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Lipid Catabolism
- 1. Lipid Catabolism Metabolic Pathways & Clinical Correlations Kazi Tarmeem Noor #2016431008 Department of Genetic Engineering & Biotechnology Shahjalal University of Science & Technology, Sylhet
- 2. Definition & Function LIPID Non polar Water insoluble Carbonyl containing Organic compound Membrane structural component Storage depot & transport form of metabolic fuel Nerve ending receptors & neuro- transmitters Bacterial membrane & exoskeleton Enzyme co-factor
- 3. Metabolism Catabolism Breakdown of nutrient molecules Energy stored as ATP or yielded as heat Bioenergetic applications Clinical approaches Anabolism Biosynthesis of macromolecules from catabolic products Energy absorbed Cell structure maintenance
- 4. Digestion, Absorption & Metabolic Fate Lingual Lipase degrades TG to free FA & glycerol Gastric Lipase Hydrolyzes TG to micelles Intestinal Mucosa forms chylomicrons Chylomicrons travel through blood & Lymph Lipoprotein Lipase & apo-C II releases FA & Glycerol Free FA & Glycerol enter cell to be oxidized
- 5. Clinical Correlation Weight loss & Steatorrhea
- 6. Free Fatty Acid Mobilization Receptors activated by hormones (glucagon, epinephrine) cAMP from activated receptor activates Protein Kinase PKA then activates Hormone Sensitive Lipase (HSL) PKA phosphorylates perilipin (blocks access to fat globules when not phosphorylated) HSL then hydrolyses TAGs in adipose storage to release FFA FFA then enters blood stream Transported to tissues like myocytes bound to albumin
- 7. Lipid Activation Glycerol produced from hydrolysis of TAG is converted to Dihydroxy Acetone Phosphate DAH is isomerized to Glyceraldehyde-3- Phosphate G-3-P moves through Glycolysis and then into Krebs Cycle to produce Energy by Lipolysis
- 8. β oxidation Fatty Acid Activated to Fatty Acyl Co-A FA Co-A dehydrogenated to make double-bond between α and β carbon Double bond hydration Β-hydroxyl group dehydrogenated to ketone Co-A added & acetyl Co-A Produced
- 9. β oxidation energetics Each β-oxidation cycle C(n)Acyl-CoA + CoA-SH + FAD + NAD+ + H2O → C(n-2)Acyl CoA + Acetyl CoA + FADH2 + NADH + H+ Complete oxidation of Palmitoyl CoA Palmitoyl CoA + 7CoA-SH + 7FAD + 7NAD++ 7H2O → 8Acetyl CoA + 7FADH2+ 7NADH + 7H+ Converting NADH and FADH2 to their corresponding ATP equivalents Palmitoyl CoA + 7CoA-SH + 7O2 + 28Pi + 28ADP → 8Acetyl CoA + 28ATP + 7H2O After Acetyl CoA molecules enter Krebs cycle and Electron Transport System 8Acetyl CoA + 16O2 + 80Pi + 80ADP → 8CoA + 80ATP + 16CO2 + 16H2O Thus complete energy release Palmitoyl CoA + 23O2 + 108Pi + 108ADP → CoA + 108ATP + 16CO2 + 23H2O There is utilization of ATP during the conversion of palmitic acid to palmitoyl-CoA the net gain is ≈106 ATP. All the above calculations are done considering one molecule of NADH gives 2.5 molecules of ATP and one molecule of FADH2 gives 1.5 molecules of ATP in the Electron Transport System.
- 11. Odd Numbered FA Oxidation
- 12. Clinical Correlation Hypoglycemia & Neurological Disorders
- 13. α oxidation ω oxidation y acid a- en β- Min Take retic Bec dysf or th syst
- 14. Ketogenesis
- 15. Clinical Correlation Metabolic Acidosis & Bad Breath
- 16. Thank you for your time
Editor's Notes
- In Biochemistry, a metabolic pathway (anabolic pathway + catabolic pathway) is referred to as a linked up series of various chemical reactions occurring within a cell or a tissue. The various intermediates which are thus formed in the course of the metabolic pathway are referred to as metabolites. Metabolic pathways are enzyme depended or we can say enzyme mediated biochemical react that leads to biosynthesis (anabolism) or breakdown (catabolism) of natural products .Neither of the two pathways can be ignored as both are required for maintaining the cells energy balance. catabolic pathways involve the breakdown of nutrient molecules into usable forms that is building blocks. In this process, energy (in the form of ATP) is either stored (for later use) or released (in the form of heat). Anabolic pathways then build new molecules out of the products of catabolism, using energy. The new molecules are useful for building cell structures and maintaining the cell.
