The Patient: Lipids

What are the 4 main types of lipids? What are they involved in? - Free fatty acids - carried around the body bound to albumin, used as a source of energy. - Triglycerides - depot fats, made of fatty acids and glycerol, and stored in adipocytes. - Phospholipids - found in membranes and signalling pathways. - Sterols - found in membranes and myelin sheath, precursors for hormones, bile salts. What are the two types of phospholipids? - Phosphoglycerides - Sphingolipids 2 fatty acids, glycerol, phosphate and alcohol. Examples include phosphatidylserine, phosphatidylWhat are the structure of phosphoglyc- choline, phosphatidylethanolamine, and erides and what are some examples? phosphatidylinositol. fatty acid, sphingosine backbone, phosphate and alcohol. What is the structure of sphingolipids? Sphingomyelin is a major component of the myelin sheath and often has long What is sphingomyelin and what is it in- chain fatty acids with 24 carbon atoms. volved in? Where does phospholipid synthesis occur? On the endoplasmic reticulum 1. Formation of phosphatidate (same for triglyceride synthesis) What are the steps involved with phos2. Activation of a diacylglycerol or an alpholipid synthesis? cohol 3. Esterification 1 / 11 Glycerol 3-phosphate (formed from a glycolytic intermediate) is converted to lysophosphatidate by adding a saturated fatty acid. Lysophosphatidate is then converted to phosphatidate (also known How is the phosphatidate formed in step as diacylgylcerol-3-phosphate) by addi1 of phospolipid synthesis? tion of an unsaturated fatty acid. Overall, 2 fatty acids are transferred from 2 fatty acyl CoA using the enzyme glycerol phosphate acyl transferase. Phosphatidate is converted to CDP-diacylglycerol by CTP (cytidine triphosphate), driven by hydrolysis of pyrophosphate. 2 phosphates are lost from CTP How is a diacylglycerol (DAG) activated and cytidine monophosphate joins to in step 2 of phospholipid synthesis? phosphatidate to form CDP-diacylglycerol. Ethanolamine is first activated by ATP (which is hydrolysed to ADP) to form phosphorylethanolamine. CMP is added Alternatively, how is an alcohol activated by CTP to form CDP-ethanolamine and in step 2 of phospholipid synthesis? 2 phosphates are lost from CTP. How does esterification of a diacylglycerol occur in step 3 of phospholipid synthesis? 2 / 11 Addition of an alcohol (inositol) to CDP-diacylglycerol creates phosphatidylinositol. Cytidine monophosphate (CMP) is released. Addition of DAG to CDP-ethanolamine creates phosphatidylethanolamine How does esterification of an alcohol oc- (phospholipid). Cytidine is released from cur in step 3 of phospholipid synthesis? CDP-ethanolamine, creating CMP. Phosphatidylinositol has numerous functions as an anchoring system for proteins, secondary messenger, cell signalling, cytoskeleton assembly, nerve guidance, cell membrane potential maintenance, breakdown of fats, gene expression. What are the uses of the two different products formed from esterification in step 3 of phospholipid synthesis? (Phosphatidylinositol and Phosphatidylethanolamine) Phosphatidylethanolamine is important in the heart, helps flow of blood and plays a role in secretion of glycoproteins in the liver. It also assists folding of membrane proteins. The most common phospholipid is phosphatidylcholine. Choline comes from the What is the most common phospholipid? diet, but phosphatidylcholine can also How can it be synthesised? be synthesised in the liver from phosphatidylethanolamine. Phosphatidylserine can be synthesised from phosphatidylcholine or phosHow is phosphatidylserine synthesised phatidylethanolamine by base exchange. and what is it important in? It is important in apoptosis as exposure of it on surface of old erythrocytes flags/signals them for destruction. - Formation of ceramide intermediate (fatty acid and sphingosine) - Addition of phosphate and alcohol (phosphoryl choline for example) What are the two stages involved in the synthesis of sphingolipids? - Condensation of palmitoyl CoA and serine. 3 / 11 - Reduction - Addition of fatty acid - Oxidation What are the steps involved in forming the ceramide intermediate? Decarboxylation reaction, releasing carbon dioxide and generating 3-ketosphinganine. The enzyme used is serine What is involved in the condensation of palmitoyl transferase and there is a pyripalmitoyl CoA and serine in sphingolipid doxal phosphate (vitamin B6) cofactor. synthesis (forming the ceramide)? 