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Lipids
Biochem and medical genetics
Question | Answer |
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Lipids | Insoluble in water but soluble in non-polar solvents due to their structure. Large non-polar regions of hydrocarbons mean they cannot for H bonds with water. They are known as amphipathic, as they contain both hydrophilic and hydrophobic moieties |
Examples of lipid function | Energy source Membrane bilayer Matrix for assembly and function for catalysis Chaperones for protein folding Light absorber Energy transduction Electron transfer Hormones Vitamins Antioxidants Signalling molecules |
Lipid classification systems | Humans have 1000 major lipid species with many minor species. Tears have over 30000 lipid species. All systems have fatty acids. |
Different types of fatty acid | Complex - broken down to give multiple free fatty acids Simple - hydrolysed into individual components |
Different types of lipid | Fatty Acid Glyerolipid Glycerophospholipid Sphingolipid Sterol lipid Prenol lipid Saccharolipid Polyketide |
Fatty acids | Major building block of cell membrane lipids. A monocarboxylic acid with a long unbranched aliphatic tail that is saturated or unsaturated. Building blocks from our diet but can be synthesised de novo. These may contain up to 6 double bonds |
Saturated fatty acids | FA with no double bonds. Three most common types are myristic (C-14), palmitic (C-16) and stearic (C-18) The number of carbons, type (cis trans) and position of each double bond must be described |
How to name fatty acids | Double bonds tend to be in the C9 position, with double bonds assumed to be cis unless followed by a T. |
What is an essential fatty acid | A polyunsaturated FA with fewer then 7 carbon atoms after the last double bond Must be acquired from the diet via plant material |
Omega carbon | The last carbon in the alkyl chain. We can designate lipid names based on counting from the omega carbon. Omega 3 FAs play an important role in cardiac brain and neurological function. e.g. alpha-linolenic acid, Eicosapentaenoic acid |
Role of the double bond | The primary function of double bonds is to disrupt tight lipid packing in membranes, increasing volume for normal membrane protein function. Saturated lipids pack together Unsaturated lipids are kinked so do not pack as closely |
Complex fatty acids - glycerides | Glycerol is a major acceptor of fatty acids. To do this, the carboxyl group of the fatty acid is made more reactive by addition of CoA, containing a reactive thiol group/ The final fatty acyl CoA can be used to generate di and triglycerides |
Bonds connecting acyl chains | FA tend to be connected to the rest of the lipid by an oxygen ester. Sphingolipids use an amide. Some lipids also use thioesters. Triacylglycerol is a non-polar ester containing lipids which can be hydrolysed with KOH to produce glycerol and 3 K+ salts |
Phospholipids | The major constituent of cell membranes. Actual name is glycerophospholipids 1 glycerol, 1 phosphate, 2 fatty acids and 1 alcohol This alcohol is known as the head group and determines the properties of the phospholipid |
Main types of phospholipid | Phosphatidic acid, Phosphatidylethanolamine, Phosphatidylcholine, Phosphatidylserine, Phosphatidylinositol, phosphatidylglycerol and Cardiolipin |
Phosphatidic Acid | Simple with no head group. Small, highly charged head. PA shape allows this to induce high curvature in membranes. Membrane PAs can be aggregated by Ca2+ resulting in PA rich domains that are sensitive to pH, temperature and cation concentration |
Phosphatidylethanolamine | Second most common. A major structural lipid in membranes. PE, PC and cholesterol are major components of egg yolk. Found in nervous tissue. A primary amine containing phospholipid and therefore has a highly reactive chemical handle to be modified |
Phosphatidylcholine | The major structural lipid found in human membranes due to its can shape, which facilitates close packing. PC is a zwitterion, possessing a positive and negative charge at physiological pH, so is neutral |
Phosphatidylserine | An essential lipid with many functions, especially found in brain tissue. Many clinical trials have suggested PS plays an important role in cognitions as concentrations decline with age. Involved in anchoring proteins to the membrane e.g. kinases |
Phosphatidylinositol | Anionic structure, so contributes to lipid bilayer stability. Plays only a small role in membranes, often more important for signalling. Abundant in the brain > 10% total lipid. Often phosphorylated at different positions, most commonly 4 and 5 |
Phosphatidylglycerol | An anionic lipid in mammalian membranes in low amounts. Plays an important role as a lung surfactant. Its level is used to determine maturity of a babies lung |
Cardiolipin | Most unusual of the phospholipids. Essentially two PAs glued together by glycerol. Found in the mitochondrial inner membrane to stabilise proteins in the electron transport chain |
Phospholipid bilayers | Fluid mosaic model Emphasis on dynamics with lipids, proteins and carbohydrates ever changing. This has to also account for proteins being tethered to the cytoskeleton. Contains lipid rafts - lipid rich domains made of cholesterol and sphingolipid. |
