Sphingolipids

SPHINGOLIPIDS Andrés Mauricio Muñoz Moreno SURCOLOMBIAN UNIVERSITY Medicine 2009

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

• 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

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

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

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

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

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

• 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)

• 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

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

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

Proteins activated by Ceramide

Actions of ceramide and activation depending on certain signals

• 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

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

Acid and neutral sphingomyelinase pathway

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

Transduction mechanism are activated by S1P receptors

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

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

Gangliosides synthesis

• 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

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

• 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

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

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

• 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

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