Lecture 2- Carbohydrate as a Macronutrient 3 macronutrients: 1) carbohydrate, 2) lipid and 3) protein Ingesting starch(->maltose) is our main source of carbohydrates, followed

followed by glycogen Carbohydrates have @1,4 bonds in glucose chains and a combination of 1,4 and 1,6 in amylopectin and glycogen Amylase hydrolyses carbohydrates- salivary or pancreatic. It cleaves 1, 4 glycosidic bonds but cant hydrolyse 1, 6 bonds. It breaks the chain at every 2nd residue into maltose and glucose Pancreatic isomaltose breaks the limit dextrin (the stuck 1, 6 point left after amylase stops) and cleaves the bond Brush border cells absorb monosaccharides and disaccharides by active transport. They line the intestines and contain invaginations that curve up and down to increase the surface area for better absorption. Disaccharides can also hydrolyse their specific substrates such as sucrose, lactase and maltase. Gut epithelia cells perform facilitated diffusion out of the cells and into the bloodstream. Lactase is needed to break down lactose into glucose and galactose. Without lactase, lactose intolerance occurs. Failure to hydrolyse it allows lactose to persist in the intestine where it is hydrolysed by bacteria- produces gas, acidity, excessive bacterial growth and diarrhoea Galactose from milk must be isomerised to glucose before its metabolised. Deficiencies in enzymes for this pathway lead to galactosaemia. Fructose derived from sucrose is phosphorylated by fructokinase to make fructose 1 phosphate that can be broken down to glyceraldehydes 3 phosphate in the glycolytic and TCA pathways Fructose metabolism bypasses phosphofructokinase Unregulated production of acetyl CoA contributes to obesity- acetyl CoA is used for lipid synthesis

Lecture 3: Vitamins and Cofactors B Vitamins COENZYMES Small molecules which participate in enzymes catalytic activities Mostly cannot be synthesised in human cells, or contain a chemical component that cant be synthesised so they must be present in the diet Unchanged by the reaction they catalyse- can be re used many times we only require small amounts of this Identical with vitamins. They fall into the category of micronutrients rather than macronutrients (only needed in small amounts) Vitamins are/ can be cofactors but not all cofactors are derived from vitamins Adenosine triphosphate (ATP) - nucleotide based cofactor. Can be phosphorylated by substrate level phosphorylation or by mitochondrial oxidative phosphorylation. ATP can be used as a source of biochemical energy. No component of ATP is essential in the diet but its still fundamentally important that everyone can make it Nucleoside triphosphates are used to drive energy dependent reactions GTP hydrolysis is used in protein synthesis reactions. UTP is used as a carrier for carbohydrate interconversion and polymerization. CTP is used in phospholipid biosynthesis. THIAMINE (VITAMIN B) Thiamine deficiency is called beriberi. People who only take white rice develop this as only the husks of rice contain thiamine. Present in a variety of foods- meats, grains, nuts and vegetables. Water soluble and heat labile (can be lost through food preparation). Added to bread or cereals as a supplement. Thiamine deficiency is also associated with alcoholism. When phosphorylated to thiamine pyrophosphate (TPP) or thiamine diphosphate (TDP), it becomes a cofactor for metabolic reactions One of these reactions is the oxidative decarboxylation of alpha keto acids (pyruvate, alpha-ketoglutarate and alpha keto acids corresponding to leucine, isoleucine and valine. The transketolase reactions of the pentose phosphate pathway also use TPP as a cofactor Oxidative decarboxylation of pyruvate is the pyruvate dehydrogenase reaction. Pyruvate is converted to acetate (acetyl CoA) and CO2. This connects glycolysis to the TCA cycle. The pyruvate dehydrogenase is a multi-subunit enzyme with separate, multiple pyruvate decarboxylase, dihydrolipoyl transacetylase and dihydrolipoyl dehydrogenase enzyme subunits. TPP acts as a cofactor for the first- acts as a carrier for the acetyl C2 part of the pyruvate substrate Other cofactors are used by other components of the enzyme Lipoic acid passes in the activated 2C unit of acetaldehyde to coenzyme A to form acetyl CoA. FAD accepts electrons and protons from the dehydrogenase reaction to pass them onto NAD+ The transketolase reactions in the PPP involve a 2C unit transfer. Inherited variants in this appear to create a predisposition to Wernicke-Korsakoff Syndrome CoA is a carrier of the acetyl group and can also carry other organic acids like succinate and malonate. Assembled from thioethanolamine and ADP (made in human cells) and from pantothenate (cant be synthesised, must be present as a vitamin). Its often abbreviated as CoA-SH to emphasize the sulphydryl group- forms a thioester with the organic acid. 4-Phosphopantetheine (thioethanolmine linked to pantothenate) binds to acyl carrier protein (ACP) via a phosphoester linkage to its serine residue. This allows the ACP to act as a carrier protein for lipid biosynthesis