Infant respiratory distress syndrome | Surfactant on the lungs is needed to reduce surface tension in the lungs and allow them to inflate. Synthesis of phospholipids (mainly phosphatidylcholine) is not complete until birth, so the surfactant level is too low. Lungs cannot inflate |
Phospholipid degradation | Each hydrolysable bond is attacked by a phospholipase. Phospholipases A1 and A2 remove acetyl chains while phospholipase C removes the phosphorylated head group. |
Mechanism of a phospholipase | Vasopressin binds to a receptor which activates phospholipase C which increases production of IP3 and DAG from PA. These increase secretion of Ca2+ which activates protein kinase C and leads to cell growth |
What is a sphingolipid | Contain the parent C-18 amino alcohol sphingosine attached via an amide link to the C2 on glycerol. There are 60 different forms differing at the C1 alcohol group. They are largely derived from ceramide (a glycerol with OH groups) |
Sphingolipids | Most common is sphingomyelin where the head group is phosphocholine. The chain is usually longer than most phospholipid acyl chains e.g C-24 lignoceric acid and C24:1 nervonic acid. |
Different forms of sphingolipid | Sphingomyelin - phosphorylcholine head group Ceramide - H head group Cerebroside - glucose head group Globoside - more that one sugar head group Ganglioside - complex saccharide head group |
Diseases related to abnormal sphingolipid turnover | Sphingomyelinase defect - SM accumulation in spleen, brain and liver evident in infants. Leads to mental retardation and death Hexosaminidase A absent - cannot add terminal sugar. Ganglioside accumulation in spleen and brain, progressive retardation, |
Sterols | Major component of membranes. Major sterol is cholesterol - 3 six membered rings, 1 five carbon ring, a short aliphatic chain and a hydroxyl group. Sterols exist in a free or conjugated form e.g. cholesterol esters. These are rigid. |
Cholesterol synthesis from Acetyl CoA | Acetyl CoA forms hydroxymethyl glutaryl CoA. This is acted on by HMG-CoA reductase (synthesised in ER), which forms mevalonate and then cholesterol. Alternatively HMG-CoA lysae may act to form acetoacetate then ketone bodies. (occurs in liver) |
How statins inhibit cholesterol synthesis | HMG-CoA reductase is the critical enzyme in cholesterol biosynthesis. This has been targeted as a means to lower serum cholesterol levels. Lovastatin is the most active agent to date and acts by competing favourably with HMG-CoA for binding to the enzyme |
Cholesterol as a precursor to bile salts | Cholesterol is broken down to give bile salts. Most important are Cholic acid and chenodeoxycholate. These are conjugated in the liver with glycine/taurine to form bile acids. These are hydrophilic so are used to emulsify lipids in digestion |
Key functions of lipids | Structural components of membranes e.g. phospholipids and sphingolipids Signalling molecules e.g. phosphoinositides, arachidonic acid and steroids hormones Rules e.g. triglycerides |
Structural roles of lipids | Cell membranes can bend via changing composition of lipids. Positive or negative bending can be induced by changing the phospholipid environment. This allows cells to moved e.g. |
Cholesterol in membranes | Cholesterol modulates membrane stability by broadening the solid/liquid transition. It restricts motion of fatty acids so decreases fluidity high temps and prevents fatty acid chains lining up and freezing at low temps |
Where are fatty acids found in cells | Fatty acids are never free in the body. They are esterified to glycerol in membranes, non-covalently bound to albumin in serum or covalently bound to CoA in cells |
Roles of lipids in biomembranes | Impermeable to non-polar molecules or ions Give flexibility to membranes Durable so can withstand shear forces Provide optimal conditions for function of enzymes Fluid so proteins can move around |
Asymmetry of lipids | Transleaflet asymmetry - e.g. sphingolipids tend to be outside the cell while Phosphatidylcholine is inside the cell. This allows for endo/exocytosis, pro coagulation and signal for apoptosis Intraleaflet asymmetry- associated with particular proteins |
Lipids and signalling - PIP2 | PIP2 is broken down by phospholipase C into IP3 and diacylglycerol. IP3 bunds to receptors on the EP to increase Ca2+ concentration. This along with diacylglycerol activates protein kinase C |
Lipids and signalling - Arachidonic acid | Any phospholipid with an unsaturated FA in the an2 position is acted on by phospholipase A2 to form arachidonic acid, a second messenger that activates prostaglandins, eicosanoids and leukotrines. This can therefore cause many effects e.g. inflammation, |
Examples of steroid hormones | Progesterone - prepares uterus for implantation and prevents ovulation in pregnancy Cortisol - promotes gluconeogenesis and suppresses inflammation Testosterone - promotes male sexual development and characteristics Estradiol - same as above for female |
Triglycerides as energy stores | Highly efficient - 108 ATP per fatty acid (7 per carbon) which is 3 x more than glucose. In glucose H is effectively already oxidised, whilst not in fats so more energy is released via this oxidation occurring. More energy per g=less weight to carry |