3-ketosphinganine is converted to dihyWhat is involved in the reduction reaction drosphingosine using NADPH. of spingolipid synthesis (forming the ceramide)? Dihydrosphingosine forms dihydroceramide by adding on a fatty acid. The fatty What is involved in the addition of a fatty acid attaches to an N atom. acid in sphingolipid synthesis (forming the ceramide)? What is involved in the oxidation step in sphingolipid synthesis (forming the ceramide)? Dihydroceramide is converted to ceramide (fatty acid attached to sphingosine) using FAD which generates FADH2. For sphingomyelin, you use phosphatidyl choline. Phosphatidyl choline forms DAG and converts ceramide to What is involved in the addition of a phossphingomyelin. phate and alcohol for a sphingomyelin? 4 / 11 What is the role of sphingolipids? Sphingolipids are involved in signal transmission and cell recognition. Believed to protect cell surfaces from harmful environmental factors by forming a chemically resistant barrier. Disorders of sphingolipid metabolism will affect neural tissue. What is the structure of glycosphingolipids? Fatty acid, sphingosine and saccharide such as glucose. Found on the cell membrane with the oligosaccharide extending from the Where are glycosphingolipids found and membrane, important for cell adhesion, what are they important for? cell signalling, cell-cell interactions. Have a role in oncogenesis. What are the different types of glycolipids? What is the structure of a ganglioside and what does it do? - Cerebrosides have glucose/galactose - Sulphatides - Globosides - Gangliosides include acid sugars. Ceramide and oligosaccharide chain joined to the ceramide by a glucose residue. The oligosaccharide chain contains at least one acidic sugar (sialic acids such as GALNAc and NAN). They modulate cell signal transduction events. What is respiratory distress syndrome caused by? Dipalmitoyl phosphatidylcholine forms 80% of total lipids in the ECF in alveoli. It lowers the surface tension to prevent collapse on expiration. Insufficient synthesis leads to respiratory distress syndrome in premature babies and is responsible for 15-20% of neonatal mortality. The potential to get this syndrome is assessed by measurement of lecithin (where PC is): sphingomyelin ratio in am5 / 11 niotic fluid. What is done to assess whether a baby If the baby is going to be born prematurehas the syndrome and prevent it happen- ly, the mother is given glucocorticoids to ing in premature babies? accelerate maturation of the foetal lung. Genetic mutation affecting beta-N-acetylhexosamidase, an enzyme involved in lipid (ganglioside) degradation in the lysosomes. What causes Tay-Sachs disease? This causes a build-up of gangliosides, particularly in the brain, leading to weakWhat happens to people with Tay-Sachs ness, retarded psychomotor skills, dedisease? mentia, blindness. Eventual death by the age of 3. What is the function of cholesterol? - Adds rigidity to cell membranes - Precursor of steroid hormones - Raw material for bile salts and vitamin D. What is the structure of cholesterol and what is it derived from? - Based on a four-ring structure. - Contains 27 carbon atoms. - Derived solely from acetyl CoA. 1. Formation of isopentenyl pyrophosphate. What are the stages in cholesterol syn2. Condensation of 6 molecules to form thesis? squalene. 3. Cyclisation Where does each stage of cholesterol synthesis occur? Stage 1 takes place in the cytoplasm, stage 2 and 3 take place on the endoplasmic reticulum. - Formation of 3-hydroxy-3-methylglutaryl CoA (HMG CoA). What are the steps involved in stage 1 of - Reduction to mevalonate cholesterol synthesis? - Conversion to isopentenyl pyrophosphate. 6 / 11 2 acetyl CoAs reacts to form acetoacetyl CoA and CoA using 3-ketothiolase. This is the opposite of thiolysis in beta oxidation of fats. Acetoacetyl CoA and another acetyl CoA react in a condensation reaction (using water) to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) How is HMG CoA formed in stage 1 of and a CoA. This is done using the encholesterol synthesis? zyme hydroxymethylglutaryl (HMG) CoA synthase. 3-hydroxy-3-methylglutaryl CoA is reduced to mevalonate. This uses How is mevalonate formed in stage 1 of 2NADPH and 2H+ to produce CoA and 2 NADP+ as byproducts. The enzyme cholesterol synthesis? used is HMG-CoA reductase. How is the conversion to isopentenyl py- It has 3 phosphorylation steps (using 3 rophosphate done in stage 1 of choles- ATP) and a decarboxylation. terol synthesis? In stage 1 of cholesterol synthesis, what is used overall in all 3 steps? 2 NADPH and 3 ATP - Isomerisation to dimethylallyl pyrophosphate. - Condensation to form 10-carbon moleWhat are the steps involved in forming cule. squalene in stage 2 of cholesterol syn- Condensation to form a 15-carbon molthesis? ecule. - Tail-to-tail condensation to form 30-carbon molecule. 