 Pantothenic acid is vitamin B5. Deficiency states are rare except for when grossly malnutrtioned.

Lecture 4: Folic acid and Sulphonamides FOLIC ACID Some b vitamins that are crucial to oxidation-reduction reactions are riboflavin (b2), niacin (b3). They are components of FAD and NAD+ respectively When oxidised, these cofactors accept protons and electrons (get reduced) and can pass the electrons onto another acceptor Act as intermediaries between metabolic oxidation reactions They represent an element in the process of recovering useful biochemical energy from the oxidation of food Niacin deficiency causes pellagra. Its associated with the consumption of maize and is characterised by photosensitive dermatitis, diarrhoea, dementia, leading to death Niacin can be made from the amino acid tryptophan which maize doesnt have Protein is the nitrogenous macronutrient- broken down to amino acids- create purines, pyrimidines and nucleotides Folic acid (B9) some active cofactors derived from this, important in the 1C transfer reactions One of these is the conversion of deoxyuridine monophosphate into one of the 4 nucleoside phosphates needed for DNA synthesis. A methyl croup is added into the pyrimidine ring. N5, N10- methylene tetrahydrofolate is the cofactor for the reaction catalysed by thymidylate synthetase and is converted to dihydrofolate when donating a methyl group. DHF is recycled to tetrahydrofolate by an NADPH dependent reduction catalysed by dihydrofolate reductase. It acquires a CH2 from serine to regenerate N5, N10- methylene tetrahydrofolate. N10-formyl tetrahydrofolate is used in purine ring synthesis that leads to ATP and GTP Folate derived cofactors are used in many reaction sin amino acid metabolism. Folate deficiency is seen as various forms of anaemia- both red and white blood cell inhibition because of the failure to synthesize DNA. Megaloblastic (megaloblasts in bone marrow) and macrocytic (over-large red cells) anaemia are seen. Folate is found in fresh fruit and vegetables. Intestinal bacteria also contribute to our daily requirement. Pregnancy and alcoholism are the main causes of folate deficiency (folate supplementation is recommended in early pregnancy) SULPHONAMIDES Domagk discovered that an active compound in a red dye with antibacterial activity was sulphanilamide, a structural analogue of p-aminobenzoic acid (PABA) in folate. It belongs to a class of available antibacterial known as the sulphonamides. Folate reductase converts folate to dihydrofolate and then tetrahydrofolate as part of the coenzyme mechanism of folate Trimethoprim inhibits folate reductase in some bacteria but not in humans. It can be used as an antibacterial compound. Methotrexate is another inhibitor which can act on the human enzyme and can be used as an anticancer agent

Lecture 5: Vitamins B12 and C VITAMIN B12 Vitamin b12 deficiency has similar symptoms to folate deficiency but also includes intestinal and neurological symptoms in addition to hematopoietic symptoms Vitamin b12 is cyanocobalamin- incorporates a cobalt atom. This is known as extrinsic factor and is an antidote to pernicious anaemia. Liver, kidney, whole milk, eggs, oyster, shrimp, pork and chicken are good sources of b12. Daily requirements are small so deficiencies develop slowly. The transfer of the methyl group from 5 methyltetrhydrofolate by methionine synthetase is b12 dependent, so without b12 the cellular folate pool will be trapped as methyltetrahydrofolate. Ingested b12 forms a complex with intrinsic factor- a protein secreted by gastric cells. It binds the vitamin and helps it transport across the intestinal wall. Loss of the intrinsic factor (occurs with ageing) removes the ability to absorb b12 which is known as pernicious anaemia. This can only be treated with injections. VITAMIN C Vitamin C (ascorbic acid) is the anti-scorbutic vitamin which prevents scurvy. Its a water soluble antioxidant that decays during cooking or storage. Reduces dietary iron to the Fe2+ for intestinal absorption Acts as a coenzyme for biochemical hydroxylation reactions- important to make bile acids, needed for fat digestion & of biogenic amines, used as signalling molecules Symptoms of scurvy are due to the failure to hydroxylate lysine and proline amino acids in collagen. These are post translational modifications of the proteins of connective tissue. Tissue weakness and damage result from the failure to maintain functional collagen proteins

