-Acetyl-coA and glucose-6-phosphate are examples of key compounds of biochemistry because they are involved in more than one pathway.

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1 Nitrogen metabolism made by : enas omar corrected by: LINA AL-HIARY date:

2 -nitrogen is fertilized by bacteria which converts it into nitrite and nitrate. plants absorb nitrite and nitrate, convert them into nutrients in which animals(incuding humans) utilize them for growth. -it's important to know that is citric acid cycle involved in both catabolic process (energy production) and anabolic process. -citric acid cycle produce amino acids for proteins synthesis. #the main difference between carbohydrates & lipids & proteins metabolism is that: -there is no storage form of proteins. Proteins are either used or removed ( daily catabolic rate of proteins). -glycogen is the storage form of carbohydrates. -triglyceride is the storage form of lipids. In addition, it's the main source of energy(lipolysis). - turnover number means that all cells such as RBCs, skin, hair have limited life span(ex: intestinal cell 3-5 days). once they die they would be degraded and their proteins would be absorbed by the intestine and extra material is excreted. They differ also in the amount of produced energy.(protein give Kcal while lipids give Kcal) -Acetyl-coA and glucose-6-phosphate are examples of key compounds of biochemistry because they are involved in more than one pathway. -intermediates of citric acid cycle will give compounds for other biosynthesis i.e.1- oxaloacetate will give amino acids 2-Succinyl-coA will give different amino acids. -3Citrate give Acetyl-coA for fatty acid biosynthesis

3 4-Acetyl-coA gives us keton bodies also found in the beginning of cholesterol biosynthesis. Amino acid metabolism 7:44 The continuous degradation and synthesis of cellular proteins occur in all forms of life. Each day humans turn over 1 2% of their total body protein, principally muscle protein. Ex: To maintain the skin Approximately 75% are reutilized. Degradation that occurs in muscles and intestine is recycled. Alanine which comes out of exercising muscles will inter the liver in which its converted into glucose in a process called ( alanine-glucose cycle ). The excess nitrogen forms urea. Proteins represent % of total energy supply. Main energy supply is lipids but the easiest energy source is carbohydrates(available for daily use). We said that glycogen give us energy for overnight fast also energy in exercise for 12 min. Digestion and absorbtion of proteins 9:13

4 -proteins are degraded by proteolytic enzymes (from pancreas ) such as trypsin and chymotrypsin and elastase.- then proteins will be converted to oligopeptides and free amino acids in the intestine. -free amino acids, dipeptides, tripeptides are absorbed into the intestinal cells. -dipeptides and tripeptides which are absorbed are degraded by dipeptidases and tripeptidases in the intestine. - only free amino acids are absorbed directly from the intestinal cells into the blood. They are absorbed by different mechanisms according to their R groups ( neutral, acidic, basic.aromatic group). - they are absorbed mainly with sodium by a carrier like carbohydrates. -proteins are not absorbed without degradation because of two reasons : 1- they are large. 2-proteins in the body are treated as antigens. If they were absorbed as whole proteins the body would recognize them as antigens and it will produce antibodies against them. Ps: polio vaccination is the only case in which protein is absorbed without degradation. It's administered by drops in the mouth.(intestine is not well developed in children so a whole absorption occurs). 12:30 Amino acids have an ammonia and ammonium ion which are toxic and should be removed so that: The main aim of amino acid degradation is to transport the amino group from one amino acid to another until they reach the liver where they are converted into urea which is excreted with water in kidneys. The α-amino group of many amino acids is transferred to α-ketoglutarate to form glutamate, which is then oxidativelydeaminated to yield ammonium ion (NH4+).

5 Glutamate Atp give us glutamine -Glutamine is neutral,non toxic, can cross BBB (where it converted into glutamate. a neurotransmitter in the brain),glutamine is carrier for ammonia from peripheral tissues & delivers it to the liver for urea formation. Transamination 14:14 Amino acids have a general metabolic pathways for all of them unlike carbohydrates (one for glucose.another for galactose and so on) On of these is transamination that involve a group of enzymes called aminotranferases.: There are 10 essential a.a & 10 non essential a.a.the body will synthesize these 10 non essential a.a if the 10 essential a.a were taken. One of mechanisms for synthesis is transamination : a.a + alpha keto acid new alpha KG + new a.a ex: glutamate + oxaloacetate give us alpha-ketoglutarate + asparatate enzymes aminotransferases are named according to the products. Aspartate aminotransaminase(ast) is found mainly in heart. AST is one of the cardiac enzyme marker such as LDH, CKMP, CPK, trobnine C, trobnine I. Alanine aminotransaminase(alt) is found mainly in liver and it's involved in liver function tests that comprise ( enzymes, proteins,bilrubin.) If Alt is higher than Ast this indicates liver dysfunction and vice versa. Normal level of these enzymes is 30 or 40 units per liter. 45 or 50 values don t indicate problems. In liver\heart problems you are looking for 5 to 10 times of normal levels. All the protein amino acids are involved in transamination except lysine, threonine, proline, and hydroxyproline participate in transamination. Transamination is readily reversible, and aminotransferases also function in amino acid biosynthesis.

