Metabolism of Lipids PDF

METABOLISM OF LIPIDS. November 20, 2024 1  Learning outcomes At the end of this topic, the student should be able to:  Explain the structure and classifications of lipids  Describe the mechanisms of biochemical pathways such as β-oxidation, Krebs cycle, electron transport...

METABOLISM OF LIPIDS. November 20, 2024 1  Learning outcomes At the end of this topic, the student should be able to:  Explain the structure and classifications of lipids  Describe the mechanisms of biochemical pathways such as β-oxidation, Krebs cycle, electron transport chain, lipogenesis, ketogenesis, ketolysis, glyoxylate cycle and discuss their physiological aspects.  Discuss the functions of different types lipidic biomolecules  Discuss the metabolism of cholesterol (structure, biosynthesis, function) and its derivates. November 20, 2024 2  Structure of lipids Lipids are organic compounds insoluble in water but soluble in non-polar solvents (benzene, acetone, petroleum ether, etc). The complex lipids are composed of monomers linked together by the ester bonds.. O H2O O R CH2 OH HO C R R CH2 O C R + Fatty alcohol Fatty acid Esterase (lipase) ester (lipid) Classification of lipids 4  Fatty acids Fatty acids are the organic carboxylic acids with the long hydrocarbon chain. General structure: CH3 (CH2)n COOH n = 0 : CH3COOH n = 1 : propionic acid n is almost always even The classification of fatty acids is based on the number of bonds between carbon atoms and the chain length. 5 Fatty acids Saturated fatty acids: myristic acid (C14), palmitic acid (C16), stearic acid (C18), arachidinic acid (C20). Unsaturated fatty acids: Monoenoic acids (1 double bond): C16: Δ9 = palmitoleic acid C18 : Δ9 = oleic acid Dienoic acids (2 double bonds) C18 : Δ9,12 = linoleic acid (essential for humans) Trienoic acids (3 double bonds) C18 : Δ9,12,15 = linolenic acid (essential for humans) Tetraenoic acids (4 double bonds) C20 : Δ5,8,11,14 = arachidonic acid 6  Leukotrienes & prostaglandins These are eicosanoids which are produced by some modifications & transformations of eicosanoic acids such as arachidonic acid (C20 ).. 7  Prostaglandins & Leukotrienes Prostaglandins & Leukotrienes act as hormones that stimulate the contraction of smooth muscles of the human body, especially in GIT (gastrointestinal tract= human digestive tract) allowing the process of movement of substances. 8  Glycerides They have a glycerol skeleton O O O O O R O R O R OH OH R O OH O R O R O O MONOGLYCERIDE DIGLYCERIDE TRIGLYCERIDE 9  Glycerophospholipids Glycerophospholipids, comprising half of the brain's lipids, are made up of glycerol backbone, two fatty acid chains esterified to the glycerol backbone at C-1 & 2 positions, and a polar head group is attached to C-3 of glycerol backbone. Glycerophospholipids are dominant in cell membranes providing stability, fluidity, and permeability. 10 Structure of glycerophospholipids 11  Sphingolipids They have a sphingosine backbone. There are 3 types which differ in their hydrophilic attachments: ceramides, sphingomyelins, and glycosphingolipids. Sphingomyelins act as myelin sheath in the CNS. 12 Myelin sheath allows the electrical impulses to travel quickly and efficiently between one nerve cell and the next in the Nervous system. 13  Sphingoglycolipids: antigens Ac AcN Gal N Glu-sphi ngosine Structure of antigen A L-Fucose Gal Gal NAc-Glu-sphingosine Structure of antigen B L-Fucose Structure of antigen H Gal NAc--Glu-sphi ngosine L-Fucose 14  Antigens & blood groups.. 15 Cholesterol 16.. 17 Structure of lipoproteins. Lipoproteins are complex molecules with a lipidic part and a proteinic part (amino acids) 18  Digestion of dietary lipids Among different types of lipids, the main dietary lipids are glycerolipids, glycerophospholipids and sterides. The enzymatic digestion of the above mentioned lipids in the human digestion tract (small intestine) is always preceded by the process of emulsification. 