SHINGOLIPIDS SHINGOPHOSPHOLIPIDS METABOLISM In humans at least 60

SHINGOLIPIDS/ SHINGOPHOSPHOLIPIDS METABOLISM

• In humans at least 60 different sphingolipids have been identified • Very prominent in neuronal plasma membranes. • Carbohydrate moieties of sphingolipids define the human blood groups. • The kinds and amounts of gangliosides vary dramatically during development.

Role of sphingolipids • These lipids are in a continuous state of turnover, defects in this metabolism leads to various diseases • Abundant component of myelin sheath (25% in humans)

SPHINGOMYELIN • Sphingomyelin is present in plasma membranes and in lipoproteins • It is very abundant in myelin • Sphingomyelin is abundant in specialized plasma membrane microdomains called LIPID RAFTS

LIPID RAFTS • Lipid rafts are specialized microdomains in the plasma membrane that are rich in sphingomyelin and cholesterol Raft association may aid in signaling through proteins anchored by glycosylphosphatidylinositol, particularly in hematopoietic cells and neurons. Rafts may also function in sorting and trafficking through the secretory and endocytic pathways.

Sphingolipids • Sphingomyelin contains sphingosine with a longchain fatty acid attached in amide linkage ( = ceramide) • Ceramide plus a phosphocholine group constitutes a sphingomyelin • Ceramide is also the core component of glycosphingolipids

. • The backbone of sphingomyelin is the amino alcohol sphingosine, rather than glycerol (Figure 17. 4). A long-chain fatty acid is attached to the amino group of sphingosine through an amide linkage, producing a ceramide. The alcohol group at carbon 1 of sphingosine is esterified to phosphorylcholine, producing SPHINGOMYELIN

-Histological classification of axons: 1 - myelinated : have myelin sheath (diameter more than 1 um) 2 - unmyelinated (diameter less than 1 um ) -type C : postganglionic autonomic &pain fibers

- -Myelin sheath is formed by schwann cell which deposit sphingomyelin Functions of myelin sheath 1 -insulator 2 - increase conduction velocity

INBORN ERRORS OF PHOSPHOLIPID, SPHINGOLIPID METABOLISM • Demyelination: Sclerosis multiplex • White matter decrease of [phospholipid], [plasmenyl ethanolamine], [sphingolipid] • Sphingolipidosis: • • Accumulation of complex lipids Synthesis of complex lipids is not effected Lack of specific (hydrolytic) lysomal enzymes All tissues are effected • Multiple sulfatase deficiency Biosynthesis of membrane lipids and steroids 1 13

SPHINGOLIPIDS SPHINGOSINE: a long-chain, unsaturated amino alcohol, a major constituent of sphingolipids, including sphingomyelins. The 3 -carbon backbone is analogous to the 3 -carbons of glycerol. At C 3 there is the long chain amino alcohol sphingosine.

SPHINGOLIPIDS At C 2 there is a fatty acid which is usually saturated or monounsaturated, and can be either 16, 18, 22, or 24 carbons long.

SPHINGOLIPIDS Ceramide is the parent compound. Other polar head groups can be attached at position X.

SPHINGOLIPIDS Glycosphingolipids are a sub-group of sphingolipids that contain sachharide headgroups

Galactosyl – ceramide / Galactocerebroside Monohexoside Dihexozid Gal Biosynthesis of membrane lipids and steroids 1 Gal Ceramid 18

Glucosyl-ceramide / Glucocerebroside Monohexoside Dihexoside Trihexoside Gal Glu Ceramide Biosynthesis of membrane lipids and steroids 1 19

ABO blood group system Glu Gal. NAc Gal „O” (H) antigen Fuc Glu Gal Gal. NAc „A” antigen Gal „B” antigen Fuc Glu Gal. NAc Gal Fuc Biosynthesis of membrane lipids and steroids 1 20

The ABO system: • Four main ABO groups: A, B, AB, O • Depends on whether the red cells contain one, both or neither of the two blood antigens: A and B.

Sphingolipids = blood typing Type O Universal donor Recognize by all as self

The ABO Blood groups Group. Blood Agglutinogen (antigen) Agglutinin (antibody) B B Anti-A AB A &B - O - A A Anti-B Anti A+B

Definitions • Agglutinogens: Blood group antigens on RBC membrane (A and B) • Agglutinin: The respective antibody to the antigen • Agglutination: Reaction between agglutinogen on RBC and the respective Ab.

The ABO blood groups • The table shows the four ABO phenotypes ("blood groups“) and the genotypes that give rise to them. Blood Antigens Group on RBCs Antibodies in Serum Genotypes A A Anti-B AA or AO B AB O B A and B Neither Anti-A and anti-B BB or BO AB OO

GANGLIOSIDES A group of glycolipids that are found especially in the plasma membrane of cells of the gray matter and have sialic acid, hexoses, and hexosamines in the carbohydrate part and ceramide as the lipid. A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e. g. n-acetylneuraminic acid, NANA) linked on the sugar chain (NANA)

Gangliosides GM 3 Gal Glu Ceramide NANA GM 2 Gal. NAc Gal Glu Ceramide NANA GM 1 Gal. NAc Gal Cholera toxin NANA 28

Gangliosides: These are the most complex glycosphingolipids, and are found primarily in the ganglion cells of the central nervous system, particularly at the nerve endings. They are derivatives of ceramide oligosaccharides, and contain one or more molecules of NANA. The notation for these compounds is G (for ganglioside), plus a subscript M, D, T, or Q to indicate whethere is one (mono), two (di), three (tri), or four (quatro) molecules of NANA in the ganglioside, respectively. Additional numbers and letters in the subscript designate the monomeric sequence of the carbohydrate attached to the ceramide. (See Figure 17. 15 for the structure of GM 2. ) Gangliosides are of medical interest because several lipid storage disorders involve the accumulation of NANAcontaining glyco sphingolipids in cells