Ch 19 - N-containing Substances PDF

Date: /  Nitrogen Metabolism Disposal of nitrogen. Urea cycle. Catabolism of the carbon skeleton. N-containing substances: 1. Porphyrins; heme. 2. Creatine. 3. Histamine. 4. Serotonin. 5. Catecholamines. 6. Melanin. ...

Date: /  Nitrogen Metabolism Disposal of nitrogen. Urea cycle. Catabolism of the carbon skeleton. N-containing substances: 1. Porphyrins; heme. 2. Creatine. 3. Histamine. 4. Serotonin. 5. Catecholamines. 6. Melanin.  Conversion of amino acids to specialized a.a are precursors of many N-containing compounds and are building blocks of proteins. Pophyrins Porphyrins: are cyclic compounds that bind metal ions usually Fe+2,Fe+3. Metaloporphyrin in human is heme which is prosthetic group for hemoglobin, myoglobin, cytochromes, catalase and tryptophan pyrrolase Heme: one ferrus ion coordinated in the center of porphyrins. Heme is highly turned over: 6 – 7 gm is synthesized and destroyed daily Structure of porphorins Ring structure of 4 pyrrole rings linked with methylenyl bridge. Side chains: different porphyrins vary of the side chain that are attached to pyrrole rings. Distribution of side chains: different types I, II, III, IV of porphyrins. Biosynthesis of porphyrins The major site of heme is the liver. The biosynthesis occurs in a cycle in which the first reaction and the last three reactions occur in mitochondria, other reactions occur in the cytosol. Formation of δ-amino levulinic acid (ALA) All carbons and nitrogens of porphyrin are provided by glycine + succinyl CoA. The reaction is catalyzed by ALA synthase and it is the rate-limiting step in the biosynthesis of porphyrins. This enzyme is inhibited by Hemin. Formation of porphobilinogen Two molecules of ALA condense to form it by the enzyme amino levulinic acid dehydrase. Biosynthesis of porphyrins Formation of uroporphyrinogen. Condensation of 4 molecules of porphobilinogen ➔ uroporphyrin III. Formation of heme. Uroporphyrin III is converted to heme by a series of decarboxylation processes. Date: /  Degradation of heme The lifetime of RBC is 120 days, RBCs are taken up by the liver, spleen, and macrophages, and degraded by the reticulo-endothelial system (RE). Formation of bilirubin The first step in the degradation is catalyzed by the microsomal heme oxygenase enzyme of the ER cells. The enzyme adds the –OH to the methylene bridge oxidation➔ CO and Fe+3 is released. The product is Billiverdin and it is reduced into Bilirubin.  Degradation of heme Uptake of Bilirubin by liver Bilirubin is slightly soluble in water ➔transported in the blood through complexion to albumin, then taken by hepatocytes. Formation of Bilirubin diglucuronide In hepatocytes, the solubility of Bilirubin is increased by addition of two molecules of Glucuronic acid catalyzed by “Bilirubin glucuronyl transferase” using UDP-glucuronic acid. Heme Degradation  Excretion of Bilirubin into bile Bilirubin diglucuronide is transported actively into bile. Formation of urobillins in the intestine Bilirubin diglucuronide is hydrolyzed and reduced by bacteria in the gut to yield urobillinogen. Reabsorbed, go to kidneys and converted to Urobillinogen urobillin (yellow color) Most are oxidized by bacteria to stercobillin (brown color) Jaundice Yellow color of skin and sclera resulted from high level of bilirubin. High level bilirubin is toxic to CNS. 1. Hemolytic jaundice: sickle cell anemia, or malaria. 2. Obstructive jaundice: bile duct obstruction. 3. Hepatocellular Jaundice: liver damage, cirrhosis, hepatitis. Jaundice in newborns Decrease in the activity of Bilirubin glucuronyl transferase. Jaundice  Creatine Creatine phosphate, high energy compound, formed in the muscle, can reversibly donate a phosphate group to ADP. Creatin-P + ADP creatine kinase ATP + creatine This reaction is important to maintain intracellular level of ATP during the first few minutes of intense muscular contraction. The presence of creatin kinase in the plasma is used for the diagnosis of myocardial infarction. Synthesis of creatine – Creatine is synthesized from glycine + guanidino group of arginine plus methyl group of activated methionine. Degradation of creatine Creatine and phosphocreatine spontaneously cyclize at a slow but constant rate to form creatinine which is excreted into the urine. The amount of creatinine that is excreted in urine is proportional to the creatine level in plasma. Creatinine is used to estimate the total body mass. Also creatinine level in the urine is an indicator of kidney function. Synthesis of Histamine Histamine is the chemical messenger that mediates a wide range of cellular responses including allergy, inflammation, gastric acid secretion, and neurotransmission in the brain. Histamine resulted from the decarboxylation of histidine. It is secreted from mast cells as a result of allergic reactions; runny nose or sneezing. Antihistamines.  Serotonin Serotonin is synthesized from tryptophan. It can be synthesized and stored in different sites of the body (small intestine, platelet, CNS). It has multiple physiological roles: pain, blood pressure, temperature, sleep, … Catecholamines Dopamine, epinephrine, nor-epinephrine are biologically active amines are collectively called catecholamines. Dopamine and nor-epinephrine function as neurotransmitters in the brain and CNS. Nor-epinephrine and epinephrine are synthesized also in adrenal medulla. Functions Out side of the nervous system: epinephrine and nor-epinephrine act as regulators of CHO, and lipid metabolism, and also regulate blood pressure. These amines are released in response to fright, exercise, cold, and low level of glucose. Increase epinephrine ➔ increase the degradation of glucose, TG, increases the output of heart “ Fight or Flight reactions” Synthesis of catecholamines Tyrosine by tyrosine hydroxylase ➔ 3,4-dihydroxy phenylalaninen (DOPA) is the rate limiting step in the biosynthesis.  Degradation of Catecholamines Catecholamines are inactivated by oxidative deamination catalyzed by monoamin oxidase (MAO) and by O- methylation catalyzed by catechol-O- methyl transferase (COMT). Melanin Melanin is a pigment occurs in number of tissues (eye, hair, skin). In the skin, the pigment forming cells are called melanocytes. Protect the cells from harmful effects of sunlight. Tyrosine ➔ T.H ➔ Dopa ➔ Melanin. The End