Lecture 6: Nitrogen Metabolism, Proteins as Macronutrients Protein requirement for an adult = 40-5-g daily to replace amino acids lost during protein turnover Protein turnover= cellular process of degrading proteins which are damaged or must be inactivated. These include hormones which tend to be degraded rapidly so that their signal transmission is rapidly terminated Degradative pathways all involve proteinases. Protein breakdown occurs in the cytoplasm, catalysed by calpains or proteasomes. Lysosomal proteinases known as cathepsins help recycle amino acids from proteins. Amino acids and some dipeptides are absorbed by intestinal epithelia cells and reexported into the blood. Dietary proteins must be hydrolysed by cleavage of peptide bonds, thus a range of proteinase enzymes is needed for their complete degradation. Some protein digestion occurs in response to pepsin and by acid hydrolysis. Pepsin is secreted by gastric cells as pepsinogen. The major site of protein digestion is in the small intestine, where a cascade of proteinases operates. The enzymes are secreted from the pancreas, into the small intestine as zymogens or proproteinases. A circulatory pool of free amino acids (generated by protein turnover) in the blood is carried to all cells to be available for protein synthesis and other metabolic reactions. Humans can synthesise about half of the 20 amino acids but the other half must be present in the diet so that their concentration in the pool is maintained. All 20 amino acids must be present for protein synthesis to occur. The essential amino acids are his, ile, leu, lys, met, phe, thr, trp and val. Arg and his are semi essential- we can make enough for needs but not enough for growth. Non essential amino acids can be made in the body by transamination of the corresponding keto acid. Adults are normally in nitrogen equilibrium (no net protein synthesis). Some amino acids are required to replace losses in protein turnover and amino acid metabolism. Children and pregnant women are normally in positive nitrogen balance- they utilise dietary protein to support protein synthesis and growth Malnutrition, starvation may result in negative nitrogen balance Protein digestion is enhanced by protein denaturation Protein digestibility is high but may be reduced by pancreatic disease or foods rich in proteinase inhibitors Amino acid absorption in the intestine is by Na+ symporters. They are specific for acidic, basic and neutral amino acids. High quality protein contains adequate quantities of the essential amino acids. Usually from animal origin. Protein complementation occurs when foods are combined to give adequate quantities of essential amino acids.

Lecture 7: Nitrogen Metabolism 2 Amino Acid Catabolism NITROGEN METABOLISM Purine and pyrimidine nucleotides are important for metabolism, gene expression and genetic maintenance so almost all cells retain the enzymes needed for the synthesis Salvage pathways allow the bases to be re-converted to nucleotides and recycled. Theres no need for human requirement for dietary nucleic acid derivatives because of their biosynthetic capacity. Excessive concentrations of these derivatives may cause problems such as gout ( results from the deposition of insoluble uric acid as a breakdown product of purines) AMINO ACIDS Linked by peptide bonds to form polypeptide chains. The key reaction is transamination- an amino acid is formed from a keto-acid by acquiring the amino group from glutamate The glutamate is converted to a-ketoglutarate (intermediate in the TCA cycle) Transaminases accept different keto-acids as substrates but only glutamate as the other substrate. This means that the products of each transaminase will be a different amino acid and a-ketoglutarate. They use pyridoxal phosphate (from vitamin b6) as a cofactor Glutamate dehydrogenase is an enzyme that recreates glutamate starting with aketoglutarate and ammonia: NH4+a-KG+NADPH+H+=glutamate+NADP++H2O Keto acids corresponding to amino acids are known as their carbon skeletons. If an organism can synthesise the carbon skeleton there will be a transaminase to convert it into the amino acid-except for 9 of them. There are many interconversions of amino acids and other metabolites Amino acids are the starting point for some biosynthetic pathways leading to other biochemicals (tyrosine->melanin or adrenalin). Surplus amino acids are degraded by the transamination to yield keto-acids. Glutamate is deaminated by glutamate dehydrogenase. The keto acids/ carbon skeletons can be metabolised. Glucogenic derivatives are oxidised in the glycolytic and TCA pathways, may also be used in gluconeogenesis. Ketogenic amino acids yield carbon skeletons that enter lipid metabolism pathways Free ammonia is very toxic- its transported as part of glutamate/glutamine. Ammonia is liberated by deamination of amino acids, which is then converted into urea and excreted in the urine Urea is generated by the urea cycle. It contains 2 amino groups: one produced by condensing together an ammonium ion and carbon dioxide to form carbamoyl phosphate. Carbamoyl phosphate synthetase and ornithine transcarbamoylase are mitochondrial enzymes. Argininosuccinate synthetase, argininosuccinase and arginase are cytosolic Micronutrients are a class of minerals essential in the diet