- In the human body, there are three fat sources for obtaining energy: Fat obtained from the diet Fat stored in the adipose tissue Fat produced in liver from excess carbohydrates for transfer to other tissues For the utilization of dietary fat, Before absorption through the intestine these hydrophobic fat particles have to be converted to microscopically small micelles to increase their solubility in order to get diffused through the epithelial mucosa. Once through the epithelial mucosa, they are converted back to triacylglycerols and aggregated with cholesterol and apolipoproteins to form chylomicrons. Cell surfaces have specific receptors for their lipoproteins. Thus for passage from the intestinal mucosa to the lymphatic system the chylomicrons containing apolipoprotein C-II .are taken up by attachment to the receptors. These chylomicrons then reach either to the adipose tissue or the muscle via blood depending upon their requirement. In the capillaries of the adipose tissue and muscles, apolipoprotein C-II activates the enzyme lipoprotein lipase which breaks down the chylomicrons and hydrolyses the triacylglycerols to fatty acids and glycerol. These end products are utilized by the muscles for energy, whereas in the adipose tissue they are reesterified to triacylglycerols for storage.
- **CLICK** Some drugs prescribed for weight loss inhibits pancreatic lipase leading reduced TAG malabsorption and weight loss. **CLICK** Malabsorption of lipids (steatorrhoea) results from bile acid insufficiency eg liver disease, gastrointestinal resection. Pancreatic insufficiency eg pancreatitis
- After digestion of fats, lipids have two fates: they are either metabolized to provide energy as per the body’s need or are stored as lipid droplets in the adipocytes. Whenever required by the body, this stored fat is mobilized and transported for use. When the body signals for metabolic energy at low glucose levels, hormones like epinephrine and glucagon are released. These hormones go and bind to their specific receptors on the membrane of the adipocytes. This binding activates the enzyme adenylyl cyclase on the membrane. Activation of adenylyl cyclase triggers the formation of intracellular messenger cAMP. The increase in levels of cAMP activates protein kinase (PKA) which phosphorylates the perilipins on the surface of the lipid droplet as well the hormone-sensitive lipase. Phosphorylation of the perilipins on the lipid droplet triggers the movement of the phosphorylated hormone-sensitive lipase towards it, thus hydrolyzing the triacylglycerols stored in the core of the lipid droplet. Hydrolysis of triacylglycerol produces free fatty acids and glycerol. This free fatty acid reaches the blood and binds to the plasma protein called serum albumin in a non covalent manner. Binding to this protein increases their solubility and are carried to the required tissues by blood. When the serum albumin bound fatty acids reach their target tissue cellular uptake begins. This happens by the presence of fatty acid transporter on the membrane surface which have high affinity for fatty acids. The albumin serum-fatty acid complex breaks and the free fatty acid is transported into the target cell via the fatty acid transporter.
- After a fatty meal, the fats have a sequence of stages to go through in the body. Firstly the fats have to get digested in the intestine with the help of bile salts. After digestion it is either metabolized to produce energy after activation and transportation to the mitochondria from the cytosol via the carnitine shuttle . Or it is stored in the adipose tissue as lipid droplets. For utilization of these stored fats, the fatty acids from the lipid droplets undergo mobilization and cellular uptake by the target. Once in the target cell, for the fatty acid to undergo metabolism it has to reach the mitochondria as all the enzymes required for fatty acid oxidation are present there. For oxidation, fatty acids with carbon chains more than 14 carbons need activation before passing through the mitochondrial membrane. Free fatty acids obtained from diet or which are stored in the adipocytes are mainly 14 carbons or more in length. Fatty acids having less than 12 carbons can surpass activation and can easily pass through the mitochondrial membrane. For activation of fatty acids, they are converted to fatty acyl-CoA by the enzyme thiokinase in the cytosol and then with the help of carnitine, it is transported through the mitochondrial membranes into the mitochondrial matrix.
