Lipid Metabolism PDF

METABOLISM OF LIPIDS. November 13, 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 13, 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 13, 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