Bio chem.docx

 Digestion and Absorption of Lipids In the intestinal cells monoacylglycerols and free fatty acids are repackaged to form TAGs These new TAGs combine with membrane lipids (phospholipids and cholesterol) and lipoproteins to form chylomicrons Chylomicrons transport TAGs...

 Digestion and Absorption of Lipids In the intestinal cells monoacylglycerols and free fatty acids are repackaged to form TAGs These new TAGs combine with membrane lipids (phospholipids and cholesterol) and lipoproteins to form chylomicrons Chylomicrons transport TAGs from intestinal cells to the bloodstream through the lymphatic system From the lymphatics the fats flow through the thoracic duct into the bloodstream and then to the liver In the liver some of the fats are changed to phospholipids, so the blood leaving the liver contains both fats and phospholipids These phospholipids, such as sphingomyelin and lecithin are necessary for the formation of nerve and brain tissues Lecithins are also involved in the transport of fat to the tissues Cephalin, another phospholipid, is involved in the normal blood clotting From the liver, some fat goes to the cells through the bloodstream Digestion and Absorption of Lipids In the bloodstream TAGs are completely hydrolyzed by lipase enzymes Fatty acids and glycerol are absorbed by the cell and are either broken down to the acetyl Co-A for energy or repacked to store as lipids The fat in excess of what the cells need is stored in specialized cells called adipocytes (the largest cell in the body) in the adipose tissue \- Located primarily beneath the skin especially In abdominal region and vital organs \- Adipose tissue also serves as a protection against the heat loss and mechanical shock Triacylglycerol energy reserves (fat reserves) are the human body\'s major source of stored energy: \- Energy reserves associated with protein, glycogen, and glucose are small to very small when compared to fat reserves Glycerol Metabolism Taken to liver or kidney by blood - converted to dihydroxyacetone phosphate Recall that DHAP is part of the glycolysis pathway This compound may be converted to lactic acid or to glycogen in the liver or muscle tissue or to pyruvic acid, which enters the TCA cycle Thus, the glycerol part of a fat is metabolized through the carbohydrate sequence Oxidation of Fatty Acids There are three parts to the process by which fatty acids are broken down to obtain energy. 1.Activation of the fatty acid by binding to Coenzyme-A-product is called acyl Co-A 2\. Transport of acyl Co-A to mitochondrial matrix 3\. Repeated oxidation (fatty acid spiral) to produce acetyl Co-A, FADH and NADH Note: the difference between the designations acyl CoA and acetyl CoA is that acyl refers to a random-length fatty acid carbon chain that is covalently bonded to coenzyme A, whereas acetyl refers to a two-carbon chain covalently bonded to coenzyme A. Oxidation of Fatty Acids Reactions of the Beta-Oxidation Pathway Repeated oxidation of fatty acid, cycling through a series of four reactions to produce acetyl CoA, FADH, and NADH. The oxidation of fatty acids follow the ß-oxidation theory that involves the oxidation of the 2nd carbon atom from the acid end of the saturated fatty acid molecule, the B-carbon atom. In this process, ß-oxidation removes two carbon atoms at a time from the fatty acid chain; i.e., an 18-carbon fatty acid is oxidized to a 16-carbon fatty acid, then to 14-carbon fatty acid, and so on until the oxidation process Is complete the process Is also known as fatty acid spiral because the fatty acid goes through the cycle again and again until it is finally degraded to acetyl CoA. the fatty acid spiral is a repetitive series of four reactions (dehydrogenation, hydration, dehydrogenation, release of acetyl CoA) In which each sequence produces acetyl CoA, FADH, NADH, and an acyl CoA that is shorter than the previous acyl CoA by two carbon atoms. Oxidation of Fatty Acids Four Steps of the Beta-Oxidation Pathway Step 1: Oxidation (dehydrogenation): \- FAD is the oxidizing agent, and a FADH molecule is a product. Step 2: Hydration: \- A molecule of water is added across the trans double bond, producing a secondary alcohol at the beta-carbon position Step 3: Oxidation (dehydrogenation): \- The beta-hydroxyl group is oxidized to a keto functional group with NAD\* serving as the oxidizing agent. Step 4: Chain Cleavage: \- The fatty acid chain is broken between the alpha and beta carbons by reaction with a coenzyme A molecule. \- The result is an acetyl CoA molecule and a new acyl CoA molecule that is shorter by two carbon atoms than Its predecessor. Oxidation of Fatty Acids The acetyl CoA produced enters the citric acid cycle and the new. molecule of active fatty acid (active acyl CoA) goes through the same sequence again, each time losing two carbon atoms until the