Short description about sphingolipids and his functions

1. SPHINGOLIPIDS
Andrés Mauricio Muñoz Moreno
SURCOLOMBIAN UNIVERSITY
Medicine
2009

2. • They are located in plasma membrane
• Have structural function
• Serve as sites of adherence of
extracellular proteins

3. • Important function in cellular physiology
• Current as second messengers
• They are part of lipids rafts
• Sphingosine is the most simple sphingolipid
• Ceramide is precursor of many molecules

4. STRUCTURE
• Long – chain base
(Sphingosine)
• Fatty acid of variable
length bind to C2 of
long – chain base
• Various pollar´s head
bind to C1 of long –
chain base

5. METABOLISM
Generation of Ceramide (principal precursor
of metabolites) follow this pathway
• De novo synthesis
• Membrane Sphingomyelin degradation

6. DE NOVO SYNTHESIS
• Occur in Endoplasmic
Reticulum and Golgi
apparatus
• Sphingomyelinase
catalizes
Sphingomyelin
synthesis transferring
Phosphorilcholine to
Ceramide forming

7. SPHINGOMYELINE
DEGRADATION
• Catalyzed by
Sphingomyelinase
enzyme (SMasa)
• It is the principal
pathway for
Ceramide`s
production

8. LIPIDS RAFTS
• Sphingolipids with
cholesterol outside of
lipid bilayer
• Lipid and protein
composition is
different for each raft
• Signaling activity is
due to interaction of
lipids and proteins

9. • The caveolaes are rafts specialized of invaginated shape
than regulates receptor activity (tyrosin kinase, growth factor
receptor etc)
• Allow entry of various biological entities to cell (virus,
hormones, bacteria etc)

10. • Rafts promotes signaling in response to a
stimule
• Regulates signaling because they kidnaps
signaling molecules in inactive status
• Activated receptor changes the composition of
Sphingolipids raft altering the structure of the
membrane and thereby initiates the signaling
cascade
• Sphingolipids of caveolaes allows interaction of
pathogen entities with the cell iniciating

11. SIGNALING
APOPTOSIS MITOSIS
• Esfingosina 1 fosfato
• Ceramida
• Ceramida 1 fosfato
Balance between Ceramide and his metabolites is important for cellular
survival regulation

12. CERAMIDE`S ACTION
Ceramide acts as second messenger, is
formated by:
• Activation of cell dead receptors
• Gamma and UV radiation
• Hypoxia
• Deprivation of growth factors
• Thermic shock
• Pharmacs

13. Proteins activated by Ceramide

14. Actions of ceramide and activation depending on certain signals

15. • CAPK: Ras suppressor kinase
• PKCζ: Active the NF-кB survival pathway
• JNK: His activation produces apoptosis
• PP1: Bad phosphorilation, producing apoptosis
• PP2A: Bcl-2 dephosphorilation, becoming in apoptotic
molecule doing permeable mitochondrial membrane
• Ceramide can produce oxidative stress by ON
synthetase and antioxidantes enzymes desregulation

16. CERAMIDAE 1 PHOSPHATE
ACTION
C1P is produced by a Ceramide kinase ATP-ligand. This
C1P is implicated in inflammatory responses, apoptosis
inhibition and cell survival.
• Current in the araquidónic acid release
• Acid sphingomyelinase inhibition, this decrese
ceramide`s levels inhibiting apoptosis
• PI3K/PKB pathway activation, increasing cell survival

17. Acid and neutral sphingomyelinase pathway

18. SPHINGOSINE 1
PHOSPHATE ACTION
S1P originates from
sphingosine by
kinase`s action:
• SphK1: Increased in
tumorals cells
• SphK2: His increase
inhibits cell growth

19. Transduction mechanism are activated by S1P receptors

20. S1P can act as second messenger or act in extracellular
surface by transporters who carry from intracellular to
extracellular space
• 5 S1P receptors are linked to various kind of G protein
(S1P1-5)
• Receptors linked to G12/13 protein activate the Rho
GTPasa than regulates cytoskeleton and cell motility
• Receptors linked to Gq protein coupling to
Phospholipase C increasing intracellular calcium
• Receptors linked to Gi protein regulate the PI3K/Akt and
Ras/ERK pathways

21. GANGLIOSIDES
• Glycosphingolipids
than contain sialic
acid residues (NANA)
• Are the 25% of lipids
in outside of neural
membrane
• There are 188
differents kinds of
gangliosides

22. Gangliosides synthesis

23. • Glycosphingolipids precursors of gangliosides into the
Golgi apparatus and wrapped in reactions of
glycotransferases and sialotransferases
• Extraneural primary gangliosides in vertebrates is GM3
• A sialidase different from the Golgi apparatus is located
in the plasma membrane where it changes the
composition of gangliosides in surface
• Myelinic maintenance and neural regeneration functions
• Cerebral primary gangliosides are GM1, GD1a, GD1b y
GT1

24. GANGLIOSIDES AND
DISEASE
• Certain types of gangliosides found in
cancer cells and not in healthy tissue
• GM3 has therapeutic applications to
promote apoptosis of tumor cells by
suppressing the phosphorylation of
receptors for growth hormone in her
surface
• GD1a promote proliferation and tumoral
cells metastasis

25. • Gullain – Barré syndrome there are
gangliosides antibodies
• GM1 disorder in the Alzheimer disease
cause β amyloid protein accumulation in
brain
• Damages in metabólicas pathways for
gangliosides are involved in Huntington`s
disease
• In childhood epylepsia there is mutation in
Sialotransferase gen

26. CEREBROSIDE S
• Monohexoses
Ceramides
• They are primary in
brain, but too in
spleen and
erythrocytes

27. Cerebrosides are synthesized from the Ceramide
and activated sugar nucleotides UDP-galactose and
UDP-glucose
Biosynthesis is in endoplasmic reticulum and the
involved enzymes in this process are glycosil and
galactosil transferases

28. • Promote the increase of body temperature
to form networks compact hydrogen
bridges with other cerebrosides
• Increased cerebrosides in liver, spleen,
bone marrow and lungs causing Gaucher
disease due to defects in the enzyme
glycocerebrosidase

29. REVIEW
• http://www.tdx.cbuc.es/TESIS_UV/AVAILABLE/TDX-0608109-141934//FER
RER.pdf
• http://www.lipidlibrary.co.uk/Lipids/introsph/index.htm
• http://www2.uah.es/dianas/00101001_sanchez.pdf
• http://lh5.ggpht.com/_FLe5Kbctaeg/SjJlj1VjSDI/AAAAAAAACQM/7QxWIlXP
zsk/Sphingosine1phosphate2_thumb14.jpg
• http://www.cell-research.com/images/99photo/1-1.jpg