number 26 Done by حسام أبو عوض Corrected by Zaid Emad Doctor فيصل الخطيب 1 P a g e
A small note about phosphatidyl inositol-4,5-bisphosphate (PIP2) before moving on: This molecule is found in the membrane and (in response to a hormonal signal) when phospholipase C is activated the bond between the glycerol and the phosphate group is broken producing a Di-Acyl-Glycerol (DAG) and Inositol- 1,4,5-tri-Phosphate) (IP3). What do IP3 and DAG remind you of? Yep, one of the two main types of G- protein-coupled receptors (the other being the camp one). IP3 goes to the cytoplasm where it activates Ca²+ release from intracellular stores, which acts as a second messenger (you know the rest) and DAG stays in the membrane where it activates other components (like protein kinase C ). Sphingophospholipids and Glycosphingolipids In these molecules (which are also membrane components) the back-bone is NOT glycerol, it is sphingosine. As we would expect from the ine part in sphingosine, the molecule contains an amine group, this is the structure of sphingosine: If we are to compare this structure to the glycerol-derivatives, it indeed looks like the monoacylglycerol. As if the first binding area is already occupied by the backbone (sphingosine) itself (note the double bond and the amine group in the structure). The amine group can form an amide bond with a carboxyl group, this makes it possible for a fatty acid to join our molecule by forming an amide bond with NH₂. The new molecule (see the diagram) now looks quite similar to the diacylglycerol and it is called ceramide. The ceramide structure is common between all the sphingosine family molecules we are going 2 P a g e
to talk about, the differences between them are only in the third (final) binding site of sphingosine. Sphingomyelin This molecule is made by adding phosphocholine (see previous lecture) to the OH of the CH₂OH in ceramide. The synthesis process of this molecule occurs via several steps and we only need to know two of them (there are many steps in between though): 1- Palmitoyl CoA + Serine Sphinganine + CO₂ ΔG= -ve (this is because CoA and CO₂ are released in the process). Sphinganine is a molecule that is very similar to sphingosine, but it lacks sphingosine s double bond. Pyridoxal Phosphate (vitamin B6) is needed for this reaction. - After several steps we will end up with ceramide, 2- Ceramide + Phosphatidyl Choline Sphingomyelin + Diacylglycerol Sphingomyelin is very similar in structure to phosphatidyl choline such that both can actually do the same functions, so sphingomyelin can be part of the cell membrane or micelles. In fact, sphingomyelin is present in large quantities in the membranes of the neurons and especially in the myelin sheath. Glycolipids When a carbohydrate group is added to ceramide instead of the phosphate group, the new molecule formed is called a glycolipid. There are several classes of glycolipids according to which molecule is added to ceramide (memorise them): Ceramide + Glucose/Galactose Cerebroside(was first separated in the cerebrum) Ceramide + Sulfated galactose Sulfoglycosphingolipid (Sulfogalactocerebroside) Ceramide + Oligosaccharide Globoside Ceramide + Oligosaccharide with NANA Gangliosides (found mainly in ganglions) 3 P a g e
NANA is N-Acetyl Neuraminic Acid (Neuraminic = found mainly in neurons). NANA is also known as sialic acid. In all the glycolipids above, the carbohydrate is bonded to the ceramide via a glycosidic bond and are accordingly given names that end with oside. Another way to divide glycolipids can be according to their acidity Neutral glycolipids: -Glucosylceramide (Glucose + ceramide) -Galactosylceramide (Galactose + ceramide) -Globosides Acidic glycolipids: -Gangliosides (due to the presence of sialic acid) Gangliosides are further divided to GM₁, GM₂ and GM₃ (G=ganglio, M= monoacid NANA, the number will be explained later on) -Sulfatides (Sulfoglycosphingolipids) Synthesis of glycolipids In the synthesis of the glycolipids the donors must be activated, that is be in the form of UDP-sugar (UDP-glucose, UDP-galactose, UDP-Nacetylgalactoseamine) or CMP-NANA. For the sugar to be transferred specific transferases are needed, e.g. for glucose: glucose-transferase is needed. In this reaction the direction is determined by the type of transferase present as the structures are very similar to each other (Glucose and galactose are C-4 epimers). Transferring a sulfate group to galactosylceramide (also known as galactocerebroside) produces a sulfogalactocerebroside (also known as Sulfoglycosphingolipid).The sulfate group donor is a molecule that is quite close in structure to 4 P a g e
ATP, but instead of the third phosphate a sulfate group is present. This molecule is called 3-phosphoadenosine 5-phosphosulfate (PAPS). - The presence of specific enzymes is what determines which sugar is to be added to the molecule, so the sequence of sugars can give a lot of information about cells (like the ABO blood grouping). Degradation of Sphingolipids There are specific hydrolytic enzymes for each sugar: - α-galactosidase - β-galactosidase - neuraminidase - Hexoaminidase These enzymes are present in the lysosomes firmly bound to the lysosomal membrane. Their optimum phs are acidic (3.5-5.5) which means that they cannot leave the lysosome and if such a thing happens they will not be able to function as the required ph will not be present. The degradation of the sphingolipids occurs sequentially, that is they are removed one-by-one beginning with the molecule that was last added to the structure. Degradation of Sphingomyelin Sphingomyelinase enzyme removes the phosphocholine group producing ceramide and the ceramidase enzyme breaks the amide bond removing the fatty acid and producing sphingosine. Degradation of Gangliosides Here we will get to know why the gangliosides got their specific numbers (GM₁, GM₂, GM₃). The first molecule seen in the image is GM₁, the 2 nd is GM₂ and the third is GM₃. So, the gangliosides were named according to their order of degradation not their synthesis. That is because degradation is more important than synthesis as the 5 P a g e
synthetic enzymes were never seen to be absent in any individual (no synthetic diseases related to sphingolipids), but the degrading enzymes were indeed noted to be absent in many individuals causing the diseases called Sphingolipidoses. Sphingolipidoses The old name of this family of diseases was lipid storages diseases as it was thought that the problem was in storing the lipids, however, later it was found that these diseases arose when a defect in any of the sphingolipids degrading enzymes was present. These diseases are inherited and the defective allele is the recessive one (you can survive with the 50% remaining enzymes if you are a carrier of the disease, in fact, even just 20% would be enough as the process of degradation takes a long time). The substrate of the defective enzyme would accumulate and cause problems. It is noted that the most affected cells are those of the brain (as they can't regenerate). In the following diagram all the sphingolipidoses diseases are mentioned and described, but you only need to memorise the three that are marked: Tay-Sachs disease is common in jews of eastern-european origin. 6 P a g e