19  Emulsification of food lipids The process of emulsification takes place in the small intestine and is always facilitated by bile salts produced by the liver. These bile salts reach the small intestine in composition of bile. The main bile salts are: - Sodium (Na+)/Potassium (K+) taurocholate - Sodium (Na+)/Potassium (K+) glycocholate - Sodium (Na+)/Potassium (K+) deoxyglycocholate 20  Emulsification of dietary lipids Emulsification is the breaking up of fat globules into much smaller emulsion droplets. The process of emulsification breaks fat globules apart into small droplets that are coated with bile salts, preventing the emulsion droplets from re- associating. 21  Enzymatic digestion of triglycerides The triglyceride molecule contains 3 ester bonds between glycerol and 3 fatty acids: 22 Enzymatic digestion of phospholipids The phospholipid molecule contains 4 ester bonds that are broken down by 4 phospholipase enzymes (PL A1, PL A2, PL C, PL D) as follows: 23  Enzymatic digestion of steride If the food contains the steride molecules, the ester bond between cholesterol and fatty acid will be broken down by cholesterol-esterase H H O H H H H HO R O usually palmitate Formation of a steride molecule 24  Metabolism of lipids Metabolism of lipids is linked to the following biochemical pathways:  β-oxidation  Lipogenesis  Ketogenesis  Ketolysis  Krebs cycle  Electron transport chain  Glyoxylate cycle 25  β-oxidation β-oxidation is a process by which fatty acids are broken down in mitochondria and/or in peroxisomes to generate acetyl- CoA molecules. Inputs: Fatty acid, Coenzyme A (CoA), ATP, FAD, NAD, water. Outputs: Acetyl-CoA (/propionyl-CoA) molecules, FADH2 and NADH2. 26  Activation of fatty acids. ANT: Adenine Nucleotide Translocase  Oxidation of fatty acids The fatty acid oxidation involves activation, β-oxidation, KC & ETC.  β-oxidation 1. Dehydrogenation of acyl CoA by Acyl. CoA dehydrogenase with liberation of FADH2 and formation of a double bond between α and β carbon. 2. Hydration of double bond between a and β carbons by enoyl-CoA hydratase and formation of β–hydroxyacyl-coA. 3.Dehydrogenation by β -hydroxy-acyl CoA dehydrogenase with liberation of NADH2 and formation of β ketoacyl-coA. 4.Thiolysis is a cleavage of two carbon fragments by a thiolase then generate acetyl CoA and acyl CoA 29 β-oxidation for stearic acid (C18). 30  Physiological importance of β-oxidation  The acetyl-CoA molecules released by oxidation of fatty acids can be involved in the following metabolic pathways:  KC & ETC (for energy production)  lipogenesis (biosynthesis of fatty acids)  ketogenesis (for biosynthesis of ketone bodies)  cholesterol biosynthesis  glyoxylate cycle (for conversion of lipids to proteins & carbohydrates).  The FADH2 & NADH2 enter ETC for energy production. 31 Krebs cycle Electron transport chain Electron transport chain  Calculation of ATPs  N= total number of carbon atoms (C18 )  Total number of Acetyl-CoA is 9 (N/2) x 12 ATP (these 12 ATP are provided by one round of Krebs cycle which always produces 3 NADH2 & 1 FADH2 & 1 ATP)  Total number of rounds of -oxidation is [(N/2)- 1] x 5 ATP (these 5 ATP are provided by one round of - oxidation which always produces 1 NADH2 & 1 FADH2)  For N= C18 , N/2 = 9 (N/2)-1 = 8  Total number of energy (ATP) produced = [9 x 12 ATP ] + [8 x 12 ATP ]= 148 ATPs 37 β-oxidation of fatty acids with odd number of carbon atoms Chains with an odd-number of carbon atoms are oxidized in the same way as even- numbered chains, but the last round of - oxidation produces a molecule of propionyl-CoA and one acetyl-CoA (instead of 2 acetyl-CoA). Propionyl CoA is converted to succinyl-CoA (which is an intermediate of Kreb’s cycle) in a reaction that involves vitamin B12. 