Lecture 9: Better Antibiotics Antibiotics affect nucleic acids in different ways and some also affect protein synthesis and interact with membranes Antibiotics that target bacterial structures or processes which arent found in humans are potentially more useful for humans as they cant be affected by the antibiotics Penicillins site of action is the bacterial cell wall. The selective toxicity of penicillin and related compounds is high. Penicillin was discovered by Alexander Fleming in 1929. A lot of work is needed to isolate and purify the compound from Penicillium notatum and to make it in sufficient quantity for clinical use. After penicillin was readily available, its effects upon bacteria were studied. Penicillin causes bacteria to become osmotically unstable and lyse. This causes them to release compounds called Park nucleotides which consist of UDP attached to N-acetylmuramic acid (NAMA) or N-acetylglucosamine (NAG) - has short peptide fragments coupled to the NAMA. UTP is the carrier for the assembly of glycopeptides that are linked to form the rigid cell wall of the bacteria Bands of polysaccharide- alternating NAMA and NAG molecules with B1-4 glycosidic bonds run in one direction. Multiple peptide cross links occur at right angles between the NAMA molecules, forming a 3D layer enclosing the cell. This is a single, cell shaped peptidoglycan macromolecule which prevents the cell from swelling or shrinking as the external osmotic pressure changes Penicillin blocks the formation of peptide cross links. It contains a B-lactam bond structurally analogue of the D-ala-D-ala peptide bond broken during the cross linking, making penicillin an inhibitor of transpeptidase. Peptidoglycan is continually being cleaved and extended so that bacteria can grow. Penicillin resistance was recognised right after the clinical introduction of penicillin. The main mechanism for this is the bacterial productin of an enzyme that hydrolyses the B-lactam bond. This is a penicillinase or Blactamase. Penicillin variants are often more resistant to B-lactamase. Cephalosporins are a group of fungal B-lactam compounds which work in the same way. Clavulanic acid has recently been discovered. Its not active against bacterial cell walls but inhibits B-lactamases. Because of this, it is often given in conjunction with penicillin if a resistant infection is suspected B-lactams and B-lactamases coexist in their natural environments which inducates the coevolution of microorganisms which seek to secure their ecological niches against competitors

 Vancomycin and ristocetin act at the same site as penicillin but binds to the D-ala-D-ala structure which prevents hydrolysis and cross linking. Its favoured as an antibiotic because resistant strains are rare Resistance transfer occurs when bacteria acquire a plasmid carrying genes for antibiotic resistance factors. Plasmids can be transferred between cells of the same strain, different strains and different species. Prevalence of antibiotics in the environment promotes the acquisition and spread of antibiotic resistance Other antibiotics affect the bacterial nucleic acid synthesis. Nucleotide analogues inhibit polymerases or create a defective nucleic acid when incorporating into DNA or RNA Intercalating compounds stabilise the DNA double helix, making strand separation hard for replication. Some antibiotics also act on protein synthesis... Cloramphenicol inhibits the peptidyl transferase activity of the ribosome, stopping peptide bond formation. Tetracycline blocks the ribosomal A site which prevents the binding of aminoacyl-tRNAs Erythromycin prevents ribosomal translocation (movement along the mRNA). These antibiotics are specific for the smaller 70S bacterial ribosomes instead of the 80S ribosomes in the cytoplasm of eukaryotic cells. Because mitochondrial ribosomes are also 70S, chloramphenicol is toxic to humans if used for extended periods of time