- β-oxidation of fatty acids resulting in cleavage of two-carbon units (α and β carbons) from the carboxyl end of fatty acyl-CoA with the formation of acetyl CoA. This reaction keeps occurring till the entire fatty acyl chain is broken down to acetyl CoA molecules. For eg. Palmitoyl CoA (16 carbon chain) on β-oxidation will give eight acetyl CoA molecules. The acetyl groups produced from β-oxidation of the fatty acid participate in the Krebs cycle resulting in the formation of NADH and FADH2. The reduced coenzymes (NADH and FADH2) are oxidized by giving up the protons and electrons to oxygen present in the mitochondria to synthesize ATP by oxidative phosphorylation in the Electron Transport System. Once the fatty acids have been transported to the mitochondrial matrix via carnitine pathway, β-oxidation of fatty acyl-CoA (n carbons) occurs within the mitochondria Fatty acyl-CoA is acted upon by an enzyme acyl-CoA dehydrogenase which is FAD dependent. Fatty acyl-CoA undergoes dehydrogenation and forms a trans-double bond at the α and β carbons to form trans-Δ2-enoyl-CoA. The electrons which were removed from the fatty acyl-CoA chain are transferred to FAD which gets reduced to FADH2. This FADH2 immediately via the Electron Transport System gets converted to ATP molecules. Enoyl-CoA hydratase catalyzes this reaction where water is added. Hydration occurs at the double bond resulting in the formation of β-hydroxyacyl-CoA. β-hydroxyacyl-CoA undergoes dehydrogenation to form β-ketoacyl-CoA in the presence of β-hydroxyacyl-CoA dehydrogenase. The electrons available as a result of dehydrogenation are accepted by NAD+ to form NADH+H+ which immediately exchanges these electrons with oxygen in the Electron Transport System to form ATP molecules. The next reaction is called as thiolysis as acyl-CoA acetyltransferase (also known as thiolase) in the presence of CoA-SH causes the cleavage of β-ketoacyl-CoA to form acetyl CoA and the thioester of the original fatty acid with two carbons less. The new fatty acyl-CoA formed again participates in the β-oxidation cycle to form a new fatty acyl-CoA with two carbons and a new molecule of acetyl CoA. This process continues till the entire fatty acid is converted into acetyl CoA molecules. Acetyl CoA formed from the above steps now enters the Kreb’s cycle to get oxidized to CO2 and H2O.
- β-oxidation of fatty acids resulting in cleavage of two-carbon units (α and β carbons) from the carboxyl end of fatty acyl-CoA with the formation of acetyl CoA. This reaction keeps occurring till the entire fatty acyl chain is broken down to acetyl CoA molecules. For eg. Palmitoyl CoA (16 carbon chain) on β-oxidation will give eight acetyl CoA molecules. The acetyl groups produced from β-oxidation of the fatty acid participate in the Krebs cycle resulting in the formation of NADH and FADH2. The reduced coenzymes (NADH and FADH2) are oxidized by giving up the protons and electrons to oxygen present in the mitochondria to synthesize ATP by oxidative phosphorylation in the Electron Transport System. Once the fatty acids have been transported to the mitochondrial matrix via carnitine pathway, β-oxidation of fatty acyl-CoA (n carbons) occurs within the mitochondria Fatty acyl-CoA is acted upon by an enzyme acyl-CoA dehydrogenase which is FAD dependent. Fatty acyl-CoA undergoes dehydrogenation and forms a trans-double bond at the α and β carbons to form trans-Δ2-enoyl-CoA. The electrons which were removed from the fatty acyl-CoA chain are transferred to FAD which gets reduced to FADH2. This FADH2 immediately via the Electron Transport System gets converted to ATP molecules. Enoyl-CoA hydratase catalyzes this reaction where water is added. Hydration occurs at the double bond resulting in the formation of β-hydroxyacyl-CoA. β-hydroxyacyl-CoA undergoes dehydrogenation to form β-ketoacyl-CoA in the presence of β-hydroxyacyl-CoA dehydrogenase. The electrons available as a result of dehydrogenation are accepted by NAD+ to form NADH+H+ which immediately exchanges these electrons with oxygen in the Electron Transport System to form ATP molecules. The next reaction is called as thiolysis as acyl-CoA acetyltransferase (also known as thiolase) in the presence of CoA-SH causes the cleavage of β-ketoacyl-CoA to form acetyl CoA and the thioester of the original fatty acid with two carbons less. The new fatty acyl-CoA formed again participates in the β-oxidation cycle to form a new fatty acyl-CoA with two carbons and a new molecule of acetyl CoA. This process continues till the entire fatty acid is converted into acetyl CoA molecules. Acetyl CoA formed from the above steps now enters the Kreb’s cycle to get oxidized to CO2 and H2O.