38 Conversion of propionyl-CoA to succinyl-CoA 1. The carboxylation of propionyl- CoA to D-methylmalonyl-CoA 1 by propionyl-CoA carboxylase 2. convert D-methymalonyl-CoA to L-methylmalonyl-CoA by methylmalonyl-CoA epimerase 2 3. L-methylmalonyl-CoA to TCA succinyl-CoA by methylmalonyl-CoA epimerase 4. succinyl-CoA enter Krebs cycle 3 39  Oxidation of fatty acids with odd numbers Example: oxidation of heptadecanoic acid (C17) Total number of rounds of -oxidation is 7 x 5 ATP (these 5 ATP are produced by one round of -oxidation which always provides 1 NADH2 & 1 FADH2). Total number of Acetyl-CoA is 7 x 12 ATP (these 12 ATP are produced by one round of Krebs cycle which always provides 3 NADH2 & 1 FADH2 & 1 ATP) The one molecule of propionyl-CoA provided by the last round of -oxidation will be converted to succinyl- coA. Then, this later can enter Krebs cycle (from the step of succinyl-CoA up-to oxaloacetate) to produce 6 ATP (1 ATP & 1 FADH2 & 1 NADH2). Total number of ATP produced = [7 x 5 ATP ] + [7 x 12 ATP ]+6= 125 ATPs 40 Oxidation of fatty acids with ramifications  The fatty acids with ramifications (methyl groups) are oxidized almost in the same way as fatty acids without ramifications (with even/odd numbers of carbon atoms, BUT the round of -oxidation on those carbon atoms attaching the methyl groups will produce a molecule of propionyl-CoA instead of a molecule of acetyl-CoA). Then, the propionyl- CoA will be converted to succinyl-CoA as shown in the previous slide. 41  Oxidation of fatty acids with ramifications Example: dimethyl-8,12-heptadecanoate (with odd number & ramifications). Total number of rounds of -oxidation is 7 x 5 ATP (these 5 ATP are produced by one round of -oxidation which always provides 1 NADH2 & 1 FADH2). Total number of Acetyl-CoA is 5 x 12 ATP (these 12 ATP are produced by one round of Krebs cycle which always provides 3 NADH2 & 1 FADH2 & 1 ATP) The 3 molecules of propionyl-CoA provided by the last round of -oxidation will be converted to succinyl-coA. Then, these laters can enter Krebs cycle (from the step of succinyl-CoA up- to oxaloacetate) to produce 6 x 3 ATP [3 (1 ATP & 1 FADH2 & 1 NADH2)]. Total number of ATP produced = [7 x 5 ATP ] + [5 x 12 ATP ]+ 42 (6 x 3)= 113 ATPs  Oxidation of unsaturated fatty acids The unsaturated fatty acids (with double bonds) are oxidized almost in the same way as saturated fatty acids up to the carbon atom with the double bond. Then, at the point of double between α & β carbon atoms, the first reaction of that round of -oxidation won’t take place (there is no production of FADH2) because there is already a double bond.  So, when calculating the ATP produced for this round there will be 3 ATP instead of 5 ATP. 43  Oxidation of unsaturated fatty acids Example: Oleic acid (oleate /C18 : Δ9). Total number of rounds of -oxidation is 8 (7 full rounds + 1 uncompleted round). At the end of the 3rd round, the double bond between 9th & 10th carbons will be relocated (isomerization) to 8th & 9th carbon to place the double bond between α & β carbons, then the oxidation process shall continue (without production of FADH2) Total number of full rounds of -oxidation is 7 x 5 ATP Total number of uncompleted rounds of -oxidation is 1 x 3 ATP (because this round produces 1 NADH2 only). Total number of Acetyl-CoA is 9 x 12 ATP (these 12 ATP are produced by one round of Krebs cycle which always provides 3 NADH2 & 1 FADH2 & 1 ATP)  Total number of ATP produced = [7 x 5 ATP ] + [9 x 12 ATP ]+ 44 3 ATP = 146 ATPs  Oxidation of fatty acids: summary  The ramification of fatty acids reduces the total number of ATP (example: compare palmitate & 6-methy-lpalmitate).  The appearance of double bonds reduces the total number of ATP (example: compare stearate & oleate).  A fatty acid can have at the same time the odd number of carbon atoms, ramifications (methyl groups) & double bonds! 45 β-Oxidation of fatty acids with the odd-number calculation of ATP produced by 4,7,11 trimethyl- hexadecanoic acid: At the position of methyl groups the molecules of propionyl-CoA will be formed (instead of acetyl-CoA):  Number of acetyl-coA: 5 x 12 ATP=60 ATP  Rounds of -oxidation : 7 x 5 ATP=35 ATP  Succinyl-coA (propionyl-CoA): 3 x 6 ATP =18 ATP  Total ATP produced=113 ATP 46 -oxidation of unsaturated fatty acids The unsaturated fatty acids go through the -oxidation cycle as usual many times as they can before reaching the double bond. At the point of double bond, the -oxidation round will be taking place without the 1st reaction involving FAD. 47 -oxidation of unsaturated fatty acid Energy production with oleic acid (C18 : Δ9): the total generated ATP can be illustrated as below:  Number of acetyl-coA: 9 x 12 ATP= 108 ATP  Rounds of -oxidation : (7 x 5) +3 =38 ATP Total ATP produced: 146 ATP (net gained: the process of activation consumes some ATP, to be removed). 