metabolism of sphingolipids and glycosphingolipids

8/19/2019 Metabolism of Sphingolipids and Glycosphingolipids

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METABOLISMMETABOLISMOF THEOF THE

SPHINGOLIPIDS ANDSPHINGOLIPIDS ANDGLYCOSPHINGOLIPIDSGLYCOSPHINGOLIPIDS

Floro B. Madarcos, MDFloro B. Madarcos, MD


2/21

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


5/21


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


6/21


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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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


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


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


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


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


Galac0oc'r'/ros*d'Galac0oc'r'/ros*d'

3$s1l2a0'3$s1l2a0'

S1l2a0*d'"S1l2a0*d'"

P$P P$P

SulfotransferaseSulfotransferase

!alactosyl !alactosyl


P$PS P$PS

UDP$UDP$

alalc0os'alalc0os'

UDPUDP


10/21

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


11/21

9. STRUCTURE OF GANGLIOSIDE G9. STRUCTURE OF GANGLIOSIDE GM!M!


12/21

9I. STRUCTURE OF G9I. STRUCTURE OF GM!M!

GalNAcGalNAc GalGal GlcGlc CeramideCeramide

GalGal

NANANANA


13/21

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 $$


14/21

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


15/21

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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metabolism of sphingolipids and glycosphingolipids

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