- Fatty acids occur as saturated and unsaturated. Fatty acids majorly in triacylglycerols and phospholipids are present as unsaturated fatty acids in plants and animals. Saturated fatty acids undergo β-oxidation but unsaturated fatty acids have a slight variation in the pathway. β-oxidation pathway for unsaturated fatty acids includes two additional enzymes isomerase and reductase. Oleic acid is an 18 carbon chain length fatty acid with a cis double bond present between the ninth and the tenth carbons. Oleoyl CoA undergoes three cycles of β-oxidation like normal saturated fatty acids to yield 3 molecules of acetyl CoA and results in the formation of 12-carbon fatty acyl-CoA with a cis double bond now between carbon 3 and 4. This product is known as cis-Δ3-Dodecenoyl-CoA. The above product formed has a cis double bond and cannot further participate in β-oxidation. Thus by the action of Δ3,Δ2-enoyl-CoA isomerase, cis-Δ3-Dodecenoyl-CoA is converted to trans-Δ2-Dodecenoyl-CoA. trans-Δ2-Dodecenoyl-CoA now is acted upon by the enzymes of β-oxidation pathway in five continuous cycles to yield another 6 molecules of acetyl CoA. The acetyl-CoA molecules now enter the Krebs cycle. **CLICK** Linolenic acid is an 18 carbon chain length fatty acid with 2 cis double bonds between 9th and 10th carbons & 12th and 13th carbons. Like saturated fatty acids the poly-saturated fatty acid undergoes three cycles of β-oxidation to yield three molecules of acetyl CoA along with a 12 carbon chain fatty acyl-CoA with cis double bonds at position 3 and 6 (cis-Δ3,cis-Δ6). Since the mitochondrial enzymes cannot break down cis double bonds, Δ3,Δ2-enoyl-CoA isomerase converts it to (trans-Δ2,cis-Δ6) fatty acyl-CoA. The latter product now undergoes one more cycle of β-oxidation to yield the fourth molecule of acetyl CoA and the remaining product left behind is cis-Δ4 fatty acyl-CoA. By the action of acyl-CoA dehydrogenase, the first step of β-oxidation is achieved, resulting in formation of a double bond at position 2 forming the product (trans-Δ2,cis-Δ4) fatty acyl-CoA. The newly formed product is now acted upon by the enzyme 2,4-dienoyl CoA-reductase to form trans-Δ3 fatty acyl-CoA which on further action by enoyl-CoA isomerase gives trans-Δ2 fatty acyl-CoA. trans-Δ2 fatty acyl CoA now undergoes four cycles of β-oxidation to yield another five molecules of acetyl CoA. The acetyl-CoA molecules now enter the Kreb’s cycle.
- Most of the fatty acids present have even carbon chain length while there are some fatty acids in plants and marine species which have odd carbon chain length. Just the way even chain carbon length fatty acids undergo β-oxidation, odd carbon chain fatty acids undergo the same pathway leaving propionyl CoA as an end product along with acetyl CoA molecules. This propionyl-CoA is formed because during the last β-oxidation cycle the fatty acyl-CoA with five carbons is cleaved to give a three carbon compound and a two carbon compound unlike even carbon chain length fatty acid. Acetyl CoAenters the Kreb’s cycle but propionyl CoA has a different fate. Propionyl-CoA in presence of the enzyme propionyl-CoA carboxylase is carboxylated either by CO2 or HCO3–. This is an ATP dependent step and utilizes one ATP molecule. The enzyme propionyl-CoA carboxylase contains the co-factor biotin, where HCO3– binds. This binding requires energy (ATP) resulting in the production of the carboxybiotin intermediate. This intermediate further progresses to form D-Methylmalonyl-CoA. D-Methylmalonyl-CoA is then acted upon by the enzyme methylmalonyl-CoA epimerase to form the ‘L’ isomer, L-methylmalonyl-CoA. The ‘L’ isomer species then undergo intramolecular rearrangement catalyzed by the enzyme methylmalonyl-CoA mutase. Intramolecular rearrangement results in the formation of succinyl-CoA. Succinyl-CoA formed now enters the Kreb’s cycle and gets converted to CO2 and H2O with the release of energy.
- Medium chain acyl CoA dehydrogenase (MCAD) deficiency is an autosomal recessive genetic disorder common in Europeans. **CLICK** Accumulation of Medium chain Fatty Acid can be leading to hypoglycemia and neurological symptoms β-oxidation of long chain fatty acids also takes place in peroxisomes yielding H2O2 and Acetyl CoA. H2O2 is immediately cleaved to O2 and H2O by catalase. In Zellweger syndrome cells lack peroxisomes. As a result there is also Accumulation of Very Long Chain Fatty Acids
- The fate of Acetyl CoA is either the entry into the Krebs cycle or the ketogenetic pathway Ketogenesis leads to the production of ‘ketone bodies’ in the form of acetone, hydroxybutyrate and acetoacetate In diabetes and starvation when β-oxidation of fatty acids increase leading to increased acetyl CoA. Because of increased gluconeogenesis, there is depletion of Krebs cycle intermediates leading to shunting of Acetyl CoA into ketogenesis which primarily occurs in mitochondria of the liver.
- In uncontrolled diabetes, lack of insulin leads to increased fatty acid oxidation to provide fuel for tissues. Increased Acetyl CoA leads to increased ketone bodies which are acidic and therefore in large quantities will lead to metabolic acidosis potentially fatal if untreated Acetone formed is volatile and exhaled as a characteristic smell to the breath In starvation, there is depletion of Krebs cycle intermediates for gluconeogenesis and increased fatty acid breakdown. This leads to increased ketone body formation for alternate source of energy