48.. 49  Ketogenesis Ketogenesis is a process by which ketone bodies are produced in liver to temporally store the acetyl-CoA molecules which haven’t been immediately utilized by the living cells. The ketone bodies are: Acetoacetate, Acetone, β-hydroxybutyrate 50 Ketogenesis. 51  Importance of ketogenesis  The production of ketone bodies occurs at a relatively low rate during normal feeding.  Carbohydrate shortages cause the liver to increase the production of ketone bodies, the condition which allows the extrahepatic tissues (heart and skeletal muscles) primarily to use them for energy production, thereby preserving the limited glucose molecules for use by the brain. 52  Importance of ketogenesis  Ketone bodies serve as major substrate for the biosynthesis of neonatal (newborn) cerebral lipids (such as cholesterol, phospholipids (PC &PE) and sphingolipids).  Ketogenesis occurs when there is a lack of or resistance to insulin. This usually occurs in people with type I diabetes, although it can happen to people with advanced type II diabetes as well. In most cases of type II diabetes, enough insulin production continues to prevent excessive ketogenesis. 53.. 54.. 55  Reactions of ketolysis. 56  Ketolysis It is catabolic pathway by which ketone bodies are broken down into acetyl-CoA molecules. 57  Lipogenesis Lipogenesis is the synthesis of fatty acids from acetyl-CoA molecules produced by -oxidation. Lipogenesis uses reduced coenzyme NADPH2 (produced by PPPW) and requires an acyl carrier protein (ACP). 58  Lipogenesis In lipogenesis, some acetyl CoA molecules combine with bicarbonate to form malonyl-CoA: O || CH3—C—S—CoA + HCO3- + ATP Acetyl-CoA O O || || -O—C—CH —C—S—ACP + ADP + P 2 i Malonyl-CoA 59 Formation of Acetyl-ACP and Malonyl-ACP Acetyl CoA and malonyl CoA combine with acyl carrier protein (ACP) to form acetyl-ACP and malonyl-ACP: O || CH3—C—S—ACP Acetyl-ACP O O || || -O—C—CH —C—S—ACP 2 Malonyl-ACP 60  Lipogenesis 1.Condensation by a synthase combines acetyl-ACP with malonyl-ACP to form acetoacetyl-ACP (4C) and CO2 (reaction 1). 2. Reduction converts a ketone to an alcohol using NADPH (reaction 2). 61  Lipogenesis 3. Dehydration forms a trans double bond (reaction 3). 4. Reduction converts the double bond to a single bond using NADPH (Reaction 4). 62  Lipogenesis cycle repeats Fatty acid synthesis continues: Malonyl-ACP combines with the four-carbon butyryl-ACP to form a six- carbon-ACP. The carbon chain lengthens by two carbons each cycle. 63 Lipogenesis cycle completed Fatty acid synthesis is completed when palmitoyl ACP reacts with water to give palmitate (C16) and free ACP. 64 Lipogenesis: Summary 65. 66  Cholesterol Cholesterol is a lipid substance found in the body, needed to make the healthy cell (component of cell membranes), hormones and vitamin D. There are two sources of cholesterol: the eaten food and liver (liver synthesizes all the needed cholesterol molecules). BUT the high levels of cholesterol can increase the risk of heart disease. 67  Cholesterol biosynthesis Cholesterol is synthesized via a series of the enzymatic reactions known as mevalonate pathway: oxidation, cyclization and loss of three methyl groups which results in conversion of squalene to cholesterol molecule. 68 Cholesterol biosynthesis 69 Cholesterol. 70 Derivatives of cholesterol 71  Importance of cholesterol  It is an important component in the cell membrane and facilitate its fluidity.  It is a precursor of hormones especially reproductive ones like progesterone, estrogen and testosterone.  