7 / 11 What is involved in the isomerisation to Isopentenyl pyrophosphate is isodimethylallyl pyrophosphate in stage 2 of merised to dimethylallyl pyrophosphate. cholesterol synthesis? Dimethylallyl pyrophosphate loses two phosphate groups to form am allylic carbocation. The addition of 3-isopentenyl What is involved in the condensation to pyrophosphate forms geranyl pyrophosform a 10-carbon molecule in stage 2 of phate using the enzyme geranyl transferase. cholesterol synthesis? Geranyl pyrophosphate and isopentenyl pyrophosphate react to form farnesyl pyWhat is involved in the condensation to rophosphate and 2 phosphates using the form a 15-carbon molecule in stage 2 of same enzyme (geranyl transferase) cholesterol synthesis? Reductive condensation of 2 farnesyl pyrophosphate molecules to make squaWhat is involved in the tail-to-tail conlene using squalene synthase. It uses densation to form a 30 carbon molecule NADPH. (squalene) in stage 2 of cholesterol synthesis? Squalene forms a squalene epoxide intermediate using NADPH and oxygen. Addition of a proton (by oxidosqualene How is lanosterol formed in cyclisation cyclase) to oxygen in squalene epoxide (stage 3) of cholesterol synthesis? triggers cyclisation forming a protosterol cation which spontaneously rearranges to form lanosterol. 8 / 11 There is a complex, 19-step process to make cholesterol, using NADPH and creHow is lanosterol converted to cholesating methanoic acid and carbon dioxide. terol in the cyclisation stage of cholesterol synthesis? Occurs via HMG CoA reductase (rate-limiting step). What enzyme is cholesterol synthesis regulated by? It is dependent on amount of cholesterol in cell. - mRNA of enzyme - Translation of enzyme to protein - Control of enzyme degradation - Phosphorylation - Hormonal control How is the enzyme HMG CoA reductase regulated? How is the synthesis of mRNA of HMG A regulatory protein in the ER is a sensor CoA reductase controlled? for cholesterol levels in the cell. inhibited by dietary cholesterol and non-sterol metabolites of mevalonate (feedback). How is translation of mRNA of HMG CoA reductase inhibited? a sensory domain on the enzyme looks at intracellular cholesterol levels and levWhat is degradation of HMG CoA reducels of other sterols (like lanosterol). This tase enzymes controlled by? How is it results in ubiquitination, where the endegraded? zyme is tagged and then destroyed by proteasomes. How does phosphorylation affect HMG CoA reductase? Phosphorylation by AMP-activated protein kinase decreases activity. What hormones control HMG CoA reductase activity? increased by insulin and thyroid hormone. It is decreased by glucagon and cortisol. 9 / 11 There is a connection linking fats to heart disease. In 1948, a heart study should link between high cholesterol and heart disease. The screen of natural products yielded the first statin - lovastatin - to treat high cholesterol and other synthetic compounds have been developed. What are fats/cholesterol linked to? - Treat hypercholesterolaemia and atherosclerosis (plaque build-up in the arteries). What are statins used for and what is the - It is a competitive inhibitor of HMG CoA mechanism of action? reductase and leads to up-regulation of LDL transporters. - Can reduce circulating cholesterol by 30-60% Natural product from Aspergillus cereus. Part of the structure resembles the 3-hydroxy-3-methylglutaryl (HMG) CoA moiWhat is lovastatin and how does it work ety. as a competitive inhibitor? What are other statins in addition to lovastatin? Other statins include simvastatin, atorvastatin and rosuvastatin which also have similar groups resembling HMG-CoA. What are the conflicting opinions on statins for heart problems? - The link between high cholesterol and heart disease overestimates the risk and a meta-analysis of the link is inconclusive. - The effect of stains as a preventative measure is lower than stopping smoking or angioplasty. - Statins have a more significant effect in the prevention of a second event. 10 / 11 - Link between intake of saturated fats and cholesterol biosynthesis but this cause and effect has been challenged. - A meta-analysis did not show a strong link between saturated fats and CVD. What is the link between saturated fats, - Review of literature shows reduced incholesterol and heart disease? take of saturated fats has some effect on CVD if replaced with some unsaturated fats. - Replacement with carbohydrates suggests links to increase in obesity. 11 / 11