entire molecule has been oxidized The sequence presupposes the presence of fatty acids containing an even number of carbon atoms, a condition usually encountered in nature If fatty acid containing an odd number of carbon atoms are oxidized they follow the same steps except that the final products are acetyl CoA and propionyl CoA. The propionyl CoA is changed in a series of steps to succinyl CoA, which enters the citric acid cycle, as does the acetyl CoA; these reactions require the presence of cobamide and biotin The unsaturated fatty acids are metabolized slowly; they must first be reduced by some of the dehydrogenases found In the cells, then they can follow the fatty acid spiral for oxidation The FADH, and the NADH + H enter the respiratory chain Ketone Bodies Ordinarily, most of the acetyl CoA produced from the fatty acid spiral is further processed through the Krebs cycle. Therefore an adequate balance in carbohydrate and lipid metabolism is required The first step of the Krebs cycle involves the reaction between oxaloacetate and acetyl CoA; Sufficient oxaloacetate must be present for the acetyl CoA to react with. Oxaloacetate concentration depends on pyruvate produced from glycolysis; pyruvate can be converted to oxaloacetate by pyruvate carboxylase. Certain body conditions upset the lipid-carbohydrate balance required for the acetyl CoA generated by fatty acids to be processed by the TCA cycle: (under these conditions, the problem of inadequate oxaloacetate arises) \- Dietary intakes high in fat and low in carbohydrates \- Diabetic conditions - glucose not used properly \- Prolonged fasting conditions When oxaloacetate supplies are too low for all acetyl CoA to be processed through the TCA cycle, ketogenesis takes place where excess acetyl CoA Is converted to ketone bodies Ketone Bodies Synthesis of ketone bodies from acetyl CoA is primarily in liver mitochondria the three ketone bodies produced are: acetoacetic acid, P-hydroxybutyric acid, and acetone; they are carried by the blood to the muscles and tissues where they are converted back to acetoacetyl CoA and then oxidized normally. during diabetes, however, the production of ketone bodies by the liver exceeds the ability of the muscles and tissues to oxidize them so that they accumulate in the blood ketosis is the overall accumulation of ketone bodies in the blood (ketonemia) and in the urine (ketonuria) Ketone Bodies during ketosis acetone may be detected on the patient\'s breath because it is a volatile compound and is easily excreted through the lungs \* ketosis may occur with diabetes mellitus, in starvation, or severe liver damage, or on a diet high in fats and low in carbohydrates during diabetes mellitus, the body is unable to oxidize carbohydrates and instead oxidizes fats, leading to an accumulation of ketone bodies in the blood and the urine; the ketone bodies are acidic and tend to decrease the pH of the blood leading to acidosis which may lead to a fatal coma. during acidosis, an increased amount of water intake is needed to eliminate the products of metabolism. Unless the water intake of a diabetic is increased, dehydration will occur. Dehydration of diabetics may also be caused by polyuria due to an increased amount of glucose in the urine. Ilkewise, during prolonged starvation or on a high-fat, low-carbohydrate diet, the body tends to burn fat instead of carbohydrates, leading to ketosis and acidosis. in severe liver damage, the liver cannot store glycogen in the required amounts so that the carbohydrates are not available for the normal oxidation of fats, leading to ketosis Biosynthesis of Fatty Acids: Lipogenesis The Citrate-Malate Shuttle System Acetyl CoA is the starting material for lipogenesis. Acetyl CoA needed for lipogenesis is generated in mitochondria, therefore it must first be transported to the cytosol. Citrate-malate transport system helps transport acetyl CoA to cytosol indirectly. Biosynthesis of Fatty Acids: Lipogenesis Cytoplasmic acetyl CoA is converted to malonyl CoA in a carboxylation reaction that Involves CO, and ATP. The reaction occurs only when cellular ATP levels are high catalyzed by acetyl CoA carboxylase complex, which requires both Mn?