Several molecules are synthesized from cholesterol: bile acids which play a direct role in the control of pancreatic lipase and facilitate absorption of fat-soluble vitamins (D) from the intestines; bile salts which facilitate the digestion (emulsification) of lipids in the small 4 intestines 72 Importance of cholesterol 73  Glyoxylate cycle  Glyoxylate cycle is an anabolic pathway which mainly occurs in microorganisms (generally absent in animal and human tissues) converting the acetyl-CoA molecules into oxaloacetate (via succinate) for biosynthesis of very large amounts of complex structural carbohydrates required during the growth of microorganisms (bacteria, fungi,..etc).  Glyoxylate cycle is a variation of Krebs cycle as it uses five of the eight enzymes associated with this pathway.  Glyoxylate cycle. Inter-relations of the metabolism of lipids, carbohydrate & proteins Firstly, lipids (fatty acids) are converted (by - oxidation) to acetyl-CoA molecules which enter the glyoxylate cycle to produce succinate which (via Krebs cycle reactions) is transformed into oxaloacetate as follows: succinate  fumarate  malate  oxaloacetate. Conversion of lipids to carbohydrate: the molecule of oxaloacetate undergoes reaction of phosphorylant decarboxylation to become phosphoenolpyruvate (PEP). Then, the two PEP molecules enter the process of glyconeogenesis to produce a glucose (carbohydrate). 76 Inter-relations of the metabolism of lipids, carbohydrate & proteins Conversion of lipids to proteins: the molecule of oxaloacetate can enter transamination reaction to make Aspartate (D); it can undergo decarboxylation reaction to produce pyruvate which, by transamination will lead to Alanine (A). Then, D & A shall be combined with the other aminocids for the biosynthesis of proteinic molecules (note: a proteinic biomolecule becomes “a protein” when it contains at least 50 aminoacids). 77  Conversion of carbohydrates to proteins & lipids carbohydrates  proteins: carbohydrates (glucose) enter glycolysis to produce two pyruvate molecules which undergo trasmination to become two Alanine (A).The pyruvate molecules can enter carboxylation reaction to produce oxaloacetate which, by transamination become Aspartate (D). Then, D & A shall be combined with the other aminocids for the biosynthesis of proteins. carbohydrates  lipids: the two pyruvate molecules can enter decarboxylation reaction to become acetyl-CoA molecules. Then, these molecules shall enter lipogenesis to produce fatty acids (then complex lipids), ketogenesis to produce ketone bodies of cholesterol biosynthesis. 78  Conversion of proteins to carbohydrates & lipids Proteins  carbohydrates: proteins undergo digestion to provide amino acids which, by deamination or transamination become pyruvate/oxaloacetate.The oxaloacetate molecule undergoes reaction of phosphorylant decarboxylation to become phosphoenolpyruvate (PEP). Then, the two PEP molecules enter glyconeogenesis to produce a glucose (carbohydrate) molecule. Proteins  lipids: The two pyruvate molecules can enter decarboxylation reaction to become acetyl-CoA molecules. Then, these molecules shall enter lipogenesis to produce fatty acids (then complex lipids), ketogenesis to produce ketone bodies of cholesterol biosynthesis. 79 Conversion of lipids to carbohydrate: summary 80.. 81 Lipoproteins. Lipoproteins are complex molecules with a lipidic part and a proteinic part (amino acids) 82  Functions of lipoproteins 1. Chylomicrons transport dietary triglycerides from the intestine to other body locations (adipose, cardiac, and skeletal muscle tissues) for storage. 2. Low-density lipoproteins (LDL) transport mainly cholesterol and cholesterol esters from liver to extrahepatic tissues. 3. Very-low-density lipoproteins (VLDL) carry the endogenous triglycerides from liver to peripheral extrahepatic tissues. 4. Intermediate-density lipoproteins (IDL) transports a variety of triglyceride fats and cholesterol. 5. High-density lipoproteins (HDL) transport the excess or unused cholesterol from extrahepatic tissues back to the liver to be broken down to bile acids and excreted (protecting against th heart disease). 83..