6 The coenzyme pyridoxal phosphate (vitamin B6 phosphate)(plp) is present at the catalytic site of aminotransferases. NOTE: Citric acid cycle,β oxidation, keton body formation occur in the mitochondria (all of them give energy) Rest of processes: glycogen synthesis and degradation, glycolysis, fatty acid synthesis occur in the cytosol Glyconeogenisis &urea cycle occur between mitochondria and cytosol. Aspartate aminotransferase(ast), one of the most important of these enzymes, catalyzes the transfer of the amino group of aspartate to α-ketoglutarate Alanine aminotransferase(alt) catalyzes the transfer of the amino group of alanine to α ketoglutarate. Glucose alanine cycle 25:50 Alanine serves as a carrier of ammonia and of the carbon skeleton of pyruvate from skeletal muscle to liver. The ammonia is excreted (converted into urea)and the pyruvate is used to produce glucose, which is returned to the muscle. #Alanine is a sign for muscle degradation Oxidative deamination 26:06 another General metabolic pathway for a.a This reaction is catalyzed by glutamate dehydrogenase. This enzyme is unusual in being able to utilize either NAD+ or NADP Unusual because it use NAD+ OR NADP+ to produce NADH OR NADPH. Peripheral tissues transport n to the liver Nitrogen can also be transported as glutamine. Glutamine synthetase catalyzes the synthesis of glutamine from glutamate and NH4 + in an ATP-dependent reaction

7 The nitrogens of glutamine can be converted into urea in the liver. Fates of the Carbon Skeletons of Amino Acids Glucogenic amino acids are shaded red, and ketogenic amino acids are shaded yellow. Most amino acids are both glucogenic and ketogenic. -most amino acids are glucogenic give carbohydrates - ketogenic amino acids give keton bodies such as Acetyl coa

8 PS: you have to distinguish the contents of amino acids in each group. #Lipids when hydrolyzed give us fatty acids and glycerol Fatty acid doesn t give glucose because the reaction of pyruvate dehydrogenase (convert pyruvate into Acetyl-coA) is irreversable, while glycerol is converted into glucose(look for glyconeognesis pathway). Glycerol belongs to carbohydrate. L & D sugars classification came from glyceraldehyde. Glycerol taste is sugary. Glycerol is the backbone for triglycerides because the reaction of pyruvate dehydrogenase (convert pyruvate into Acetyl-coA) is irreversable. Ammonia 30:25 Ammonia (NH3) is a relatively strong base, and at physiological ph values it is mainly present in the form of the ammonium ion NH4+. NH3 and NH4+ are toxic, and at higher concentrations cause brain damage in particular. Ammonia therefore has to be effectively inactivated and excreted. This can be carried out in various ways liver is the main site for detoxification of ammonia If liver function is compromised, as in cirrhosis or hepatitis, elevated blood ammonia levels generate clinical signs and symptoms which may lead to coma hepatic coma. (occurs in premature babies ) Rare metabolic disorders involve each of the five urea cycle enzymes. Only traces of ammonia (10 20μg/dL) normally are present in peripheral blood. Formation & Secretion of Ammonia Maintains Acid-Base Balance 31:50 Excretion into urine of ammonia produced by renal tubular cells facilitates cation conservation and regulation of acid-base balance. Ammonia production from intracellular renal amino acids, especially glutamine, increases in metabolic acidosis and decreases in metabolic alkalosis There are 3 buffer systems in the kidneys : Ammonia, bicarbonate, phosphate. And 5 in the blood : Hemoglobin, proteins,and the same 3 of the kidneys. Aquatic animals can excrete NH4+ directly. For example, fish excrete NH4+ via the gills (ammonotelic animals). There for the smell of the sea is ammonia Terrestrial vertebrates, including humans, hardly excrete any NH3, and instead, most ammonia is converted into urea before excretion (ureotelic animals) therefore you need to drink water after eating mansaf or mashawy (ptotiens) & sweets because they increase blood osmosis.

9 Birds and reptiles, form uric acid, which is mainly excreted as a solid in order to save water (uricotelic animals). Kangaroo rat produce water by converting ammonium into uric acid ( like birds ) it doesn t produce urea because it does not drink water needed for urea excretion. Urea cycle 38:44