Lecture 10: Lipid Digestion and Lipid Catabolism Dietary fat consists of triglycerides, phospholipids and cholesterol esters. Theyre all poorly soluble in water, making them hard to digest and absorb Bile acids are secreted from the gall bladder to help emulsify the lipids to form micelles which allow soluble enzymes to act Lipases (gastric or pancreatic) hydrolyse triglycerides to fatty acids and glycerol. When phospholipids are hydrolysed, fatty acids are liberated and cholesterol is liberated from cholesterol esters. Cholesterol isnt absorbed well by the intestinal epithelia cell. Short chain fatty acids can pass directly from the gut into the blood where they are bound to serum albumin. Long chain fatty acids are bound to a binding protein, reesterified with glycerol and secreted into the blood as chylomicrons. The three unsaturated fatty acids that cant be synthesised by humans and must be present in the diet are linoleic, linolenic and arachidonic acids. They help maintain membrane fluidity Having lipids in the diet not only helps with the absorption of the fat soluble vitamins, but also helps to make food palatable. Lipid is repackaged with apolipoproteins to form lipoproteins in the liver. Theyre returned to the bloodstream and supply peripheral tissues with lipid. Very low density lipoproteins (VLDLs) are first released. The triglyceride portion is hydrolysed by lipoprotein lipase (secreted by tissues like the muscle) which makes the lipoprotein particles smaller and denser. These are called IDLs and LDLs and are richer is cholesterol. Endocytosis of LDLs allows cells to acquire cholesterol High density lipoprotein particles (HDLs) contain proteins from the liver and can remove cholesterol from cell membranes which are returned to the liver. Glycerol is converted via glycerol 3-phosphate into glyceraldehydes 3phosphate. This can be metabolised in the glycolytic or gluconeogenic pathways When starved, hormone signals are released which hydrolyses triacylglycerols in adipose tissue to yield free fatty acids and glycerol. Cells have a membrane fatty acid binding protein which accepts FFAs from albumin and transfers them to a cytoplasmic binding protein. Fatty acyl coenzyme A synthetase uses ATP to convert FFAs into soluble CoA thioesters: FFA + CoASH + 2ATP= FA-CoA + 2ADP + 2Pi FA-CoA is transported into the mitochondria (where its oxidised), using the carnitine cycle: The FA is put onto a carnitine molecule to allow it to pass through the 2 mitochondrial membranes and then is transferred back on to a Coenzyme A molecule.

B-OXIDATION The FA-CoA undergoes a cyclic series of reaction called B-oxidation in the mitochondrial matrix. This breaks off 2C units from the fatty acid in the form of CoA. The 4 reactions are: 1) Dehydrogenation across the a-b CC bond 2) Hydration of the same bond 3) A second dehydrogenation, to yield a b-keto group 4) Attack by CoASH to from a shorter FA-CoA and acetyl CoA The reduced cofactors, FADH2 and NADH can be re-oxidised by the ETC. The acetyl CoA can be further oxidised by the TCA cycle. FA-CoA can reenter the b-oxidation complex and the reactions are repeated Saturated FAs wit even number chain lengths can be completely oxidised by this route. Odd carbon FAs are broken down in the same way, except they result in a propionyl-SCoA (3C) which is converted to methylmalonyl-CoA by CO2 fixations. This is rearranged to succinyl-CoA which can enter the TCA cycle. Unsaturated FA-CoAs can use the b-oxidation complex with the help of an additional enzyme to rearrange the double bonds.