\* and biotin for its activity. ACP (Acyl Carrier Protein) Complex Formation: \- All Intermediates in fatty acid synthesis are linked to carrier proteins (ACP-SH) \- ACP-SH can be regarded as a \"glant COA-SH molecule\" Biosynthesis of Fatty Acids: Lipogenesis Unsaturated Fatty Acid Biosynthesis and Essential FattyAcids different enzyme systems and different cellular locations are required for elongation of the chain beyond C16 and for introduction of double bonds into the acyl group (unsaturated fatty acids) production or unsaturated fatty acids (insertion of double bonds) requires oxidation by molecular oxygen (©2), which combines with the hydrogen that is removed to form water In humans and animals, enzymes can introduce double bonds only between C, and C, and between C, and C10- thus the Important unsaturated fatty acids linoleic (C18 with C, and C12 double bonds) and linolenic (C18 with Co, C12, and C15 double bonds) cannot be biosynthesized. They must be obtained from the diet. Plants have the necessary enzymes to synthesize these acids. Fate of Fatty-Acid Generated Acetyl CoA Acetyl-CoA formed from fatty acids is further channeled in various different routes: \- Oxidation in the citric acid cycle: both lipids and carbohydrates supply acetyl CoA \- Ketone body formation: Very Important when imbalance between carbohydrate and lipid metabolism \- Fatty acid biosynthesis: the buildup of excess acetyl CoA when dietary intake exceeds energy needs energy needs leads to accelerated fatty acid biosynthesis \- Cholesterol biosynthesis: It occurs when the body is in an acetyl CoA- rich state Amino Acid Utilization Degradation Pathways Degradation of an amino acid takes place in two stages: \- The removal of the -amino group and \- The degradation of the remaining carbon skeleton The amino nitrogen atom is removed and converted to ammonium lon, which ultimately Is excreted from the body as urea. The remaining carbon skeleton Is then converted to pyruvate, acetyl CoA, or a citric acid cycle Intermediate, depending on its makeup, with the resulting energy production or energy storage. Amino Acid Utilization Nitrogen Balance The state that results when the amount of nitrogen taken into the human body as protein equals the amount of nitrogen excreted from the body in waste materials. Two types of nitrogen imbalance can occur in human body. \- Negative nitrogen imbalance: Protein degradation exceeds protein synthesis Amount of nitrogen in urine exceeds nitrogen consumed Results In tissue wasting \- Positive nitrogen imbalance: Rate of protein synthesis (anabolism) is more than protein degradation (catabolism) Results in large amounts of tissue synthesis During growth, pregnancy, etc. Transamination and Oxidative Deamination Removal of amino group is a two step process: transamination and oxidative deamination Transamination - an enzyme -catalyzed biochemical process in which the amino group of an alpha-amino acid is transferred to an alpha-keto acid. \- There are at least 50 transaminase enzymes associated with transamination reactions Oxidative deamination- an amino acid is converted into the corresponding keto acid by the removal of the amine functional group as ammonia and the ammonia eventually goes Into the urea cycle. Protein Digestion and Absorption Protein digestion (denaturation and hydrolysis) starts In the stomach: Dietary protein in stomach promotes release of Gastrin hormone which promotes secretion of pepsinogen and HCI: HCI In stomach has 3 functions: Gastric acidity denatures protein thereby exposing peptide bonde Gastric acidity (pH of 1.5-2.0) kills most bacteria Activates pepsinogen (inactive) to pepsin (active) \- Enzyme pepsin hydrolyzes about 10% peptide bonds \*Large polypeptide chains pass from stomach into small intestine: \- Passage of acidified protein promotes secretion of \"Secretin\" hormone which stimulates: Bicarbonate (HCO,) production which in turn helps neutralize the acidified gastrio content Promotes secretion of pancreatic digestive enzymes trypsin, chymotrypsin and carboxypeptidase in their in active forms Protein digestive enzymes in Intestine: \- Enzymes (Trypsin, chymotrypsin carboxypeptidase, and aminopeptidase) are produced in Inactive forms called zymogens and are activated at their site of action. \- Trypsin, chymotrypsin and carboxypeptidase in pancreatic juice released into the small Intestine help hydrolyze proteins to smaller peptides \- Aminopeptidase secreted by intestinal mucosal membrane further hydrolyze the small peptides to amino acids \*Amino acids liberated are transported Into blood stream via active transport process  Transamination and Oxidative Deamination Ву transamination, the body can manufacture the amino acids that it needs but does not have an essential part of the active site of transaminases is pyridoxal phosphate (PLP), the coenzyme form of Vit B6 Amino Acid Utilization Amino acid pool Amino acids formed through digestion process enters the amino acid pool in the body: \- Amino acid pool: the total supply of free amino acids available for use in the human body. The amino acid pool is derived from 3 sources: \- Dietary protein \- Protein turnover: A repetitive process in which the body proteins are degraded and resynthesized \- Biosynthesis of amino acids in the liver \- only non-essential amino acids are synthesized Transamination and Oxidative Deamination Oxidative Deamination Oxidative deamination is a catabolic reaction whereby the a-amino group of an amino