO
IIII$$O$S$OO$S$O
IIII
OO$$
!:!:
#:#:::
3:3:
7:7:
HH
NN
NHNH!!
NN
NN
NN
OOII
$$O$P%OO$P%O
II
OO$$
OHOH
OO
HH HH HH
3;$()os()oad'+os*+'$3;$()os()oad'+os*+'$
7;$()os()os1l2a0' PAPS"7;$()os()os1l2a0' PAPS"
3:3:
CeramideCeramide
GalactoseHH
Sulfate Sulfate
group group
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9. STRUCTURE OF GANGLIOSIDE G9. STRUCTURE OF GANGLIOSIDE GM!M!
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9I. STRUCTURE OF G9I. STRUCTURE OF GM!M!
GalNAcGalNAc GalGal GlcGlc CeramideCeramide
GalGal
NANANANA
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9II. DEGRADATION OF PHOSPHOLIPIDS9II. DEGRADATION OF PHOSPHOLIPIDS
OO
IIII
CC##HH!! – O – C – R – O – C – R##
OO
IIII
CC33HH!! – O – P –O – O – P –O $$
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9III. DEGRADATION OF9III. DEGRADATION OF
GLYCOSPHINGOLIPIDSGLYCOSPHINGOLIPIDSGLYCOSPHINGOLIPIDSGLYCOSPHINGOLIPIDS
E+doc&0*c ='s*cl'sE+doc&0*c ='s*cl's
L&soso'sL&soso's
&ydrolytic' &ydrolytic'
degradati(edegradati(e enzymesenzymes
Cl'a=a' o2Cl'a=a' o2
s('c*2*cs('c*2*c
/o+ds/o+ds
“ “ last on, first off” last on, first off”
I< E l 2 D d 0* 2
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Ia(l' o2 D'rada0*o+ o2 Ia(l' o2 D'rada0*o+ o2
a S()*+ol*(*d? S()*+o&'l*+a S()*+ol*(*d? S()*+o&'l*+
HH
II
CHCH33CHCH!!""#!#!$CH%CH$C$CH%CH$C
II OHOH
HH
II
C$CHC$CH!!$ O –$ O –
II NHNH
OO
IIII
P$OCHP$OCH!!CHCH!!NCHNCH33""33
II O$O$
4
CHCH33CHCH!!""++ – C – C
IIII OO
SphingomyelinaseSphingomyelinase
%eramidase%eramidase
Fatty acidFatty acid
PhosphorylcholinePhosphorylcholine
C'ra*d'C'ra*d'
N*'a++$P*c@ D*s'as'
N*'a++$P*c@ D*s'as'N*'a++$P*c@ D*s'as'
#. A10osoal r'c'ss*=' d*s'as' d1' 0o d'2*c*'+c& o2 s()*+o&'l*+as'#. A10osoal r'c'ss*=' d*s'as' d1' 0o d'2*c*'+c& o2 s()*+o&'l*+as'
acc11la0*o+ o2 s()*+o&'l*+ *+ l*='r a+d s(l''+acc11la0*o+ o2 s()*+o&'l*+ *+ l*='r a+d s(l''+ )'(a0os(l'+o'al&.)'(a0os(l'+o'al&.
!. I+2a+0s *0) s'='r' '+0al r'0arda0*o+ a+d +'1rod''+'ra0*o+.!. I+2a+0s *0) s'='r' '+0al r'0arda0*o+ a+d +'1rod''+'ra0*o+.
3. D'a0) *+ 'arl& c)*ld)ood 2or T&(' A.3. D'a0) *+ 'arl& c)*ld)ood 2or T&(' A.
< LYSOSOMAL STORAGE DISEASES
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REFERENCESREFERENCES
• ippincotts 4llustrated 5iochemistry , 0) 'd.
• Hor0o+:s Principles of 5iochemistry , 0) 'd.
•
D'=l*+:s .et+ook of 5iochemistry , 0)
• 'd., ((. !$3J.
• Har('r:s 4llustrated 5iochemistry , !K0) 'd.
• B'r, T&oc@o, S0r&'r, 5iochemistry , J0) 'd.,
((. 3J$3.
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