Lecture 11: Ketone Bodies, the Energy Yield from Lipids & Lipid Biosynthesis KETONE BODIES Surplus of acetyl CoA cant be oxidised by the TCA cycle if the cellular levels of oxaloacatate is limiting. OAA+ acetyl CoA -> citrate. This occurs when the metabolism of fat outweighs that of carbohydrate. Oxaloacetate can be made from pyruvate using pyruvate catabolism. In the liver mitochondria, acetyl CoA is converted into ketone bodies through a series fo reactions. 2 acetyl CoAs from acetoacetyl CoA. When a third is added, b-hydroxyl b-methyl glutaryl CoA. This is broken down to acetoacetate which has the option of being reduced to b-hydroxybutyrate or decarboxylated to acetone. These substances are transported in the blood as their water soluble. Ketone bodies can be used by other body tissues as metabolic fuel (especially acetoacetate in kidneys and cardiac muscle) Ketosis is associated with diabetes. Those affected cant remove glucose in blood and its lost in urine. Because theres less glucose in the body, the alternative energy source is used. Fat is turned into acetyl CoA. Acidosis can result from this and is fatal B-hydroxy-b-methylglutaryl-CoA is the starting point for cholesterol and hormones. Acetoacetate is the 1st ketone body ( carboxylic acid+ketone group) Body fat would last for 30 days: we have approximately 353mJ of fat and our daily expenditure is around 11.7 MJ which means that our fat reserves will last for 30 days. C6H12O6 + 6O2 = 6CO2 + 6H2O To completely oxidize carbohydrates, 6mol of carbon dioxide are generated and 6 mol of oxygen are consumed which gives an RQ for carbohydrate oxidation of 1 (6/) C6H12O6 + 6O2 = 6CO2 + 6H2O To completely oxidise triglycerides, 55moles of carbon dioxide are generated and 78.5 moles of oxygen are consumed which gives an RQ for fat oxidation of 0.71 (55/78.5) C55H106O6 + 78.5O2 = 55CO2+53H2O The RQ for protein is 0.82 (63/77) : C72H112N18O22S + 77O2 = 63CO2 + 38H2O + SO3 + 9urea Respiratory quotient = moles of carbon dioxide generated/ moles of oxygen consumed After digestion is done (post prandial state) the RQ is 1. This shows that carbohydrate is preferentially oxidised in the starved state.

Generation of ATP from Oxidation of Fatty Acids 1) ATP from aerobic oxidation of palmitic acid C16 saturated. Activates using thiokinase and splits 7 times, oxidising 7 FADH2 and NADH molecules. Whe it goes through the CAC, 8 acetyl COA molecules are oxidised. Theres a total ATP yield is 129 2) ATP from aerobic oxidation of stearic acid (C18). Activates using thiokinase. It splits 8 times, producing 8 FADH2 and NADH molecules. In the CAC, 9 acetyl CoA molecules are oxidised. The total ATP yield is 146. For every addition of 2 CH2 groups, another 17 ATP are formed- 5 in the fatty acid oxidation spiral and 12 in the CAC 3) ATP from aerobic oxidation of oleic acid (C18). Activated by thiokinase. Split 8 times, oxidises 7FADH2 and 8NADH. OOxidises 9 acetyl CoA in the CAC. Produces a total ATP yield of 144. For every double bond in the fatty acid, 2 molecules of ATP are lost. FATTY ACID BIOSYNTHESIS Acetyl Cos can be used to re-synthesize FA-CoAs in the liver and adipose tissue when theres a surplus of glucose. This is a cytosolic reaction Acetyl CoA is converted into malonyl CoA by a biotin dependent Co2 fixation reaction catalysed by the enzyme acetyl CoA carboxylase Fatty acid synthase is a complex enzyme. An acetyl group in moved from acetyl CoA to the acyl carrier protein (ACP) in order to form a thioester bond to a phosphopantetheine cofactor on the protein. This acetyl group is then passed to b-ketoacyl-S-ACP-synthase where its linked by a thioester bond to the SH of a cysteine amino acid. Malonyl CoA is attached to an ACP. The acetyl and malonyl groups are condensed to form acetoacetyl-ACP with the loss of CO2. Acetoacetyl-ACP undergoes reduction, dehydration followed by another reduction to be converted to butyryl-ACP (4C), a fatty acid derivative. NADPH is the source of reducing power. Butyry-ACP reacts with another malonyl-ACP to make a 6C b-ketoacylACP. It goes through reduction and dehydration reacts to form hexoyl-ACP. 5 other repeat cycles will make palmitoyl-ACP. The palmitoyl group can be transferred to CoASH to form palmitoyl-CoA Fatty acid synthase is an enzyme with multiple subunits surrounding a hollow chamber in which an ACP forms a swinging arm to move the growing fatty acyl chain between each of the enzymes If glycerol 3 phosphate accepts acyl chains from acyl-CoAs, using a the enzyme transferase, triacylglycerides can be resynthesised.