10 Krebs discovered urea cycle when he was a student in 1932 and after 5 years he discovered Krebs cycle Urea cycle like Glyconeogenisis happens btw mitochondria & cytosol (first in the mitochondria ammonia is converted into citrulline then it will be completed in the cytosol). It consist of 5 reactions. All reactions of urea cycle up to Arginine (an essential a.a) take place in anywhere of the body in any tissue : skin\muscle\liver. Arginine reaction into urea and citrulline takes place only in the liver because arginase enzyme is found only in the liver. #thus urea cycle takes place in the liver. [1] In the first step, carbamoyl phosphate is formed in the mitochondria from hydrogen carbonate (HCO3 ) and NH4+, with two ATP molecules being consumed. In this compound, thecarbamoyl residue ( O CO NH) is at a high chemical potential. In hepatic mitochondria, enzyme [1] makes up about20% of the matrix proteins. Carbamoyl phosphate synthase I, the rate-limiting enzyme of the urea cycle, is active only in the presence of its allosteric activator N-acetylglutamate, which enhances the affinity of the synthase for ATP. Note : Major changes in diet can increase the concentrations of individual urea cycle enzymes 10-fold to 20-fold. Starvation, for example, elevates enzyme levels to cope with the increased production of ammonia that accompanies enhanced protein degradation. N-acetylglutamate is increased in starvation & in increased proteins uptake leading to activation of carbamyle phosphate synthase 1 thus increasing urea formation.. Starvation differ from fasting(which does not increase urea formation) [2] In the next step, the carbamoyl residue is transferred to the non-proteinogenic amino acid ornithine, converting it into citrulline, which is also non-proteinogenic. This is passed into the cytoplasm via a transporter. Ornithine and citrulline are extra amino acids not usually found in the protein structure [3] The second NH2 group of the later urea molecule is provided by aspartate, which

11 condenses with citrulline into argininosuccinate. ATP is cleaved into AMP and diphosphate (PPi) for this endergonic reaction. To shift the equilibrium of the reaction to the side of the product, diphosphate is removed from the equilibrium by hydrolysis. Urea contains two NH2 groups one of them comes from carbamoyl phosphate and the other from aspartae. [4] Cleavage of fumarate from argininosuccinate leads to the proteinogenic amino acid arginine, which is synthesized in this way in animal metabolism. [5] In the final step, urea is released from the guanidinium group of the arginine by hydrolysis, and is immediately rearranged into urea. In addition, ornithine is regenerated and returns via the ornithine transporter into the mitochondria, where it becomes available for the cycle once again. The rate of urea formation is mainly controlled by reaction [1]. N-acetyl glutamate, as an allosteric effector, activates carbamoylphosphate synthase. In turn, the concentration of acetyl glutamate depends on arginine and ATP levels, as well as other factors. Krebs Bi-cycles: since urea formation require 4 molecules of ATP so that there is another source that provide this energy which is citric acid cycle. Links between urea and krebs cycle and urea cycle: 1- co2 form krebs cycle is involved in the formation of carbamoyl phosphate in the urea cycle 2-asparatate and fumarate are found in both citric acid and urea cycles

12 Inherited Defects of the Urea Cycle Cause Hyperammonemia and Can Lead to Brain Damage All defects in the urea cycle lead to an elevated level of NH4+ in the blood (hyperammonemia). Some of these genetic defects become evident a day or two after birth, when the affected infant becomes lethargic and vomits periodically. Coma and irreversible brain damage may soon follow. Symptoms of Ammonia Intoxication

13 This include tremor, slurred speech, blurred vision, coma, and ultimately death. Ammonia may be toxic to the brain in part because it reacts with α-ketoglutarate to form glutamate. The resulting depleted levels of α-ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. In order to treat ammonia intoxication we use a synthetic sugar called lactulose. this drug change the PH of the intestine make it acidic so decrease the absorption of ammonia (only neutral ammonia will be absorbed),this drug will be accompanied with antibiotic. In severe cases the patient will be treated by blood transfusion. Methionine metabolism Transmethylation transfers a methyl group Homocysteine(intermediate) is one of the cardiac markers involved in atherosclerosis & heart strokes.

14 NOTES FROM THE VIDEO LUCTURE 1-The rate of oxidative phophorylation is determined by ADP 2-The rate of lipolysis is determined by level of glycerol in the blood 3- during ATP synthesis :there is a return of protons to the mitochondrial matrix 4-during starvation (3 or more days without food):brain and heart use keton bodies 5-aceton accumulation means uncontrolled diabetes 6- as we no liver do not use keton bodies 7-Acetyl-coA (2 carbon atom) + co2 by give us Monolyl-coA(3 carbon atom). 8-key compounds include 1-glucose -6-phosphate(used in glycolysis,pentose phosphate pathway,gluconeogenesis & glycogen metabolism). 2-pyruvate (in aerobic condition give us Acetyl-coA, anaerobic condition give us lactate, also used in gluconeogenesis) 3- acetyl coa degradation of acetyl keton body formation Protein degradation Fat degradation Glycolysis Cholesterol synthesis. 4-Coenzyme A 9- TOTAL ATP use in urea cycle is 4 ATP but net ATP consumption is one ATP. 10- metabolic end product of protein degradation is urea no ammonia 11-urea formed in the liver an excreted in the kidney. 12-ARGINASE enzyme found only in the liver so that urea cycle only in the liver ATP are used in synthesis of glucose (gluconeogenesis). 14- In Uncoupling of oxidative phosphorylation: energy from electron transport is converted into Heat, thus there is no ATP synthesis. 15- before beta oxidation there is activation of fatty acids in which we need 2ATP.

15 Sorry in advance for any mistake u would find Best wishes رب همة أحيت أمة