acid is removed, forming an a-keto acid and ammonia occurs primarily in the liver and the kidneys through the activity of the enzyme amino acid oxidase Two amino acids, serine and threonine, undergo direct deamination by dehydration-hydration process rather than oxidative deamination Amino Acid Utilization Amino acid pool Amino acids formed through digestion process enters the amino acid pool in the body: \- Amino acid pool: the total supply of free amino acids available for use in the human body. The amino acid pool is derived from 3 sources: \- Dietary protein \- Protein turnover: A repetitive process in which the body proteins are degraded and resynthesized \- Biosynthesis of amino acids in the liver - only non-essential amino acids are synthesized Amino Acid Utilization Amino Acids Amino acids from the body\'s amino acid pool are used in four different ways: 1\. Protein synthesis: About 75% of amino acids go into synthesis of proteins that is needed continuous replacement of old tissues (protein turnover) and to build new tissues (growth). 2\. Synthesis of non-protein nitrogen-containing compounds: Synthesis of purines and pyrimidines for nuclelc acid synthesis Synthesis of heme for hemoglobin, neurotransmitters and hormones 3\. Synthesis of nonessential amino acids: Essential amino acids can\'t be synthesized because of the lack of appropriate carbon chain 4\. Production of energy Amino acids are not stored in the body, so the excess is degraded Each amino acid has a different degradation pathway The Urea Cycle Stage 1: Carbonyl group transfer \- The carbamoyl group of carbamoyl phosphate is transferred to omithine to form citrulline Stage 2: Citrulline-aspartate condensation \- Citrulline is transported into the cytosol, citrulline reacts with aspartate to produce argininosuccinate utilizing ATP Stage 3: Argininosuccinate cleavage: \- Argininosuccinate is cleaved to arginine and fumarate by the enzyme argininosuccinate lyase Stage 4: Hydrolysis of urea from arginine: \- Hydrolysis of arginine produces \'urea and regenerates omithine - one of the cycle\'s starting materials The Urea Cycle Linkage Between the Urea and Citric Acid Cycles Fumarate from the urea cycle enters the citric acid cycle, and aspartate produced from oxaloacetate of the citric acid cycle enters the urea cycle. Amino Acid Carbon Skeletons Each of 20 amino acid carbon skeletons undergo a different degradation process 7 Degradation products are pyruvate, acetyl CoA, acetoacetyl CoA, alpha-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate \- Last four are intermediates in the citric acid cycle The amino acids converted to citric acid cycle intermediates can serve as glucose precursors (glucogenic amino acids). \- Glucogenic amino acid: An amino acid that has a carbon-containing degradation product that can be used to produce glucose via gluconeogenesis. The amino acids converted to acetyl CoA or acetoacetyl CoA can serve as precursors for fatty acids and/or ketone body synthesis (ketogenic amino acids) \- Ketogenic amino acid: An amino acid that has a carbon-containing degradation product that can be used to produce ketone bodies.   Hemoglobin Catabolism Red blood cells (RBCs) are highly specialized cells whose primary function is to deliver oxygen to cells and remove carbon dioxide from body tissues Hemoglobin is a conjugated protein with two parts: \- Protein portion Is globin \- Prosthetic group is heme Iron atom interacts with oxygen forming a reversible complex (oxygen can come on and out) with it Mature red blood cells have no nucleus or DNA - filled with red pigment hemoglobin Red blood cells are formed in the bone marrow \- - 200 billion new red blood cells are formed daily The lifespan of a red blood cell is about 4 months Hemoglobin Catabolism Old RBCs are broken down in the spleen (primary site) and liver (secondary site): Degradation of hemoglobin \- Globin protein part is converted to amino acids and are put in amino acid pool \- Fe atom becomes part of ferritin - an iron storage protein - saves the iron for use in biosynthesis of new hemoglobin molecules \- The heme (tetrapyrrole) is degraded to bile pigments and eliminated in feces or urine. Hemoglobin Catabolism Bile Pigments Bile pigments: The tetrapyrrole degradation products secreted via the bile. There are four bile pigments: \- Biliverdin - green in color \- Bilirubin - reddish orange in color. \- Stercobilin - brownish in color (gives feces their characteristic brown color). \- Urobilin - yellow in color and present in urine (gives characteristic yellow color to urine). Daily normal excretion of bile pigments: 1-2 mg In urine and 250-350 mg In feces. Jaundice: Results from liver, spleen and gallbladder malfunction. \- Results in higher than normal bilirubin levels in the blood and gives the skin and white of the eye a yellow tint.