Lecture 12: Phospholipids, Sterols, Cholesterol and Vitamin D PHOSPHOLIPIDS Amphipathic- have a polar end in addition to their apolar structures. Due to this, they form the lipid bilayer Triglycerides have 3 fatty acids esterified to the 3 alcoholic groups of glycerol, in a phosphatidic acid, one of the fatty acids is replaced by phosphate. The phosphate can make an ester link to another molecule. This would be called a phosphatidyl ester and are the most common phospholipids. Phospholipid synthesis is similar to triglyceride synthesis CHOLESTEROL Important metabolite- is a component of eukaryotic membranes and reduces membrane fluidity Used as a starting point for the synthesis of bile acids, steroid hormones and vitamin D. Present in animal tissue in the diet as free cholesterol and cholesteryl esters. Diets high in animal fats can result in high levels of blood cholesterol. Saturated fatty acids in the diet exacerbates high cholesterol whilst unsaturated fatty acids help lower blood cholesterol Its also synthesised in the liver which contributes to the blood concentration. Theres a high correlation between high blood cholesterol and the incidence of atherosclerosis. Atherosclerosis is the narrowing of arteries and subsequent damage to arterial walls due to the deposition of cholesterol and its esters- with other cell debris. Blocking of the coronary artery leads to myocardial infarction, damaging the heart muscle by oxygen deprivation. One circulatory form of cholesterol is a low density lipoprotein (LDL) particle. High cholesterol levels in cells will inhibit the synthesis of cellular LDL receptor proteins which means that LDL levels will increase and promote atherosclerosis. CHOLESTEROL BIOSYNTHESIS Is assembled from acetyl CoA units. This is catalysed by hydroxymethyl glutaryl CoA reductase (HMG CoA reductase). Inhibitors that are intended to lower blood cholesterol by inhibiting the endogenous synthesis targets HMG CoA reductase It undergoes modifications to make bile acids, which condense with glycine or taurine to form bile salts. More extensive modifications of cholesterol can be made to synthesise progesterone- the precursor of all the steroid hormones

VITAMIN D Cholesterol can be reduced with an enzyme to form 7-dehydrocholesterol. If this is exposed to UV radiation, it undergoes ring opening and makes cholecalciferol (vitamin D3) Cholecalciferol can be oxidised in the liver to 25-hydroxycholecalciferol and further oxidised in the kidney to 1,25-dihydroxycholecalciferol. 1,25-dihydroxycholecalciferol is the most active form of vitamin D. It stimulates the synthesis of a Ca binding protein that increases the absorption of Ca2+ and PO4 2+ from the intestines. It helps make these ions available for the mineralisation of bone as calcium phosphate. Deficiency of vitamin D can lead to rickets; the incomplete mineralisation that leads to soft bone with a propensity for deformity. Dietary supplementation isnt necessary if the skin is exposed to sunlight for a few hours each week

Lecture 13: Metabolic Compartmentation and Interrelationships METABOLIC INTERRELATIONSHIPS The TCA cycle is central in both catabolism and anabolism. Compartmentation of reactions makes some metabolic processes more complicated that they might be E.g. the oxidation of cytosolic NADH. NADH generated can only be reoxidised indirectly because they mitochondrial membranes are impermeable to NAD+/NADH. One route is the glyverol phosphate shuttle. The malate aspartate shuttle is more complex but also more efficient. Its common in mammalian tissues. FATTY ACID BIOSYNTHESIS: where does the acetyl CoA and NADPH come from? Acetyl CoA cant cross the mitochondrial membranes so its used to generate citrate in the mitochondria by condesning it with oxaloacatate. The citrate passes out, into the cytoplasm where it reacts with CoASH to reform acetyl CoA and oxaloacatate. Oxaloacatate is then reduced to malate so it can re-enter the mitochondria where its oxidised to citrate again. This is the citrate malate shuttle. THE FED STATE- Digestive Phase Intake of lipid, protein and carbohydrate. Digestion of these, followed by absorption. Entry into the circulation of triglycerides, amino acids, monosaccharides All but chylomicrons first enter the liver via the hepatic portal vein. Increase in blood glucose and amino acids results in the release of insulin from the pancreas. Insulin predominates in the fed state and : 1. Promotes uptake of glucose by liver, muscle and adipose tissue through the... 2. Induction of movement of GLUT4 receptors to the cell surface and... 3. Inhibits liver glycogenolysis and promotes glycogenesis which... 4. Promotes the uptake of glucose into muscle and... 5. Tends to lower blood glucose which... 6. Promotes protein synthesis in muscle. THE FED STATE- Storage Phase

Glycogensis from glucose, in the liver and muscle Fatty acid synthesis (lipogenesis) from glucose in lover and adipose tissue. Conversion and export of triglycerides form liver as VLDL Uptake of chylomicrons remnants into liver- their re-export, together with triglycerides manufactured in the liver from glucose as lipoproteins (VLDL) Uptake of fatty acids by adipose tissue. Originate form triglyceride and was carried in the plasma as lipoproteins (chylomicrons and VLDL). Stored as triglycerides, as are endogenous fatty acids. Protein synthesis in liver and muscle All tissues metabolise glucose to provide energy for biosynthesis Kidney metabolism similar to liver Brain has absolute requirement for glucose for aerobic metabolism. GLUCAGON SECRETION- from alpha cells of the islets of Langerhans is induced by decreases in plasma glucose and predominates in the starved state. GLUCAGON INDUCES...

Glycogenolysis with controlled release of glucose in the liver Gluconeogenesis in liver and kidney form glycerol and amino acids Lipolysis with controlled release of fatty acids and glycerol form adipose tissue. THE STARVED STATE- Gradual Transitions Glycogen breaks down in the liver, releasing glucose to maintain blood glucose levels Triglycerides breaks down in adipose tissue, releasing free fatty acids bound to albumin as an energy source Breakdown of protein in muscle, releasing amino acids as gluconeogenic precursors The liver uses fatty acids as an energy source to support gluconeogenesis and later is used as a carbon source for ketogenesis Peripheral organs use keone bodies preferentially to fatty acids and glucose as a fuel FUNCTIONS OF DIFFERENT ORGANS IN THE STARVED STATE Liver... Initially releases glucose generated from glycogen which is used to maintain adequate blood glucose levels for brain metabolism. The oxidation of circulating free fatty acids provides ATP and reducing power. Later, generation of glucose from precursors such as circulating amino acids, glycerol and lactic acid Generation of b-OH butyrate and acetoacetate from circulating fatty acids- ketogenesis Adipose Tissue... Releases free fatty acids (FFA) and glycerol from stored triglycerides (lipolysis) FFA are carried in the circulation, bound to albumin Brain... Oxidises glucose aerobically to generate CO2. Has absolute requirement for glucose as a fuel but some of this can eventually be replaced by ketone bodies. Kidney... Gluconeogenesis, fulfilling a similar function in the respect to the liver. Muscle... Glycogen is degraded in response to exercise Oxidises circulating FFA and keton bodies EFFECTS OF OTHER HORMONES Adrenalin (epinephrine) and cortisol are released from the adrenal gland in response to the pituitary stress hormone, corticotrophin (ACTH). Occurs during starvation. Adrenalin promotes glycogenolysis and lipolysis and inhibits insulin action. This promotes availability of metabolic energy for the flight or fight response Cortisol induces protein breakdown in muscle and gluconeogenesis in the liver. EXERCISE Adaptations to prolonged exercise are similar to processes occurring inthe starved state. Diabetes can be due to the failure to make enough insulin but can also be cause by insulin resistance. This is associated with obesity and can be reversed or delayed by regular moderate exercise, which increases the levels of glucose transporters in musclepromoting blood glucose uptake and utilisation. A heavy meal before prolonged exercise can increase insulin levels, leading to the impaired utilisation of glycogen and hypoglycaemia during exercise.